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  • 51. Druid, H.
    et al.
    Holmgren, P.
    Ahlner, Johan
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi.
    Flunitrazepam: An evaluation of use, abuse and toxicity2001Inngår i: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 122, nr 2-3, s. 136-141Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The benzodiazepine flunitrazepam is extensively prescribed to patients with insomnia in many countries, but has also become popular among alcohol- and drug abusers. Several reports indicate that it is used as a date rape drug and suggest that it may precipitate violent behavior. Furthermore, flunitrazepam is involved in many fatal intoxications in Sweden. This study was designed and conducted to explore the negative consequences of flunitrazepam abuse in Sweden, and to assess the trends in its use and abuse. The occurrence of flunitrazepam in cases referred to the Department of Forensic Chemistry in Linköping, Sweden 1992-1998, was investigated in detail. The detections were studied separately for different groups, medicolegal death investigations, drug abuse cases, driving under influence cases, and other medicolegal cases. These data were further compared with the sales, and seizures by the Swedish Customs and the Swedish Police. During 1992-1998, 641 fatalities occurred, where the cause of death was attributed to intoxication with flunitrazepam solely (130) or in combination with other drugs, or concomittant conditions (511). In 78% of all driving under influence cases, where flunitrazepam was detected, the analyses also disclosed the presence of illicit drugs. A similar association was seen in drug abuse cases. The seizures reported by the Swedish Customs revealed a substantial and increasing illegal trade. Cases, where flunitrazepam seemingly induced violent behavior were identified, and one of these is described in some detail. It is concluded that the abuse pattern and the toxicity of flunitrazepam should be kept in mind by forensic investigators and that this panorama also should be considered when decisions about the registration and classification of flunitrazepam are made in different countries. Copyright © 2001 Elsevier Science Ireland Ltd.

  • 52.
    Ekman, Elisabet
    et al.
    Regional Pharmacovigilance Unit, Clinical Pharmacology, Lund University Hospital, Lund, Sweden.
    Hägg, Staffan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Sundström, Anders
    Centre for Pharmacoepidemiology, Karolinska Institute, Stockholm, Sweden.
    Werkström, Viktoria
    Regional Pharmacovigilance Unit, Clinical Pharmacology, Lund University Hospital, Lund, Sweden.
    Antihypertensive drugs and erectile dysfunction as seen in spontaneous reports, with focus on angiotensin II type 1 receptor blockers2010Inngår i: Drug, Healthcare and Patient Safety, ISSN 1179-1365, Vol. 2, s. 21-25Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aim: To describe spontaneously reported cases of erectile dysfunction (ED) in association with angiotensin II type I blockers (ARB) and other antihypertensive drugs.

    Subjects and methods: All spontaneously reported cases of ED submitted to the Swedish Medical Products Agency (MPA) between 1990 and 2006, where at least one antihypertensive drug was the suspected agent, were scrutinized. Patient demographics, drug treatment and adverse reactions were recorded. Using the Bayesian Confidence Propagation Neural Network (BCPNN) method, the information component (IC) was calculated.

    Results: Among a total of 225 reports of ED, 59 involved antihypertensive drugs including ARB (9 cases) as suspected agents. A positive IC value was found indicating that ED was reported more often in association with antihypertensive drugs classes, except for angiotensin-converting enzyme inhibitors, compared with all other drugs in the database. Positive dechallenge was reported in 43 cases (72%).

    Discussion: All classes of major antihypertensive drugs including ARB were implicated as suspected agents in cases of ED. Few risk factors were identified. The relatively high reporting of ED in association with ARB is in contrast with previous studies, suggesting that ARB have neither a positive nor any effect on ED. This discrepancy suggests that further studies are warrnted on this potential adverse reaction to ARB.

  • 53.
    Engström, Linda
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Rosén, Khadijah
    Angel, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Utvecklingsbiologi-IKE. Linköpings universitet, Hälsouniversitetet.
    Fyrberg, Anna
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Mackerlova, Ludmila
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Konsman, Jan Pieter
    Engblom, David
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Blomqvist, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Systemic immune challenge activates an intrinsically regulated local inflammatory circuit in the adrenal gland2008Inngår i: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 149, nr 4, s. 1436-1450Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    There is evidence from in vitro studies that inflammatory messengers influence the release of stress hormone via direct effects on the adrenal gland; however, the mechanisms underlying these effects in the intact organism are unknown. Here we demonstrate that systemic inflammation in rats elicited by iv injection of lipopolysaccharide results in dynamic changes in the adrenal immune cell population, implying a rapid depletion of dendritic cells in the inner cortical layer and the recruitment of immature cells to the outer layers. These changes are accompanied by an induced production of IL-1β and IL-1 receptor type 1 as well as cyclooxygenase-2 and microsomal prostaglandin E synthase-1 in these cells, implying local cytokine-mediated prostaglandin E2 production in the adrenals, which also displayed prostaglandin E2 receptors of subtypes 1 and 3 in the cortex and medulla. The IL-1β expression was also induced by systemically administrated IL-1β and was in both cases attenuated by IL-1 receptor antagonist, consistent with an autocrine signaling loop. IL-1β similarly induced expression of cyclooxygenase-2, but the cyclooxygenase-2 expression was, in contrast, further enhanced by IL-1 receptor antagonist. These data demonstrate a mechanism by which systemic inflammatory agents activate an intrinsically regulated local signaling circuit that may influence the adrenals’ response to immune stress and may help explain the dissociation between plasma levels of ACTH and corticosteroids during chronic immune perturbations.

  • 54.
    Enskär, Karin
    et al.
    Depertment of Nursing Science, School of Health Sciences, Jönköping University, Sweden.
    Hamrin, Elisabeth
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Carlsson, Marianne
    Uppsala University.
    von Essen, Louise
    Uppsala University.
    Swedish mothers and fathers of children with cancer: perceptions of well-being, social life, and quality care.2011Inngår i: Journal of psychosocial oncology, ISSN 1540-7586, Vol. 29, nr 1, s. 51-66Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The overall aim was to describe and compare well-being, social life, and quality care among parents of children with cancer with respect to mothers versus fathers and whether the children were on versus. off treatment. The Life Situation Scale for Parents (LSS-P) was answered by 320 parents, comprising 85 mothers and 71 fathers of children on treatment, and 93 mothers and 71 fathers of children off treatment. The results show that the well-being of parents of children with cancer is affected by their child's situation, and that they experience such things as economic strain and a sense of being dependent on the care provided, especially during the child's treatment phase. Mothers whose children are receiving treatment see their life situation as less satisfying, and report being sadder and having lower self-esteem.

  • 55.
    Eriksson, Andreas C
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Lotfi, Kourosh
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Whiss, Per A
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Enhanced platelet adhesion in essential thrombocythemia after in vitro activation2010Inngår i: TURKISH JOURNAL OF HEMATOLOGY, ISSN 1300-7777, Vol. 27, nr 2, s. 82-90Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: Essential thrombocythemia (ET) is a chronic myeloproliferative disorder characterized by elevated platelet counts and increased risk of thrombosis. Ex vivo data suggest increased platelet reactivity in agreement with the increased thrombosis risk, while in vitro tests often detect decreased platelet activity. The present study aimed to investigate adhesion of ET-platelets in vitro, which is an aspect of platelet function that has been addressed in only a few studies on ET patients. Material and Methods: The study included 30 Er patients and 14 healthy controls. Platelet adhesion was measured with a static platelet adhesion assay. Results: The main finding was that ET-platelets were more readily activated by adhesion-inducing stimuli in vitro than control platelets. This was particularly evident in elderly patients and when using multiple stimuli, such as surfaces of collagen or fibrinogen combined with addition of adenosine 5-diphosphate or ristocetin. Such multiple stimuli resulted in adhesion above the control mean +2 standard deviations for approximately 50% of the patients. Conclusion: The results are in accordance with the concept of increased platelet activity in ET, but opposite to most other in vitro studies. We suggest that the conditions in the adhesion assay might mimic the in vivo situation regarding the presence of chronic platelet activation. (Turk J Hematol 2010; 27: 82-90)

  • 56.
    Eriksson, Andreas
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Lotfi, Kourosh
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Whiss, Per
    Linköpings universitet, Institutionen för medicin och hälsa, Farmakologi. Linköpings universitet, Hälsouniversitetet.
    Correction: Enhanced platelet adhesion in essential thrombocythemia after in vitro activation (vol 27 pg 82, 2010)2010Inngår i: Turkish Journal of Hematology, ISSN 1300-7777, E-ISSN 1308-5263, Vol. 27, nr 3, s. 223-223Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    n/a

  • 57.
    Fazel, S.
    et al.
    Department of Psychiatry, University of Oxford, Oxford, United Kingdom, Centre for Violence Prevention, Karolinska Institute, Stockholm, Sweden, University Department of Psychiatry, Warneford Hospital, Oxford OX3 7JX, United Kingdom.
    Grann, M.
    Centre for Violence Prevention, Karolinska Institute, Stockholm, Sweden.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Goodwin, G.
    Department of Psychiatry, University of Oxford, Oxford, United Kingdom.
    Suicides by violent means in individuals taking SSRIs and other antidepressants: A postmortem study in Sweden, 1992-20042007Inngår i: Journal of Clinical Psychopharmacology, ISSN 0271-0749, E-ISSN 1533-712X, Vol. 27, nr 5, s. 503-506Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A number of reports have linked consumption of selective serotonin reuptake inhibitors (SSRIs) with suicide by violent methods. We aimed to determine whether suicides with postmortem evidence of SSRI consumption are more likely to have used violent methods compared with suicides with no detectable antidepressants. Blood samples from all suicides in Sweden during 1992-2004 were examined. Suicides were classified into those who died by violence and nonviolent (self-poisoning) methods using information from police records and autopsy. In addition, we investigated proportions of violent suicide in individuals who died with detectable levels of tricyclic and other antidepressants.The sample consisted of 14,691 suicides. Of the 1958 suicides with detectable levels of SSRIs, 1247 were by violent means (63.7%) compared with 7835 of 11,045 suicides (70.9%) in antidepressant-free group (?1 = 7.6, P < 0.01). We found no significant differences in the proportion of violent suicides in the SSRI group compared with the antidepressant-free group by sex or age band (15-24, 25-39, and over 40 years). When subdivided by gender and age-bands, we found specific groups with significantly lower proportions of violent suicides compared with the antidepressants-free group, including men aged 15-24 years. © 2007 Lippincott Williams & Wilkins, Inc.

  • 58.
    Fazel, Seena
    et al.
    Univ Oxford, Dept Psychiat, Oxford, England.
    Grann, Martin
    Karolinska Inst, Ctr Violence Prevent, Stockholm, Sweden.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Goodwin, Guy
    Univ Oxford, Dept Psychiat, Oxford, England.
    Letter: SSRI-induced violent suicide: Does forensic toxicology hold the answer? Reply to comments by Mr Carlin and Mr Hardisty2008Inngår i: Journal of Clinical Psychopharmacology, ISSN 0271-0749, E-ISSN 1533-712X, Vol. 28, nr 4, s. 477-477Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    n/a

  • 59.
    Forsman, M.
    et al.
    National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Artillerigatan 12, SE 587 58, Linköping, Sweden.
    Nystrom, I.
    National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Artillerigatan 12, SE 587 58, Linköping, Sweden.
    Roman, M.
    National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Artillerigatan 12, SE 587 58, Linköping, Sweden.
    Berglund, L.
    National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Artillerigatan 12, SE 587 58, Linköping, Sweden.
    Ahlner, Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Kronstrand, Robert
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Urinary detection times and excretion patterns of flunitrazepam and its metabolites after a single oral dose2009Inngår i: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 33, nr 8, s. 491-501Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We investigated the excretion profiles of flunitrazepam metabolites in urine after a single dose. Sixteen volunteers received either 0.5 or 2.0 mg flunitrazepam. Urine samples were collected after 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 240, and 336 h. Samples were screened using CEDIA (300 µg/L cutoff) and quantitated using liquid chromatography-tandem mass spectrometry. The cutoff was 0.5 µg/L for flunitrazepam, N-desmethylflunitrazepam, 7-aminoflunitrazepam, 7-aminodesmethylflunitrazepam, 7-acetamidoflunitrazepam, and 7-acetamidodesmethylflunitrazepam. None of the subjects receiving 0.5 mg were screened positive, and only 23 of 102 samples from the subjects given 2.0 mg were positive with CEDIA. The predominant metabolites were 7-aminoflunitrazepam and 7-aminodesmethylflunitrazepam. For all subjects given the low dose, 7-aminoflunitrazepam was detected up to 120 h, and for two subjects for more than 240 h. Seven subjects given the high dose were positive up to 240 h for 7-aminoflunitrazepam. We conclude that the ratio 7-aminodesmethylflunitrazepam to 7-aminoflunitrazepam increased with time, independent of dose, and may be used to estimate the time of intake. For some low-dose subjects, the metabolite concentrations in the early samples were low and a chromatographic method may fail to detect the intake. We think laboratories should consider this when advising police and hospitals about sampling as well as when they set up strategies for analysis.

  • 60.
    Fransson, Martin
    et al.
    Linköpings universitet, Institutionen för datavetenskap, PELAB - Laboratoriet för programmeringsomgivningar. Linköpings universitet, Tekniska högskolan.
    Fritzson, Peter
    Linköpings universitet, Institutionen för datavetenskap, PELAB - Laboratoriet för programmeringsomgivningar. Linköpings universitet, Tekniska högskolan.
    Lindqvist Appell, Malin
    Linköpings universitet, Institutionen för medicin och vård. Linköpings universitet, Hälsouniversitetet.
    Hindorf, Ulf
    Almer, Sven
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Gastroenterologi och hepatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    A preliminary study of modeling and simulation in individualized drug dosage – azathioprine on inflammatory bowel disease2007Inngår i: SIMS 2006: Proceedings of the 47th Conference on Simulation and Modelling, Helsinki, Finland, Helsinki: Kopio Niini Oy , 2007, s. 216-220Konferansepaper (Fagfellevurdert)
    Abstract [en]

    Individualized drug dosage based on population pharmacokinetic/dynamic models is an important future technology used to reduce or eliminate side effects of certain drugs, e.g. cancer drugs. In this paper we report preliminary results from work-in-progress: a simplified linear model of the metabolism of a cancer treatment drug was estimated from experimental data. The model was then validated against the same data as a test of the adequacy of the model structure. From this investigation it became apparent that the model structure could not be used due to its inability to recreate the dynamic properties of the system.

  • 61.
    Fransson, Martin
    et al.
    Linköpings universitet, Institutionen för datavetenskap, PELAB - Laboratoriet för programmeringsomgivningar. Linköpings universitet, Tekniska högskolan.
    Gréen, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Comparison of two types of population pharmacokinetic model structures of paclitaxel2008Inngår i: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 33, nr 2, s. 128-137Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Two main types of model structures have been proposed for the pharmacokinetics of paclitaxel; an empirical model structure based on total plasma concentrations of paclitaxel, and a mechanism-based model structure derived from both total and unbound paclitaxel concentrations and concentrations of the formulation vehicle Cremophor EL. The purpose was to compare the two pharmacokinetic model structures when only total paclitaxel concentrations are available. To support the mechanism-based model structure with Cremophor EL concentrations, in silico concentrations were obtained from simulations of a pharmacokinetic model available in the literature. Local algebraic observability was tested on both model structures; the mechanism-based model structure was found, with high probability, not to be algebraically observable if total paclitaxel concentration is considered to be the only model output, and if no kind of prior information is used. Sensitivity analysis was performed to reveal which parameter should be fixed in order to make it locally observable. Parameter estimation was then performed on both model structures using nonlinear mixed effects and data from a clinical study. The estimated mechanism-based model turned out to have a somewhat better fit to data than the corresponding empirical model, , where AIC is the Akaike Information Criterion. Hold-out validation was performed on three patients, but did not favour any of the models. In conclusion, since the mechanism-based model structure behaved at least as good as the empirical model structure, it is suggested that the former model structure should be used since it offers a more accurate description of the disposition.

  • 62.
    Fransson, Martin N
    et al.
    Karolinska Institute, Sweden .
    Brugard, Jan
    MathCore Engn AB, Linkoping, Sweden .
    Aronsson, Peter
    MathCore Engn AB, Linkoping, Sweden .
    Green, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Semi-physiologically based pharmacokinetic modeling of paclitaxel metabolism and in silico-based study of the dynamic sensitivities in pathway kinetics2012Inngår i: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 47, nr 4, s. 759-767Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: To build a semi-physiologically based pharmacokinetic model describing the uptake, metabolism and efflux of paclitaxel and its metabolites and investigate the effect of hypothetical genetic polymorphisms causing reduced uptake, metabolism or efflux in the pathway by model simulation and sensitivity analysis.less thanbrgreater thanless thanbrgreater thanMethods: A previously described intracellular pharmacokinetic model was used as a starting point for model development. Kinetics for metabolism, transport, binding and systemic and output compartments were added to mimic a physiological model with hepatic elimination. Model parameters were calibrated using constraints postulated as ratios of concentrations and amounts of metabolites and drug in the systemic plasma and output compartments. The sensitivity in kinetic parameters was tested using dynamic sensitivity analysis.less thanbrgreater thanless thanbrgreater thanResults: Predicted plasma concentrations of drug and metabolites were in the range of what has been observed in clinical studies. Given the final model, plasma concentrations of paclitaxel seems to be relatively little affected by changes in metabolism or transport, while its main metabolite may be largely affected even by small changes. If metabolites prove to be clinically relevant, genetic polymorphisms may play an important role for individualizing paclitaxel treatment.

  • 63.
    Frödin, Ulla
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Omvårdnad. Linköpings universitet, Hälsouniversitetet.
    Börjeson, Sussanne
    Linköpings universitet, Institutionen för medicin och hälsa, Omvårdnad. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Lyth, Johan
    Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Lotfi, Kourosh
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    A prospective evaluation of patients' health-related quality of life during auto-SCT: a 3-year follow-up2011Inngår i: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 46, nr 10, s. 1345-1352Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Few studies have evaluated long-term health-related quality of life (HRQL) in patients during auto-SCT. This prospective study examined HRQL in 96 eligible patients before, during and up to 3 years after auto-SCT. The aim of the study was to make a comprehensive assessment of the frequency and severity of different symptoms in patients undergoing auto-SCT. The European Organization for Treatment and Research of Cancer Quality of Life Questionnaire (EORTC QLQ C-30) was administered 13 times. The second week during treatment was the period when patients had the lowest HRQL regarding both total quality of life and function and symptom scales. The patients recovered quickly and just two months after transplantation the baseline values were restored. Three years after transplantation most of the items in the questionnaire had stabilized, except role function and dyspnea, which had improved. There were significant differences between multiple myeloma (MM) and lymphoma patients’ physical function, quality of life, fatigue and pain during week 2. At the 3-year follow-up, lymphoma patients indicated a better HRQL than MM patients. The quick recovery of patients after transplantation suggests that treatment is well tolerated; however, the supportive care could be improved at week 2, especially for the lymphoma patients.

  • 64.
    Frödin, Ulla
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Omvårdnad. Linköpings universitet, Hälsouniversitetet.
    Lotfi, Kourosh
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Fomichov, Victoria
    Östergötlands Läns Landsting, Centrum för hälso- och vårdutveckling, Regionalt cancercentrum.
    Juliusson, Gunnar
    Department of Hematology and Coagulation, Skåne County Council, Stem Cell Center, Lund University, Lund, Sweden.
    Börjeson, Sussanne
    Linköpings universitet, Institutionen för medicin och hälsa, Omvårdnad. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Early and Long-Term Follow-Up of Health-Related Quality of Life Following Allogeneic Hematopoietic Stem-Cell Transplantation2013Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Health-related quality of life (HRQL) of 94 consecutive patients undergoing allogeneic stem cell transplantation (SCT) with myeloablative conditioning (MAC, n = 18) or reduced intensity conditioning (RIC, n = 76) was evaluated using the EORTC QLQ C-30 questionnaire at baseline and 12 times up to 3 years after SCT. Functional status and the global quality of life decreased from baseline to weeks 2 and 3, especially role and social functions. Symptoms increased significantly during the first three weeks, particularly appetite loss, nausea and vomiting, diarrhea, and fatigue. It took at least one year for HRQL to return to the baseline level. The only function that improved significantly three years after SCT was role function. MAC patients experienced worse HRQL at baseline than RIC patients, and subsequently more pain, sleep disturbance, and appetite loss in weeks 3 and 4. Patients with extensive chronic graft-versus-host disease (GvHD) experienced reduced HRQL. These results provide a good overview of patients’ symptoms and HRQL during and after SCT and indicate when they require increased support. The results also demonstrate the importance of close follow-ups during the first year after SCT in order to improve the preventive interventions, particularly regarding appetite loss and chronic GvHD.

  • 65. Bestill onlineKjøp publikasjonen >>
    Fyrberg, Anna
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Nucleoside analoge cytotoxicity-focus on enzyme regulation, metabolism, and mechanisms of resistance2010Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The aim of this thesis was to determine the role of nucleoside analog activating and deactivating enzymes in nucleoside analog metabolism and resistance development. Nucleoside analogs are anti-cancer drogs and are often used to treat different leukemias, attributably to presence of high levels of nucleoside analog activating enzymes in hematopoietic cells. More recently some of the newer analogs have been used  successfully to treat solid tumors as well.

    We have used human leukemic cell lines, and isolated cells from patients with leukemia, to investigate the nucleoside analog activating enzymes deoxycytidine kinase (dCK) and deoxyguanosine kinase (dGK) and some of the deactivating enzymes called 5'nucleotidases (5'-NTs). We have measured mRNA expressions and enzymatic activities and correlated them with the cytotoxic response to nuc1eoside analogs and changes in cell cycle progression. We optimized and evaluated a siRNA-transfection method and decreased the activities of dCK and dGK in two different cell lines in order to find out more about their respective contribution to activation of these drogs. An expression microarray analysis of a nucleoside analog resistant cell line was also performed in order to clarify which genes are involved in development of resistance.

    We found that expressions and activities of dCK and dGK were not correlated. The enzyme activities of activating and deactivating enzymes changed during cell cycle progression, giving actively proliferating cells a more favorable enzymatic profile with regard to nucleoside analog cytotoxicity.

    The activities of dCK and dGK could be reduced transiently in leukemic and solid tumor cell lines, thereby confer either resistance or increased sensitivity to nucleoside analogs to variable degrees. Expression microarray analysis was used to evaluate the effect of the transfection method and the specificity of siRNA. We concluded that cells tolerated the transfection weIl without major effects on gene expression, and considered the siRNA used to be specific to its target.

    An expression microarray experiment on a nucleoside analog-induced resistant cell line revealed a hypomethylating capacity of the drog and induction of fetal hemoglobin and a multidrog resistance efflux pump as a result of the hypomethylation. This pump should not be affected by nucleoside analoges since they are not a substrate of it, and upregulation of the pump unfortunately renders the cells highly cross-resistant to different types of drogs. Our preliminary data supports our theory that it may be upregulated in order to help excrete hemoglobin that otherwise would be toxic to the cells.

    Delarbeid
    1. The pattern of deoxycytidine- and deoxyguanosine kinase activity in relation to messenger RNA expression in blood cells from untreated patients with B-cell chronic lymphocytic leukemia
    Åpne denne publikasjonen i ny fane eller vindu >>The pattern of deoxycytidine- and deoxyguanosine kinase activity in relation to messenger RNA expression in blood cells from untreated patients with B-cell chronic lymphocytic leukemia
    Vise andre…
    2006 (engelsk)Inngår i: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 71, nr 6, s. 882-890Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Deoxycytidine kinase (dCK) and deoxyguanosine kinase (dGK) catalyze the first step in the intracellular cascade of fludarabine (2-fluoroadenine-β- d-arabinofuranoside) and cladribine (2-chlorodeoxyadenosine) phosphorylation, which leads to activation of these prodrugs, commonly used for treatment of chronic lymphocytic leukemia (CLL). Thus, resistance to nucleoside analogues may primarily be due to low levels of deoxynucleoside kinase activity. The purpose of this study was to investigate the activity profiles of dCK and dGK and characterize the possible relationship between the levels of dCK enzymatic activities and mRNA levels in B-CLL cells from untreated patient samples in an attempt to determine the best approach for predicting sensitivity to nucleoside analogues and thereby optimizing treatment of CLL. For this purpose, dCK and dGK analyses were done in blood cells from 59 untreated symptomatic patients with CLL. The dGK activity towards 2-chlorodeoxyadenosine was significantly lower than of dCK (median 73 pmol/mg protein/min (85-121, 95% CI) versus 353 pmol/mg protein/min (331-421)). The median dCK mRNA level was 0.107 (0.096-0.120, 95% CI). There was a lack of correlation between the activities of dCK and dGK, which indicates that these proteins are regulated independently. We also found that the dCK and dGK activity measurement towards their endogenous substrates were comparable to the nucleoside analogues tested. Such variations in enzyme activities and mRNA levels may well explain differences in clinical responses to treatment. There was no correlation between the levels of dCK mRNAs and enzymatic activities using a quantitative real-time PCR procedure. Sequencing of dCK mRNA did not reveal alternate splicing or mutations in the coding region. The relation between activity and mRNA levels was studied by short interfering RNA (siRNA) method, which showed that in the siRNA treated cells the down-regulation of dCK expression, and activity followed each other. However, in control cells the mRNA levels remained stable but the protein activity markedly decreased. These data demonstrate that the dCK activity is not reflected by dCK mRNA expression that indicates a post-translational mechanism(s). © 2005 Elsevier Inc. All rights reserved.

    Emneord
    Purine analogues; Deoxycytidine kinase; Deoxyguanosine kinase; Chronic lymphocytic leukemia
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-36125 (URN)10.1016/j.bcp.2005.12.007 (DOI)30004 (Lokal ID)30004 (Arkivnummer)30004 (OAI)
    Tilgjengelig fra: 2009-10-10 Laget: 2009-10-10 Sist oppdatert: 2018-03-21
    2.
    Posten ble ikke funnet. Det kan skyldes at posten ikke lenger er tilgjengelig eller det er feil id i adressefeltet.
    3.
    Posten ble ikke funnet. Det kan skyldes at posten ikke lenger er tilgjengelig eller det er feil id i adressefeltet.
    4. The role of deoxyguanosine kinase for nucleoside analog activation in leukemic and solid tumor cell lines
    Åpne denne publikasjonen i ny fane eller vindu >>The role of deoxyguanosine kinase for nucleoside analog activation in leukemic and solid tumor cell lines
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Screening malignant melanoma cell lines against nucleoside analogs revealed as high sensitivity to fludarabine, clofarabine, and gemcitabine as to leukemic cells, and especially in those cells expressing high levels of the mitochondrial enzyme deoxuguanosine kinase (dGK). This enzyme, together with the cytosolic deoxycytidine kinase (dCK), and the mitochondrial thymidine kinase 2 (TK2) contributes to the activation of natural deoxyribonucleosides and nucleoside analogs to phosphorylated compounds. dCK is the most prominent enzyme in hematopoietic cells, while dGK may be high in cells harbouring many mitochondria, such as neurons and melanocytes. We found that dGK mRNA and protein expression was considerably higher in melanoma cells than in a leukemic cell line, while the difference at the activity level was less profound.

    Downregulation of dGK in the melanoma cell line RaH5 using siRNA led to a compensatory increase in TK2 activity, which led to significantly increased sensitivity of the cells to gemcitabine. In contrast, downregulation of dGK in the human leukemic CEM cell line decreased TK2 activity, and rendered the cells more resistant to the drugs. The compensatory regulation of deoxynucleoside kinases with over-lapping substrate specificity differed in leukemic and melanoma cell lines probably because they preferably rely on different deoxynucleoside kinases for nucleoside and nucleoside analog activation. dGK and TK2 that are both located in the mitochondria, seems to be able to compensate for each other to a higher extent in the dGK-dependent melanoma cells compared to CEM cells that possess high dCK activity. Solid tumors, such as melanoma, expressing high levels of dGK should be considered for nucleoside analog therapy preferably in combination with their standard treatment.

    Emneord
    Deoxyguanosine kinase, melanoma, leukemia, nucleoside analog, RNAi
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-64066 (URN)
    Tilgjengelig fra: 2011-01-12 Laget: 2011-01-12 Sist oppdatert: 2011-01-12bibliografisk kontrollert
    5. Induction of fetal hemoglobin and ABCB1 gene expression in 9-β-D-arabinofuranosylguanine-resistant MOLT-4 cells
    Åpne denne publikasjonen i ny fane eller vindu >>Induction of fetal hemoglobin and ABCB1 gene expression in 9-β-D-arabinofuranosylguanine-resistant MOLT-4 cells
    2011 (engelsk)Inngår i: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 68, nr 3, s. 583-591Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    PURPOSE: To characterize resistance mechanisms to the nucleoside analog 9-β-D-arabinofuranosylguanine (AraG) in the T-cell acute lymphoblastic leukemia cell line MOLT-4 and its AraG-resistant variant.

    METHODS: A gene expression microarray analysis was performed, as well as gene expression and enzyme activity measurements of key enzymes in the activation of AraG. Cytotoxicity of AraG and cross-resistance to other compounds were evaluated using a standard cytotoxicity assay.

    RESULTS: Gene expression microarray analysis revealed that fetal hemoglobin genes and the multidrug resistance ABCB1 gene, encoding the drug efflux pump P-gp, were the most highly upregulated genes in the resistant cells, while genes traditionally associated with nucleoside analog resistance were not. Fetal hemoglobin and ABCB1 induction can be due to global DNA hypomethylation. This phenomenon was studied using AraG during a period of 4 weeks in MOLT-4 cells and the lung adenocarcinoma cell line A549, leading to up-regulation of hemoglobin gamma and ABCB1 as well as DNA hypomethylation. Inhibiting P-gp in the AraG-resistant MOLT-4 cells led to decreased proliferation, reduced hemoglobin expression, and highly induced ABCB1 expression.

    CONCLUSIONS: We show that AraG can cause hypomethylation of DNA and induce the expression of the fetal hemoglobin gamma gene and the ABCB1 gene. We speculate that the induction of ABCB1/P-gp may occur in order to help with excretion of hemoglobin degradation products that would otherwise be toxic to the cells, and we present data supporting our theory that P-gp may be linked to the induction of hemoglobin.

    sted, utgiver, år, opplag, sider
    Springer, 2011
    Emneord
    9-β-D-arabinofuranosylguanine - Fetal hemoglobin - P-glycoprotein - Microarray - Hypomethylation
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-63246 (URN)10.1007/s00280-010-1524-5 (DOI)000294345400004 ()21110023 (PubMedID)
    Merknad
    Funding Agencies|Swedish Cancer Foundation||Swedish Childhood Cancer Foundation||Signe and Olof Wallentin Foundation||Capios Research Foundation||County Council of Ostergotland||Swedish Fund for Research without Animal Experiments||Tilgjengelig fra: 2010-12-13 Laget: 2010-12-13 Sist oppdatert: 2017-12-11
  • 66.
    Fyrberg, Anna
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Albertioni, Freidoun
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi.
    Lotfi, Kourosh
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Klinisk farmakologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Cell cycle effect on the activity of deoxynucleoside analogue metabolising enzymes2007Inngår i: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 357, nr 4, s. 847-853Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Deoxynucleoside analogues (dNAs) are cytotoxic towards both replicating and indolent malignancies. The impact of fluctuations in the metabolism of dNAs in relation to cell cycle could have strong implications regarding the activity of dNAs. Deoxycytidine kinase (dCK) and deoxyguanosine kinase (dGK) are important enzymes for phosphorylation/activation of dNAs. These drugs can be dephosphorylated/deactivated by 5′-nucleotidases (5′-NTs) and elevated activities of 5′-NTs and decreased dCK and/or dGK activities represent resistance mechanisms towards dNAs. The activities of dCK, dGK, and three 5′-NTs were investigated in four human leukemic cell lines in relationship to cell cycle progression and cytotoxicity of dNAs. Synchronization of cell cultures to arrest in G0/G1 by serum-deprivation was performed followed by serum-supplementation for cell cycle progression. The activities of dCK and dGK increased up to 3-fold in CEM, HL60, and MOLT-4 cells as they started to proliferate, while the activity of cytosolic nucleotidase I was reduced in proliferating cells. CEM, HL60, and MOLT-4 cells were also more sensitive to cladribine, cytarabine, 9-β-d-arabinofuranosylguanine and clofarabine than K562 cells which demonstrated lower levels and less alteration of these enzymes and were least susceptible to the cytotoxic effects of most dNAs. The results suggest that, in the cell lines studied, the proliferation process is associated with a general shift in the direction of activation of dNAs by inducing activities of dCK/dGK and reducing the activity of cN-I which is favourable for the cytotoxic effects of cladribine, cytarabine and, 9-β-d-arabinofuranosylguanine. These results emphasize the importance of cellular proliferation and dNA metabolism by both phosphorylation and dephosphorylation for susceptibility to dNAs. It underscores the need to understand the mechanisms of action and resistance to dNAs in order to increase efficacy of dNAs treatment by new rational. © 2007 Elsevier Inc. All rights reserved.

  • 67.
    Fyrberg, Anna
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Albertioni, Freidoun
    Cancer Center Karolinska, Department of Oncology and Pathology, Karolinska University Hospital, Stockholm.
    Lotfi, Kourosh
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken. Linköpings universitet, Hälsouniversitetet.
    RNAi Depletion of Deoxycytidine and Deoxyguanosine Kinase in Human Leukemic CEM Cells2008Inngår i: Nucleosides, Nucleotides & Nucleic Acids, ISSN 1525-7770, E-ISSN 1532-2335, Vol. 27, nr 6-7, s. 712-719Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Resistance toward nucleoside analogues is often due to decreased activities of the activating enzymes deoxycytidine kinase (dCK) and/or deoxyguanosine kinase (dGK). With small interfering RNA (siRNA), dCK and dGK were downregulated by approximately 70% in CEM cells and tested against six nucleoside analogues using the methyl thiazol tetrazolium assay. SiRNA-transfected cells reduced in dCK activity were 3- to 6-fold less sensitive to CdA, AraC, and CAFdA. The sensitivity to AraG and FaraA was unchanged, while the sensitivity toward gemcitabine was significantly increased. dGK depletion in cells resulted in lower sensitivity to FaraA, dFdC, CAFdA, and AraG, but slightly higher sensitivity to CdA and AraC.

  • 68.
    Fyrberg, Anna
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Albertioni, Freidoun
    Cancer Center Karolinska Department of Oncology and Pathology, Karolinska University Hospital, SE-171 76 Stockholm.
    Lotfi, Kourosh
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    The role of deoxyguanosine kinase for nucleoside analog activation in leukemic and solid tumor cell linesManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Screening malignant melanoma cell lines against nucleoside analogs revealed as high sensitivity to fludarabine, clofarabine, and gemcitabine as to leukemic cells, and especially in those cells expressing high levels of the mitochondrial enzyme deoxuguanosine kinase (dGK). This enzyme, together with the cytosolic deoxycytidine kinase (dCK), and the mitochondrial thymidine kinase 2 (TK2) contributes to the activation of natural deoxyribonucleosides and nucleoside analogs to phosphorylated compounds. dCK is the most prominent enzyme in hematopoietic cells, while dGK may be high in cells harbouring many mitochondria, such as neurons and melanocytes. We found that dGK mRNA and protein expression was considerably higher in melanoma cells than in a leukemic cell line, while the difference at the activity level was less profound.

    Downregulation of dGK in the melanoma cell line RaH5 using siRNA led to a compensatory increase in TK2 activity, which led to significantly increased sensitivity of the cells to gemcitabine. In contrast, downregulation of dGK in the human leukemic CEM cell line decreased TK2 activity, and rendered the cells more resistant to the drugs. The compensatory regulation of deoxynucleoside kinases with over-lapping substrate specificity differed in leukemic and melanoma cell lines probably because they preferably rely on different deoxynucleoside kinases for nucleoside and nucleoside analog activation. dGK and TK2 that are both located in the mitochondria, seems to be able to compensate for each other to a higher extent in the dGK-dependent melanoma cells compared to CEM cells that possess high dCK activity. Solid tumors, such as melanoma, expressing high levels of dGK should be considered for nucleoside analog therapy preferably in combination with their standard treatment.

  • 69.
    Fyrberg, Anna
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Lotfi, Kourosh
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Optimization and evaluation of electroporation delivery of siRNA in the human leukemic CEM cell line2010Inngår i: CYTOTECHNOLOGY, ISSN 0920-9069, Vol. 62, nr 6, s. 497-507Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In order to study nucleoside analog activation in the CEM cell line, a transfection protocol had to be optimized in order to silence an enzyme involved in nucleoside analog activation. Hematopoetic cell lines can be difficult to transfect with traditional lipid-based transfection, so the electroporation technique was used. Field strength, pulse length, temperature, electroporation media, siRNA concentration, among other conditions were tested in order to obtain approximately 70-80% mRNA and enzyme activity downregulation of the cytosolic enzyme deoxycytidine kinase (dCK), necessary for nucleoside analog activation. Downregulation was assessed at mRNA and enzyme activity levels. After optimizing the protocol, a microarray analysis was performed in order to investigate whether the downregulation was specific. Additionally two genes were differentially expressed besides the downregulation of dCK. These were however of unknown function. The leakage of intracellular nucleotides was also addressed in the electroporated cells since it can affect the DNA repair mechansism and the efficiency of nucleoside analogs. Three of these pools were increased compared to untreated, unelectroporated cells. The siRNA transfected cells with reduced dCK expression and activity showed reduced sensitivity to several nucleoside analogs as expected. The multidrug resistance to other drugs, as seen in nucleoside analog-induced resistant cells, was not seen with this model.

  • 70.
    Fyrberg, Anna
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Kågedal, Bertil
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Lotfi, Kourosh
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Induction of fetal hemoglobin and ABCB1 gene expression in 9-β-D-arabinofuranosylguanine-resistant MOLT-4 cells2011Inngår i: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 68, nr 3, s. 583-591Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE: To characterize resistance mechanisms to the nucleoside analog 9-β-D-arabinofuranosylguanine (AraG) in the T-cell acute lymphoblastic leukemia cell line MOLT-4 and its AraG-resistant variant.

    METHODS: A gene expression microarray analysis was performed, as well as gene expression and enzyme activity measurements of key enzymes in the activation of AraG. Cytotoxicity of AraG and cross-resistance to other compounds were evaluated using a standard cytotoxicity assay.

    RESULTS: Gene expression microarray analysis revealed that fetal hemoglobin genes and the multidrug resistance ABCB1 gene, encoding the drug efflux pump P-gp, were the most highly upregulated genes in the resistant cells, while genes traditionally associated with nucleoside analog resistance were not. Fetal hemoglobin and ABCB1 induction can be due to global DNA hypomethylation. This phenomenon was studied using AraG during a period of 4 weeks in MOLT-4 cells and the lung adenocarcinoma cell line A549, leading to up-regulation of hemoglobin gamma and ABCB1 as well as DNA hypomethylation. Inhibiting P-gp in the AraG-resistant MOLT-4 cells led to decreased proliferation, reduced hemoglobin expression, and highly induced ABCB1 expression.

    CONCLUSIONS: We show that AraG can cause hypomethylation of DNA and induce the expression of the fetal hemoglobin gamma gene and the ABCB1 gene. We speculate that the induction of ABCB1/P-gp may occur in order to help with excretion of hemoglobin degradation products that would otherwise be toxic to the cells, and we present data supporting our theory that P-gp may be linked to the induction of hemoglobin.

  • 71.
    Fyrberg, Anna
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Skoglund, Karin
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Wolk, M
    Israel Minist Health Central Labs, Israel .
    Lotfi, Kourosh
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    A potential role of fetal hemoglobin in the development of multidrug resistance2012Inngår i: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 427, nr 3, s. 456-460Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Our previous data from a human leukemic cell line made resistant to the nucleoside analog (NA) 9-beta-D-arabinofuranosylguanine (AraG) revealed a massive upregulation of fetal hemoglobin (HbF) genes and the ABCB1 gene coding for the multidrug resistance P-glycoprotein (P-gp). The expression of these genes is regulated through the same mechanisms, with activation of the p38-MAPK pathway and inhibition of methylation making transcription factors more accessible to activate these genes. We could show that AraG, as well as other NAs, and P-gp substrates could induce global DNA demethylation and induction of Hb gamma and P-gp both at the mRNA and protein expression level. We speculate that the expression of HbF prior to drug exposure or in drug-resistant cell lines is a strategy of the cancer to gain more oxygen, and thereby survival benefits. We also believe that P-gp may be induced in order to excrete Hb degradation products from the cells that would otherwise be toxic. By using Hb gamma siRNA and pharmacological inhibitors of HbF production we here present a possible relationship between HbF induction and multi-drug resistance in a human leukemia cell line model.

  • 72.
    Fägerskiöld, Astrid
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi.
    Expectations of the child health nurse among mothers and fathers of infants2007Inngår i: 18th International Nursing Research Congress Focusing on Evidence-based Practice,2007, 2007Konferansepaper (Annet vitenskapelig)
    Abstract [en]

      

  • 73.
    Fägerskiöld, Astrid
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Rapport från en omvårdnadskonferens i Wien - Spädbarnsföräldrars förväntnignar på BVC-sjuksköterskan.2007Inngår i: Barnbladet, ISSN 0349-1994, Vol. 5, s. 15-17Artikkel i tidsskrift (Annet (populærvitenskap, debatt, mm))
  • 74.
    Gomez-Pinilla, Pedro J
    et al.
    - Spanien.
    Gomez, Maria F
    Lund.
    Hedlund, Petter
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Swärd, Karl
    Lund.
    Hellstrand, Per
    Lund.
    Camell, Pedro J
    Spanien.
    Pozo, Maria J
    Spanien.
    Andersson, Karl-Erik
    Lund/North Carolina.
    Effect of melatonin on age associated changes in guinea pig bladder function2007Inngår i: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 177, s. 1558-1561Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose

    The incidence of urinary incontinence increases with age but the cause and effect relationship between aging and altered bladder function is poorly understood. It was suggested that melatonin can ameliorate negative effects induced by aging by its free radical scavenging activity and its ability to decrease oxidative stress. We investigated the changes in bladder function evoked by aging and the possible benefits of melatonin treatment on age related bladder disturbances.

    Materials and Methods

    Bladder function was assessed using cystometry in conscious, freely moving female guinea pigs. Animals were grouped according to age as young adults (4 months old) and senescents (18 to 20 months old). A group of senescent animals were treated with 2.5 mg kg−1 day−1 melatonin for 21 days.

    Results

    Aging led to increased detrusor activity, as demonstrated by short micturition intervals, decreased bladder capacity and spontaneous contractions during the filling phase. During the voiding phase aged animals showed lower micturition pressures than young adults. Melatonin counteracted the cystometric changes in senescent animals and restored micturition parameters to those of young adults.

    Conclusions

    These results show that in guinea pigs aging induces detrusor overactivity. Melatonin treatment improved age induced changes in bladder function. If similar effects can be demonstrated in humans, melatonin treatment may be a new approach to decrease the impact of age related bladder disorders.

  • 75.
    Gomez-Pinilla, Pedro J.
    et al.
    University of Extremadura.
    Gomez, Maria F.
    Lund University.
    Sward, Karl
    Lund University.
    Hedlund, Petter
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Hellstrand, Per
    Lund University.
    Camello, Pedro J.
    University of Extremadura.
    Andersson, Karl-Erik
    Lund University.
    Pozo, Maria J.
    University of Extremadura.
    Melatonin restores impaired contractility in aged guinea pig urinary bladder2008Inngår i: Journal of Pineal Research, ISSN 0742-3098, E-ISSN 1600-079X, Vol. 44, nr 4, s. 416-425Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    0

  • 76.
    Gratzke, Christian
    et al.
    University Lund Hospital, Department Clin Chemistry and Pharmacol, S-22185 Lund, Sweden Ludwig Maximilians University Hospital, Department Urol, Munich, Germany Wake Forest University, Bowman Gray Sch Med, Wake Forest Institute Regenerat Med, Winston Salem, NC USA .
    Christ, George J
    Wake Forest University, Bowman Gray Sch Med, Wake Forest Institute Regenerat Med, Winston Salem, NC USA .
    Stief, Christian G
    Ludwig Maximilians University Hospital, Department Urol, Munich, Germany .
    Andersson, Karl-Erik
    Wake Forest University, Bowman Gray Sch Med, Wake Forest Institute Regenerat Med, Winston Salem, NC USA .
    Hedlund, Petter
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Localization and Function of Cannabinoid Receptors in the Corpus Cavernosum: Basis for Modulation of Nitric Oxide Synthase Nerve Activity2010Inngår i: EUROPEAN UROLOGY, ISSN 0302-2838, Vol. 57, nr 2, s. 342-348Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Anandamide, a proposed endogenous cannabinoid (CB) agonist, has been shown to enhance neurogenic responses in vitro of the rat corpus cavernosal tissue (CC). However, no information is available on the distribution of CB-receptors or effects by anandamide in CC from primates or humans. Objective: To characterize the distribution of CB-receptor isoforms in the human and primate CC and to investigate the effects of anandamide on isolated CC preparations. Design, setting, and participants: CC tissue was excised from the crura penis of six rhesus monkeys and five patients. Expression and distribution of CB1 and CB2 receptors were characterized with Western blot analyses and immunohistochemical investigations. The effects of anandamide on isolated CC preparations were analyzed during pharmacologic and nerve-mediated activation of primate tissue in aerated organ baths. Measurements: The expression and localization of CB1 and CB2 receptors in the primate CC and effects of anandamide on nerve-mediated relaxations and pharmacologically evoked contractions. Results and limitations: Western blot experiments revealed CB1 and CB2 receptors at expected band weights. Within and between strands of CC smooth muscle, CB1 and CB2 immunoreactivity (IR) was found in nerve fibers that also expressed IR for nitric oxide synthase (NOS) or transient receptor potential V1 (TRPV1). Neither CB1-IR nor CB2-IR nerves were colocalized with calcitoningene-related peptide (CGRP)-containing or tyrosine hydroxylase-containing nerves. No differences were observed between primate and human CC sections. Anandamide (10(-9) to 10(-4) M) had no contractile effects on CC smooth muscle, no relaxant effects on precontracted preparations, and no effect on phenylephrine-induced contractions. However, anandamide (10 mu M) inhibited electrically evoked smooth-muscle relaxations (34-48%; p andlt;= 0.05). Conclusions: CB1 and CB2 receptors are located on NOS-containing nerves in primate and human CC tissue. In contrast to findings in rats, anandamide antagonized nerve-mediated relaxations of the primate CC, suggesting important species differences for CB-mediated functions. The results also suggest a peripheral mechanism for cannabis-related sexual dysfunction.

  • 77.
    Gratzke, Christian
    et al.
    Wake Forest Institute.
    Streng, Tomi
    Turku University.
    Park, Anthony
    Wake Forest Institute.
    Christ, George
    Wake Forest Institute.
    Stief, Christian G
    University Munich.
    Hedlund, Petter
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Andersson, Karl-Erik
    Wake Forest Institute.
    Distribution and Function of Cannabinoid Receptors 1 and 2 in the Rat, Monkey and Human Bladder2009Inngår i: JOURNAL OF UROLOGY, ISSN 0022-5347, Vol. 181, nr 4, s. 1939-1948Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: We investigated the distribution of cannabinoid receptor subtypes 1 and 2 in the detrusor of different species and studied the effects of cannabinoid receptor 1 and 2 agonists on bladder function.

    Materials and Methods: Cannabinoid receptor 1 and 2 expression was studied with Western blot and immunohistochemistry in rat, monkey and human detrusors. Co-staining was done for markers of sensory nerves using calcitonin gene-related peptide (Euro-Diagnostica, Malmo, Sweden) and transient receptor potential vanilloid 1, and for cholinergic nerves using VAChT (Santa Cruz Biotechnology, Santa Cruz, California). Actions of the endogenous cannabinoid receptor-1 and 2 agonist anandamide (Sigma (R)), and the cannabinoid receptor 1 and 2 agonist CP55,940 (Sigma) on isolated detrusor and during cystometry in conscious rats were recorded.

    Results: Higher expression of cannabinoid receptor 2 but not cannabinoid receptor 1 was noted in the mucosa than in the detrusor. Compared to the detrusor larger amounts of cannabinoid receptor 2 containing nerves that also expressed transient receptor potential vanilloid 1 or calcitonin gene-related peptide were observed in the suburothelium. Nerve fibers containing cannabinoid receptor 2 and VAChT were located in the detrusor. Neither anandamide nor CP55,940 affected isolated detrusor carbachol (Sigma) contractions. Nerve contractions were enhanced by 10 mu M anandamide and decreased by 10 AM CP55,940 (P&lt;0.05). In vivo CP55,940 increased the micturition interval by 46% and threshold pressure by 124% (p &lt;0.05). Anandamide increased threshold pressure by 26% and decreased the micturition interval by 19% (p &lt;0.05 and &lt;0.01, respectively).

    Conclusions: The distribution of cannabinoid receptor 2 on sensory nerves and in the urothelium, and effects by CP55940 on the micturition interval and threshold pressure suggest a role for cannabinoid receptor 2 in bladder afferent signals. Co-expression of VAChT and cannabinoid receptor 2, and effects by CP55940 on nerve contractions suggest a cannabinoid receptor 2 mediated modulatory effect on cholinergic nerve activity. Anandamide may not be a good tool for cannabinoid receptor studies due to its activity at other receptors.

  • 78.
    Gratzke, Christian
    et al.
    University Lund Hospital.
    Streng, Tomi
    University Turku.
    Stief, Christian G
    University Munich.
    Alroy, Iris
    Pharmos Ltd, Rehovot, Israel .
    Limberg, Brian J
    Procter and Gamble Co.
    Downs, Thomas R
    Procter and Gamble Co.
    Rosenbaum, Jan S
    Procter and Gamble Co.
    Hedlund, Petter
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Andersson, Karl-Erik
    Wake Forest Institute Regenerat Med.
    Cannabinor, a Selective Cannabinoid-2 Receptor Agonist, Improves Bladder Emptying in Rats With Partial Urethral Obstruction2011Inngår i: JOURNAL OF UROLOGY, ISSN 0022-5347, Vol. 185, nr 2, s. 731-736Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: We studied the effects of chronic treatment with the novel selective cannabinoid 2 receptor agonist cannabinor (Procter andamp; Gamble Pharmaceuticals, Cincinnatti, Ohio) on bladder function in conscious rats with partial urethral obstruction and on the functional properties of isolated detrusor muscle. Materials and Methods: A total of 24 female Sprague-Dawley(R) rats with surgically created partial urethral obstruction received daily intraperitoneal injections of 3 mg/kg cannabinor (12) or saline as controls (12) for 2 weeks. Cystometry was done, the rats were sacrificed and the bladders were prepared for in vitro studies. Results: Mean +/- SEM bladder weight was 0.97 +/- 0.15 gm in controls and 0.53 +/- 0.08 gm in cannabinor treated rats (p andlt; 0.05). There was no difference between the groups in the mean micturition interval, or mean baseline, threshold, flow or maximum pressure. In controls and cannabinor treated rats mean post-void residual volume was 0.28 +/- 0.07 and 0.06 +/- 0.02 ml, mean micturition compliance was 0.032 +/- 0.006 and 0.069 +/- 0.016 ml/cm H2O, and mean bladder wall force at the start of flow was 950 +/- 280 and 1,647 +/- 325 mN/gm, respectively (each p andlt; 0.05). Nonvoiding contractions were significantly less frequent in cannabinor treated rats than in controls. We noted no difference in carbachol (Sigma(R)) half maximum concentration between the groups but the carbachol maximum response in detrusor strips from cannabinor treated rats was significantly higher than that in control strips. Conclusions: In rats with partial urethral obstruction treated daily for 14 days with cannabinor bladder weight was lower, the ability to empty the bladder was preserved and nonvoiding contraction frequency was low compared to those in controls. Detrusor preparations from cannabinor treated rats showed a higher response to nerve stimulation than those from controls. Selective cannabinoid 2 receptor activation may be a novel principle to enable improved bladder function after partial urethral obstruction.

  • 79.
    Gratzke, Christian
    et al.
    Lund University Hospital.
    Streng, Tomi
    Lund University Hospital.
    Waldkirch, Eginhard
    Hannover Medical School.
    Sigl, Katja
    Ludwig Maximilians University Hospital.
    Stief, Christian
    Ludwig Maximilians University Hospital.
    Andersson, Karl-Erik
    Wake Forest University.
    Hedlund , Petter
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi.
    Transient Receptor Potential A1 (TRPA1) Activity in the Human Urethra-Evidence for a Functional Role for TRPA1 in the Outflow Region2009Inngår i: EUROPEAN UROLOGY, ISSN 0302-2838 , Vol. 55, nr 3, s. 696-704Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: A role for the transient receptor potential (TRP) A1 ion channel in rat lower urinary tract (LUT) sensation and disease has been proposed, but in the human LUT no information on TRPA1 activity is available.

    Objectives: To investigate the distribution of TRPA1 in the human urethra and to study the effect of TRPA1 agonists on isolated urethral strip preparations.

    Design, settings, and participants: Urethral specimens were obtained preoperatively from 10 patients and were freshly prepared for Western blot, immunohistochemistry, and functional in vitro investigations.

    Measurements: The expression patterns of TRPA1 were studied with Western blot and immunohistochemistry. The effects of allyl isothiocyanate (A1), cinnamaldehyde (CA), and NaHS (donor of H2S) on tension of urethral strips were investigated in tissue baths.

    Results and limitations: TRPA1 immunoreactivity (-IR) was found in nerve fibres in the suburothelial space and was also located to nerve fibres of the muscle layer. Single TRPA1-IR nerves extended into the urothelium. A majority, but not all TRPA1-IR nerves also expressed immunoreactivity for CGRP or TRPV1. In the urothelium, TRPV1 was located to the outer layers whereas TRPA1 was observed in basal urothelial cells. Interspersed between strands of smooth muscle cells of the urethral wall, TRPA1- and vimentin-IR cells containing central nuclei and slender cytoplasmatic extensions were observed. In functional experiments, TRPA1-agonists had no contractile effect in urethral preparations. After precontraction with phenylephrine, AI, CA, and NaHS caused concentration-dependent relaxations of urethral strip preparations.´

    Conclusions: The localization of TRPA1 to nerves that also express TRPV1 and CGRP, and in urothelial cells and interstitial cells, as well as the findings that TRPA1 agonists can modify tone of urethral preparations, propose a role for TRPA1 in afferent and efferent sensory signaling of the human outflow region.

  • 80.
    Gratzke, Christian
    et al.
    Wake Forest Institute Regenerat Med.
    Weinhold, Philipp
    University of Munich.
    Reich, Oliver
    University of Munich.
    Seitz, Michael
    University of Munich.
    Schlenker, Boris
    University of Munich.
    Stief, Christian G
    University of Munich.
    Andersson, Karl-Erik
    Wake Forest Institute Regenerat Med.
    Hedlund, Petter
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Transient Receptor Potential A1 and Cannabinoid Receptor Activity in Human Normal and Hyperplastic Prostate: Relation to Nerves and Interstitial Cells2010Inngår i: EUROPEAN UROLOGY, ISSN 0302-2838, Vol. 57, nr 5, s. 902-910Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Ion channel transient receptor potential A1 (TRPA1) and cannabinoid (CB) receptors are involved in mechanoafferent signaling from the bladder and the urethra. Objective: To characterize TRPA1-, CB1-, and CB2-receptor activities in the human prostate. Design, setting, and participants: Prostate specimens were obtained from 12 patients undergoing radical prostatectomy. We studied expressions (n = 6) of TRPA1, CB1, and CB2 receptors and effects of the TRPA1 agonists allyl isothiocyanate (AI), cinnamaldehyde (CA), sodium hydrogen sulfide (NaHS), and CP 55940 (a CB1/CB2 agonist) on prostatic preparations. Measurements: Western blot, immunohistochemistry, and functional experiments were performed. Results and limitations: Western blot detected expected bands for CB1, CB2, and TRPA1. TRPA1 immunoreactivity was located on nerves that were positive for CB1, CB2, calcitonin gene-related peptide (CGRP), nitric oxide synthase (NOS), or vesicular acetylcholine transporter (VAChT). CB1 and CB2 immunoreactivity was found on nerves that were positive for NOS, VAChT, or CGRP. Adrenergic nerves were not immunoreactive for TRPA1, CB1, or CB2. In nodular hyperplasia, nerves containing the above markers were scarce or absent. TRPA1 immunoreactivity was detected in cyclic guanosinemonophosphate-positive basal cells of the glandular epithelium. Basal or subepithelial TRPA1-immunoreactive cells contained vimentin and c-kit immunoreactivity. CA and NaHS relaxed precontracted preparations by 55 +/- 7% and 35 +/- 3% (n = 6 for each). CP 55940, NaHS, AI, capsaicin, and CA decreased nerve contractions up to 27%, 80%, 47%, and 87%, respectively (n = 6 for each). Conclusions: The distribution and function of TRPA1 and CB receptors in prostatic tissue suggest a role for these receptors in mechanoafferent signals, epithelial homeostasis, emission, or inflammation of the human prostate.

  • 81. Bestill onlineKjøp publikasjonen >>
    Green, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Pharmacogenetic Studies of Paclitaxel in Ovarian Cancer: focus on interindividual differences in pharmacodynamics and pharmacokinetics2007Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Ovarian cancer is one of the most common female cancer diseases in the world today and in Sweden more than 800 new cases are diagnosed every year. The standard treatment consists of chemotherapy with paclitaxel in combination with carboplatin after initial cytoreductive surgery. The response to treatment and the severity of adverse drug reactions after chemotherapy varies greatly among individuals, and one of the most important factors responsible for these differences is now recognized to be the genetic variability. One of the major obstacles to successful treatment is drug resistance. Several potential mechanisms have been suggested for the resistance to paclitaxel, such as mutations in the target protein β-tubulin, single nucleotide polymorphisms (SNPs) in the gene ABCB1, which encodes the transport protein P-glycoprotein. P-glycoprotein can mediate efflux of various drugs from cancer cells as well as from the circulation into the intestinal lumen, and overexpression and/or high activity leads to drug resistance and/or increased elimination. Another reason might be the high interindividual variability of paclitaxel plasma concentrations, which has been suggested to be influenced by variability in metabolic enzymes, such as CYP2C8 and CYP3A4, and transport proteins e.g. P-glycoprotein.

    In the studies constituting this thesis we have investigated the possibilities of predicting the pharmacokinetics of paclitaxel as well as the tumor response and adverse drug reactions after chemotherapy in the preparation of personalized chemotherapy. We studied the correlation between the response and the presence of mutations in the dominant β-tubulin gene and SNPs in ABCB1. DNA from 40 ovarian tumors was screened for sequence variations in the β-tubulin gene without finding any, showing that β-tubulin mutations are rare and unlikely to be a clinically relevant resistance mechanism for paclitaxel. The SNPs G2677T/A and C3435T in the ABCB1 gene were determined in 53 ovarian cancer tumors from patients with poor (progressive disease or relapse within one year) or good (disease-free survival of more than one year) response to paclitaxel-carboplatin chemotherapy. Patients homozygously mutated for G2677T/A had a higher probability of responding to chemotherapy. There was also a dose-dependent influence of the number of mutated alleles on the response to paclitaxel treatment. No correlation was found for the C3435T variant.

    By using a newly developed quantitative LC/MS method for the simultaneous determination of paclitaxel and its hydroxymetabolites in human plasma we assessed the individual elimination of paclitaxel in 33 ovarian cancer patients. The patients were genotyped for SNPs in the ABCB1, CYP2C8 and CYP3A4 genes and their in vivo CYP3A4 enzyme activity, tumor response and toxicity, especially the neurotoxicity, were determined. Patients heterozygous for G/A in position 2677 in ABCB1 had a significantly higher clearance of paclitaxel than patients with the wild type or homozygously mutated, but not compared to patients carrying the G/T alleles. A lower clearance of paclitaxel was also found for patients heterozygous for CYP2C8*3 when stratified according to the ABCB1 G2677T/A genotype. The CYP3A4 enzyme activity in vivo affected the relative influence of CYP2C8 and CYP3A4 on the metabolism, but not the total clearance of paclitaxel. The exposure to paclitaxel was correlated to the neurotoxicity, but not to the treatment response. In conclusion, our findings suggest that the SNP G2677T/A in the ABCB1 gene, but not β-tubulin mutations, might be a predictor for paclitaxel response and that the interindividual variability in paclitaxel pharmacokinetics might be predicted by ABCB1 and CYP2C8 genotypes and provide useful information for individualized chemotherapy.

    Delarbeid
    1. β-tubulin mutations in ovarian cancer using single strand conformation analysis – risk of false positive results from paraffin embedded tissues
    Åpne denne publikasjonen i ny fane eller vindu >>β-tubulin mutations in ovarian cancer using single strand conformation analysis – risk of false positive results from paraffin embedded tissues
    Vise andre…
    2006 (engelsk)Inngår i: Cancer Letters, ISSN 0304-3835, Vol. 236, nr 1, s. 148-154Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Mutations in the β-tubulin gene have been proposed as a resistance mechanism to paclitaxel. We therefore investigated the presence of mutations in the β-tubulin M40 gene in 40 ovarian tumours (16 paraffin-embedded and 24 freshly frozen) selected for good or poor response to chemotherapy with paclitaxel or non-tubulin-affecting regimens. The presence of mutations was investigated using single strand conformation analysis followed by sequencing of the products with altered mobility. No sequence variants in the exons of the β-tubulin M40 gene were detected. Non-reproducible shifts were identified, in eight out of 16 paraffin embedded samples. This may explain some of the previously published discrepancies. In conclusion, sequence variants in the β-tubulin M40 gene are rare and are unlikely to be a clinically relevant explanation of resistance to paclitaxel.

    Emneord
    β-tubulin; Paclitaxel; Ovarian cancer; Mutation analysis; SSCA
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-14242 (URN)10.1016/j.canlet.2005.05.025 (DOI)
    Merknad
    Original Publication: Henrik Green, Per Rosenberg, Peter Söderkvist, György Horvath and Curt Peterson, β-tubulin mutations in ovarian cancer using single strand conformation analysis – risk of false positive results from paraffin embedded tissues, 2006, Cancer Letters, (236), 1, 148-154. http://dx.doi.org/10.1016/j.canlet.2005.05.025 Copyright: Elsevier Science B.V., Amsterdam. http://www.elsevier.com/ Tilgjengelig fra: 2007-01-26 Laget: 2007-01-26 Sist oppdatert: 2010-05-28
    2. mdr-1 single nucleotide polymorphisms in ovarian cancer tissue – G2677T/A correlates with response to paclitaxel chemotherapy
    Åpne denne publikasjonen i ny fane eller vindu >>mdr-1 single nucleotide polymorphisms in ovarian cancer tissue – G2677T/A correlates with response to paclitaxel chemotherapy
    Vise andre…
    2006 (engelsk)Inngår i: Clinical Cancer Research, ISSN 1078-0432, Vol. 12, nr 3 pt 1, s. 854-859Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Purpose: P-glycoprotein, encoded by the mdr-1 gene, confers multidrug resistance to a variety of antineoplastic agents, e.g., paclitaxel. Recently, different polymorphisms in the mdr-1 gene have been identified and their consequences for the function of P-glycoprotein, as well as for the treatment response to P-glycoprotein substrates, are being clarified. We analyzed the allelic frequencies at polymorphic sites G2677T/A and C3435T in ovarian cancer patients with good or poor response to treatment with paclitaxel in combination with carboplatin in order to evaluate their predictive values.

    Experimental Design: Fifty-three patients were included in the study; 28 of them had been relapse-free for at least 1 year and 25 had progressive disease or relapsed within 12 months. A reference material consisting of 200 individuals was also analyzed. The genotypes of each single nucleotide polymorphism (SNP) were determined using Pyrosequencing.

    Results: The G2677T/A SNP was found to significantly correlate with treatment outcome. The probability of responding to paclitaxel treatment was higher in homozygously mutated patients (T/T or T/A; Fisher's exact test; P < 0.05). The frequency of the T or A alleles was also higher in the group of patients who had a good response (P < 0.05). There was also a dose-dependent influence of the number of mutated alleles on the response to paclitaxel treatment (Χ2 test for linear-by-linear association; P = 0.03). However, the C3435T SNP was not found to correlate to treatment outcome.

    Conclusions: The mdr-1 polymorphism G2677T/A in exon 21 correlates with the paclitaxel response in ovarian cancer and may be important for the function of P-glycoprotein and resistance to paclitaxel and provide useful information for individualized therapy.

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-14243 (URN)10.1158/1078-0432.CCR-05-0950 (DOI)
    Merknad
    Original Publication: Henrik Green, Peter Söderkvist, Per Rosenberg, György Horvath and Curt Peterson, mdr-1 single nucleotide polymorphisms in ovarian cancer tissue – G2677T/A correlates with response to paclitaxel chemotherapy, 2006, Clinical Cancer Research, (12), 3 pt 1, 854-859. http://dx.doi.org/10.1158/1078-0432.CCR-05-0950 Copyright: American Association for Cancer Research, Inc. http://www.aacr.org/ Tilgjengelig fra: 2007-01-26 Laget: 2007-01-26 Sist oppdatert: 2010-05-28
    3. Measurement of paclitaxel and its metabolites in human plasma using liquid chromatography/ion trap mass spectrometry with a sonic spray ionization interface
    Åpne denne publikasjonen i ny fane eller vindu >>Measurement of paclitaxel and its metabolites in human plasma using liquid chromatography/ion trap mass spectrometry with a sonic spray ionization interface
    2006 (engelsk)Inngår i: Rapid Communications in Mass Spectrometry, ISSN 1097-0231, Vol. 20, nr 14, s. 2183-2189Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    A quantitative liquid chromatography/ion trap mass spectrometry method for the simultaneous determination of paclitaxel, 6α-hydroxypaclitaxel and p-3'-hydroxypaclitaxel in human plasma has been developed and validated. 6α-,p-3'-Dihydroxypaclitaxel was also quantified using paclitaxel as a reference and docetaxel as an internal standard. The substances were extracted from 0.500 mL plasma using solid-phase extraction. The elution was performed with acetonitrile and the samples were reconstituted in the mobile phase. Isocratic high-performance liquid chromatography analysis was performed by injecting 50 µL of reconstituted material onto a 100 × 3.00 mm C12 column with a methanol:1% trifluoroacetic acid/ammonium trifluoroacetate in H2O 70:30 mobile phase at 350 µL/min. The [M+H]+ ions generated in the sonic spray ionization interface were isolated and fragmented using two serial mass spectrometric methods: one for paclitaxel (transition 854 → 569 & 551) and the dihydroxymetabolite (transition 886 → 585 & 567) and one for the hydroxy metabolites (transition 870 → 585 & 567; transition 870 → 569 & 551) and docetaxel ([M+Na]+, transition 830 → 550). Calibration curves were created ranging between 0.5 and 7500 ng/mL for paclitaxel, 0.5 and 750 ng/mL for 6α-hydroxypaclitaxel, and 0.5 and 400 ng/mL for p-3'-hydroxypaclitaxel. Adduct ion formation was noted and investigated during method development and controlled by mobile phase optimization. In conclusion, a sensitive method for simultaneous quantification of paclitaxel and its metabolites suitable for analysis in clinical studies was obtained.

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-14244 (URN)10.1002/rcm.2567 (DOI)
    Merknad
    This is the pre-peer-reviewed version of: Henrik Green, Karin Vretenbrant (Öberg), Björn Norlander and Curt Peterson, Measurement of paclitaxel and its metabolites in human plasma using liquid chromatography/ion trap mass spectrometry with a sonic spray ionization interface, 2006, Rapid Communications in Mass Spectrometry, (20), 14, 2183-2189. which has been published in final form at: http://dx.doi.org/10.1002/rcm.2567 Copyright: John Wiley and Sons, Ltd http://eu.wiley.com/WileyCDA/Brand/id-35.html Tilgjengelig fra: 2007-01-26 Laget: 2007-01-26 Sist oppdatert: 2010-05-28
    4. Pharmacogenetics of Paclitaxel in the Treatment of Ovarian Cancer – a Pilot Study in Preparation of Individualized Chemotherapy
    Åpne denne publikasjonen i ny fane eller vindu >>Pharmacogenetics of Paclitaxel in the Treatment of Ovarian Cancer – a Pilot Study in Preparation of Individualized Chemotherapy
    Vise andre…
    2007 (engelsk)Inngår i: Clinical Cancer Research, ISSN 1078-0432Artikkel i tidsskrift (Fagfellevurdert) Submitted
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-14245 (URN)
    Tilgjengelig fra: 2007-01-26 Laget: 2007-01-26 Sist oppdatert: 2015-02-03
  • 82.
    Green, Henrik
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi.
    Pharmacogenomics of importance for paclitaxel chemotherapy2008Inngår i: Pharmacogenomics (London), ISSN 1462-2416, E-ISSN 1744-8042, Vol. 9, nr 6, s. 671-674Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Paclitaxel (Taxol®) has a broad activity spectrum and is clinically used, often in combination with carboplatin, to treat breast, ovarian and lung cancer. The response to treatment and the severity of adverse drug reactions after chemotherapy varies greatly among individuals, and one of the most important factors responsible for these differences is now recognized to be the genetic variability. However, so far only genetic variants of ABCB1 have been indicated to be associated with response and pharmacokinetics of paclitaxel. Commercially, the patent on paclitaxel has expired: however, from a healthcare perspective, it would be beneficial to identify patients with risk of poor response or high risk of toxicity to reduce hospitalization costs. This artiicle focuses on the pharmacogenomic background for paclitaxel response and interindividual variability.

  • 83.
    Green, Henrik
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Jakobsen Falk, Ingrid
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Lotfi, Kourosh
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Paul, E
    Karolinska University Hospital.
    Hermansson, M
    Uppsala University.
    Rosenquist, R
    Uppsala University.
    Paul, C
    Karolinska University Hospital.
    Nahi, H
    Karolinska University Hospital.
    Association of ABCB1 polymorphisms with survival and in vitro cytotoxicty in de novo acute myeloid leukemia with normal karyotype2012Inngår i: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 12, nr 2, s. 111-118Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Overexpression of the multi-drug transporter P-glycoprotein, encoded by the ABCB1 gene, is a clinically relevant problem in acute myeloid leukemia (AML). Polymorphisms in ABCB1 might contribute to cancer risk and therapeutic response. We therefore investigated the influence of polymorphisms G1199A, C1236T, G2677T/A and C3435T on cancer susceptibility, in vitro cytotoxicity and overall survival in 100 de novo AML patients with normal karyotype. Patients with 1236C/C or 2677G/G genotypes showed poorer survival than patients with other genotypes (P = 0.03 and P = 0.02, respectively). Both these genotypes were significant factors for survival in multivariate analysis, along with age, NPM1 and FLT3 mutation status. In vitro cytotoxicity studies demonstrated that leukemic cells from 1236T/T and 2677T/T patients were significantly more susceptible to mitoxantrone (P 0.02), and tended to be more susceptible to etoposide and daunorubicin (P = 0.07-0.09), but not to cytarabine. No significant difference in allele frequencies was found between patients and healthy volunteers (n = 400).

  • 84.
    Green, Henrik
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi.
    Lotfi, Kourosh
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi.
    Zackrisson, Anna Lena
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi.
    Peterson, Curt
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Spontaneous Reversal of P-Glycoprotein Expression in Multidrug Resistant Cell Lines2003Inngår i: Pharmacology and Toxicology, ISSN 0901-9928, E-ISSN 1600-0773, Vol. 93, nr 6, s. 297-304Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Increased expression of P-glycoprotein encoded by the mdr-1 gene is a well-characterised mechanism for resistance to cancer chemotherapeutic drugs in cell lines. However, the P-glycoprotein expression after removal of the selection pressure has not fully been elucidated. The stability of P-glycoprotein expression in the presence (+) and absence (-) of vincristine (30 or 150 nM) was studied in multidrug resistant K562 cell lines (VCR30+, VCR150+, VCR30- and VCR150-) for 11 months. The P-glycoprotein protein and mdr-1 mRNA levels were determined at regular intervals using flow cytometry and real-time PCR, respectively. Chemosensitivity to a panel of antineoplastic drugs was measured using an MTT assay. The presence of vincristine (VCR30+ and VCR150+) resulted in high and stable levels of P-glycoprotein and mdr-1 mRNA during the whole period compared to wild type. As for the VCR30- and VCR150- subcultures, the expressions of P-glycoprotein and mdr-1 mRNA were stable for five months, and then the levels decreased rapidly. Concomitantly, the sensitivity to drugs known as P-glycoprotein substrates was restored. In conclusion, resistant cells growing in the presence of the inducing drug have a stable P-glycoprotein expression and resistance level, but removing the inducing drug may result in a sudden and rapid lowering of P-glycoprotein and mdr-1 mRNA levels as long as five months after drug withdrawal.

  • 85.
    Green, Henrik
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi.
    Peterson, Curt
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Söderkvist, Peter
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi.
    Rosenberg, Per
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Horvath, G.
    Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden.
    In response [2]2006Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 12, nr 13, s. 4127-4129Annet (Annet vitenskapelig)
    Abstract [en]

    [No abstract available]

  • 86.
    Green, Henrik
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Rosenberg, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Horvath, György
    Department of Oncology, Sahlgrenska Academy at Göteborg University, Gothenburg, Sweden.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    β-tubulin mutations in ovarian cancer using single strand conformation analysis – risk of false positive results from paraffin embedded tissues2006Inngår i: Cancer Letters, ISSN 0304-3835, Vol. 236, nr 1, s. 148-154Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mutations in the β-tubulin gene have been proposed as a resistance mechanism to paclitaxel. We therefore investigated the presence of mutations in the β-tubulin M40 gene in 40 ovarian tumours (16 paraffin-embedded and 24 freshly frozen) selected for good or poor response to chemotherapy with paclitaxel or non-tubulin-affecting regimens. The presence of mutations was investigated using single strand conformation analysis followed by sequencing of the products with altered mobility. No sequence variants in the exons of the β-tubulin M40 gene were detected. Non-reproducible shifts were identified, in eight out of 16 paraffin embedded samples. This may explain some of the previously published discrepancies. In conclusion, sequence variants in the β-tubulin M40 gene are rare and are unlikely to be a clinically relevant explanation of resistance to paclitaxel.

  • 87.
    Green, Henrik
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Skoglund, Karin
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Rommel, Franz
    Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Hematologiska kliniken US.
    Mirghani, Rajaa A
    Karolinska University Hospital.
    Lotfi, Kourosh
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    CYP3A activity influences imatinib response in patients with chronic myeloid leukemia: a pilot study on in vivo CYP3A activity2010Inngår i: EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, ISSN 0031-6970, Vol. 66, nr 4, s. 383-386Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Imatinib is currently used for the treatment of chronic myeloid leukemia (CML). The main metabolite CGP74588 has similar potency to that of imatinib and is a product of CYP3A4 and CYP3A5 metabolism. However, the clinical significance of the metabolism on therapeutic response and pharmacokinetics is still unclear. We designed this study to investigate the role of the CYP3A activity in the response to imatinib therapy. Fourteen CML patients were phenotyped for in vivo CYP3A activity using quinine as a probe drug. The plasma concentration ratio of quinine and its CYP3A metabolite was used for assessing CYP3A activity. The patients were divided into complete molecular responders with undetectable levels of BCR-ABL transcripts after 12 months of therapy and into partial molecular responders who had failed to achieve a complete molecular response. Patients that achieved complete molecular response showed significantly (Mann-Whitney U-test, p = 0.013) higher in vivo CYP3A activity (median quinine metabolic ratio = 10.1) than patients achieving partial molecular response (median = 15.9). These results indicate a clinical significance of the CYP3A activity and its metabolic products in CML patients treated with imatinib.

  • 88.
    Green, Henrik
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Stål, Olle
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Bachmeier, K
    Central Hospital, Karlstad.
    Bäcklund, L M
    Karolinska University Hospital, Stockholm.
    Carlsson, L
    District Hospital, Sundsvall.
    Hansen, J
    Central Hospital, Karlstad.
    Lagerlund, M
    District Hospital, Kalmar.
    Norberg, B
    District Hospital, Jönköping.
    Franzén, A
    MSD Sweden, Stockholm.
    Åleskog, A
    MSD Sweden, Stockholm.
    Malmström, Annika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Närsjukvården i centrala Östergötland, LAH Linköping.
    Pegylated liposomal doxorubicin as first-line monotherapy in elderly women with locally advanced or metastatic breast cancer: Novel treatment predictive factors identified2011Inngår i: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 313, nr 2, s. 145-153Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We investigated the efficacy and safety of single-agent pegylated liposomal doxorubicin (PLD) as first-line treatment for elderly women with advanced breast cancer and evaluated predictive markers for response and toxicity. Twenty-five women ⩾65years received 40mg/m(2) PLD every 28days. Time to treatment failure (TTF), response rate, time to progression (TTP) and overall survival (OS) was calculated. The ABCB1 single nucleotide polymorphisms (SNP), tumor MRN complex, and TOPOIIα were analyzed. A mean of 7.4 cycles PLD were administered and TTF was 5.5months and OS 20.6months. ABCB1 SNPs were found to correlate to both efficacy and toxicity, while tumor expression of the MRN complex and TOPOIIα correlated to TTP. PLD is a safe and effective treatment for elderly breast cancer patients. Also potential predictive markers were identified.

  • 89.
    Green, Henrik
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Suleman Khan, Muhammad
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Jakobsen Falk, Ingrid
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Åvall-Lundqvist, Elisabeth
    Karolinska University of Hospital.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Impact of CYP3A5(*)3 and CYP2C8-HapC on Paclitaxel/Carboplatin-Induced Myelosuppression in Patients with Ovarian Cancer2011Inngår i: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 100, nr 10, s. 4205-4209Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The influence of genetic variants on paclitaxel-induced toxicity is of considerable interest for reducing adverse drug reactions. Recently, the genetic variants CYP2C8(*)3, CYP2C8-HapC, and CYP3A5(*)3 were associated with paclitaxel-induced neurotoxicity. We, therefore, investigated the impact of CYP2C8-HapC and CYP3A5(*)3 on paclitaxel/carboplatin-induced myelosuppression and neurotoxicity. Thirty-three patients from a prospective pharmacokinetics study were genotyped using pyrosequencing. Patients with variant alleles of CYP2C8-HapC were found to have significantly lower nadir values of both leukocytes and neutrophils (p andlt; 0.05) than patients with the wild-type genotype. CYP3A5(*)3/(*)1 patients were shown to have borderline, significantly lower nadir values of leukocytes (p = 0.07) than (*)3/(*)3 patients. Combining the two genotypes resulted in a significant correlation with both leukopenia and neutropenia (p = 0.01). No effect of these genetic variants on neurotoxicity could be shown in this rather small study, but their importance for paclitaxel-induced toxicity could be confirmed.

  • 90.
    Green, Henrik
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Rosenberg, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Horvath, Grörgy
    Department of Oncology Sahlgrenska Academy at Göteborg University, Gothenburg.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    ABCB1 G1199A polymorphism and ovarian cancer response to paclitaxel2008Inngår i: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 97, nr 6, s. 2045-2048Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    P-glycoprotein (P-gp), encoded by the ABCB1 gene, confers multi-drug resistance to a variety of antineoplastic agents, for example, paclitaxel. Recently, the G1199T/A polymorphism in the ABCB1 gene was shown to be important for the function of P-gp as well as for the resistance to several chemotherapeutic agents in vitro. We analyzed the allelic distribution of the G1199T/A and other polymorphisms in exons 11 and 12 of the ABCB1 gene in ovarian cancer patients treated with paclitaxel and carboplatin in order to evaluate their predictive value in vivo. The SNPs C1236T, G1199T/A, and A1308G were determined using Pyrosequencing in 51 patients with advanced ovarian cancer and correlated to the progression free survival. The G1199T/A SNP was found to affect the progression free survival. Although only two heterozygous (G/A) patients were found their mean progression free survival was only 2 months as compared to 19 months for the wild-type patients. This is in accordance with the higher resistance for the 1199A genetic variant found in vitro. Genotyping of the ABCB1 gene may be important for determining the tumor resistance to paclitaxel and provide useful information for individualized therapy.  

  • 91.
    Green, Henrik
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Rosenberg, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Horvath, György
    Department of Oncology, Sahlgrenska Academy at Göteborg University, Gothenburg, Sweden.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    mdr-1 single nucleotide polymorphisms in ovarian cancer tissue – G2677T/A correlates with response to paclitaxel chemotherapy2006Inngår i: Clinical Cancer Research, ISSN 1078-0432, Vol. 12, nr 3 pt 1, s. 854-859Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: P-glycoprotein, encoded by the mdr-1 gene, confers multidrug resistance to a variety of antineoplastic agents, e.g., paclitaxel. Recently, different polymorphisms in the mdr-1 gene have been identified and their consequences for the function of P-glycoprotein, as well as for the treatment response to P-glycoprotein substrates, are being clarified. We analyzed the allelic frequencies at polymorphic sites G2677T/A and C3435T in ovarian cancer patients with good or poor response to treatment with paclitaxel in combination with carboplatin in order to evaluate their predictive values.

    Experimental Design: Fifty-three patients were included in the study; 28 of them had been relapse-free for at least 1 year and 25 had progressive disease or relapsed within 12 months. A reference material consisting of 200 individuals was also analyzed. The genotypes of each single nucleotide polymorphism (SNP) were determined using Pyrosequencing.

    Results: The G2677T/A SNP was found to significantly correlate with treatment outcome. The probability of responding to paclitaxel treatment was higher in homozygously mutated patients (T/T or T/A; Fisher's exact test; P < 0.05). The frequency of the T or A alleles was also higher in the group of patients who had a good response (P < 0.05). There was also a dose-dependent influence of the number of mutated alleles on the response to paclitaxel treatment (Χ2 test for linear-by-linear association; P = 0.03). However, the C3435T SNP was not found to correlate to treatment outcome.

    Conclusions: The mdr-1 polymorphism G2677T/A in exon 21 correlates with the paclitaxel response in ovarian cancer and may be important for the function of P-glycoprotein and resistance to paclitaxel and provide useful information for individualized therapy.

  • 92.
    Green, Henrik
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Rosenberg, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiskt centrum.
    Mirghani, Rajaa A
    Karolinska University .
    Rymark, Per
    Västerås Hospital.
    Åvall Lundqvist, Elisabeth
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Karolinska University Hospital.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Tekniska högskolan. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiskt centrum.
    Pharmacogenetic Studies of Paclitaxel in the Treatment of Ovarian Cancer2009Inngår i: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 104, nr 2, s. 130-137Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The purpose of this study was to evaluate the role of sequence variants in the CYP2C8, ABCB1 and CYP3A4 genes and the CYP3A4 phenotype for the pharmacokinetics and toxicity of paclitaxel in ovarian cancer patients. Thirty-eight patients were treated with paclitaxel and carboplatin. The genotypes of CYP2C8*1B, *1C, *2, *3, *4, *5, *6, *7, *8 and P404A, ABCB1 G2677T/A and C3435T, as well as CYP3A4*1B, were determined by pyrosequencing. Phenotyping of CYP3A4 was performed in vivo with quinine as a probe. The patients were monitored for toxicity and 23 patients underwent a more extensive neurotoxicity evaluation. Patients heterozygous for G/A in position 2677 in ABCB1 had a significantly higher clearance of paclitaxel than most other ABCB1 variants. A lower clearance of paclitaxel was found for patients heterozygous for CYP2C8*3 when stratified according to the ABCB1 G2677T/A genotype. In addition, the CYP3A4 enzyme activity in vivo affected which metabolic pathway was dominant in each patient, but not the total clearance of paclitaxel. The exposure to paclitaxel correlated to the degree of neurotoxicity. Our findings suggest that interindividual variability in paclitaxel pharmacokinetics might be predicted by ABCB1 and CYP2C8 genotypes and provide useful information for individualized chemotherapy.

  • 93.
    Green, Henrik
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Söderkvist, Peter
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Rosenberg, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Mirghani, Rajaa A.
    Rymark, Per
    Åvall-Lundqvist, Elisabeth
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Pharmacogenetics of Paclitaxel in the Treatment of Ovarian Cancer – a Pilot Study in Preparation of Individualized Chemotherapy2007Inngår i: Clinical Cancer Research, ISSN 1078-0432Artikkel i tidsskrift (Fagfellevurdert)
  • 94.
    Green, Henrik
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Vretenbrant (Öberg), Karin
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Norlander, Björn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Measurement of paclitaxel and its metabolites in human plasma using liquid chromatography/ion trap mass spectrometry with a sonic spray ionization interface2006Inngår i: Rapid Communications in Mass Spectrometry, ISSN 1097-0231, Vol. 20, nr 14, s. 2183-2189Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A quantitative liquid chromatography/ion trap mass spectrometry method for the simultaneous determination of paclitaxel, 6α-hydroxypaclitaxel and p-3'-hydroxypaclitaxel in human plasma has been developed and validated. 6α-,p-3'-Dihydroxypaclitaxel was also quantified using paclitaxel as a reference and docetaxel as an internal standard. The substances were extracted from 0.500 mL plasma using solid-phase extraction. The elution was performed with acetonitrile and the samples were reconstituted in the mobile phase. Isocratic high-performance liquid chromatography analysis was performed by injecting 50 µL of reconstituted material onto a 100 × 3.00 mm C12 column with a methanol:1% trifluoroacetic acid/ammonium trifluoroacetate in H2O 70:30 mobile phase at 350 µL/min. The [M+H]+ ions generated in the sonic spray ionization interface were isolated and fragmented using two serial mass spectrometric methods: one for paclitaxel (transition 854 → 569 & 551) and the dihydroxymetabolite (transition 886 → 585 & 567) and one for the hydroxy metabolites (transition 870 → 585 & 567; transition 870 → 569 & 551) and docetaxel ([M+Na]+, transition 830 → 550). Calibration curves were created ranging between 0.5 and 7500 ng/mL for paclitaxel, 0.5 and 750 ng/mL for 6α-hydroxypaclitaxel, and 0.5 and 400 ng/mL for p-3'-hydroxypaclitaxel. Adduct ion formation was noted and investigated during method development and controlled by mobile phase optimization. In conclusion, a sensitive method for simultaneous quantification of paclitaxel and its metabolites suitable for analysis in clinical studies was obtained.

  • 95. Bestill onlineKjøp publikasjonen >>
    Gregers, Jannie
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Pharmacogenetic studies in childhood acute lymphoblastic leukaemia with primary focus on methotrexate2012Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Childhood acute lymphoblastic leukaemia is the most common type of cancer in children. Improvement in treatment has increased survival to approximately 85 per cent. Pharmacogenetics can influence the disposition of anticancer agents and can ideally be used as tool to further improve treatment based on the individual child’s pharmacogenetic profile.

    The hypothesis in this thesis was that polymorphisms in genes responsible for MTX influx (SLC19A1), efflux (ABCB1, studies with MTX monotherapy have demonstrated effect of variations in this gene) or other MTX pathways (ATIC, MTHFR and SHMT) could have impact on efficacy in childhood acute lymphoblastic leukaemia.

    The uptake of MTX and impact of SLC19A1 80G>A was investigated in vitro and showed that SLC19A1 80GG had decreased uptake in CD+ T cells and B cells caused by reduced capacity on receptor-to-receptor basis.

    In more than 500 patients the clinical effect of SLC19A1 80G>A genotype was evaluated and showed that patients with the SLC19A1 80AA had better survival, more bone marrow toxicity, but less liver toxicity than patients with SLC19A1 80GG or 80GA variants. Furthermore, it was demonstrated that SLC19A1 80G>A interacts with chromosome 21 copy number in the leukemic clone.

    The clinical impact of ABCB1 1199G>A, 1236C>T, 2677G<T/A and 3435C>T on the treatment was evaluated. Patients with either the 1199GA or the 3435CC variant had increased risk of relapse compared to patients with the 1199GG or 3435CT/TT variants, respectively. Toxicity was also affected by the ABCB1 polymorphisms.

    No association between polymorphisms in the ATIC, MTHFR and SHMT genes and outcome was seen. However the 677C>T and 1298 C>A in the MTHFR gene were associated with toxicity.

    The genotype frequencies between healthy donors and patients were compared, but no association to risk of developing cancer was seen in the investigated polymorphisms.

    The results in this thesis emphasise the importance of including pharmacogenetic markers in attempts to improve outcome and reduced side effects in childhood ALL.

    Delarbeid
    1. Reduced folate carrier polymorphism determines methotrexate uptake by B cells and CD4+ T cells
    Åpne denne publikasjonen i ny fane eller vindu >>Reduced folate carrier polymorphism determines methotrexate uptake by B cells and CD4+ T cells
    2008 (engelsk)Inngår i: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 47, nr 4, s. 451-453Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    OBJECTIVE: To examine if polymorphism 80G --> A in the Reduced Folate Carrier (RFC) affects uptake of MTX in B- and CD4+ T-cells.

    METHODS: Mononuclear cells were isolated from peripheral blood of healthy persons. Real-time PCR was used to detect the RFC80 variants. FITC-labelled MTX was added to cells stimulated with Candida albicans or tetanus toxoid, and the uptake of MTX was measured by flow cytometry. A FITC-conjugated monoclonal antibody against RFC was used to detect the cellular RFC expression.

    RESULTS: Antigen-stimulated CD4+ T cells and B cells from individuals with the GG variant (n = 9) exhibited lower uptake of MTX than individuals expressing the AA variant (n = 8), or the GA variant (n = 8). No difference could be demonstrated between the three groups with respect to the expression of RFC by CD4+ T cells and B cells, and CD4+ T cells from individuals homozygous for the G allele exhibited lower uptake of MTX per receptor than CD4+ T cells from individuals homozygous for the A allele.

    CONCLUSION: MTX is taken up more efficiently via the A allele than via the G allele. This difference between the variant forms of RFC suggests that genotyping could be relevant for determining the relevant dosage of MTX in the treatment of neoplastic and autoimmune disease.

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-77610 (URN)10.1093/rheumatology/ken073 (DOI)18316334 (PubMedID)
    Tilgjengelig fra: 2012-05-24 Laget: 2012-05-24 Sist oppdatert: 2017-12-07bibliografisk kontrollert
    2. The association of reduced folate carrier 80G greater than A polymorphism to outcome in childhood acute lymphoblastic leukemia interacts with chromosome 21 copy number
    Åpne denne publikasjonen i ny fane eller vindu >>The association of reduced folate carrier 80G greater than A polymorphism to outcome in childhood acute lymphoblastic leukemia interacts with chromosome 21 copy number
    Vise andre…
    2010 (engelsk)Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 115, nr 23, s. 4671-4677Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The reduced folate carrier (RFC) is involved in the transport of methotrexate (MTX) across the cell membrane. The RFC gene (SLC19A1) is located on chromosome 21, and we hypothesized that the RFC80 G greater than A polymorphism would affect outcome and toxicity in childhood leukemia and that this could interact with chromosome 21 copy number in the leukemic clone. A total of 500 children with acute lymphoblastic leukemia treated according to the common Nordic treatment protocols were included, and we found that the RFC AA variant was associated with a 50% better chance of staying in remission compared with GG or GA variants (P = .046). Increased copy numbers of chromosome 21 appear to improve outcome also in children with GA or GG variant. In a subset of 182 children receiving 608 high-dose MTX courses, we observed higher degree of bone marrow toxicity in patients with the RFC AA variant compared with GA/GG variants (platelet 73 vs 99/105 x 10(9)/L, P = .004, hemoglobin 5.6 vs 5.9/6.0 mmol/L, P = .004) and a higher degree of liver toxicity in patients with RFC GG variant (alanine aminotransferase 167 vs 127/124 U/L, P = .05). In conclusion, the RFC 80G greater than A polymorphism interacts with chromosome 21 copy numbers and affects both efficacy and toxicity of MTX.

    sted, utgiver, år, opplag, sider
    American Society of Hematology, 2010
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-58380 (URN)10.1182/blood-2010-01-256958 (DOI)000278635900013 ()
    Merknad
    Original Publication: Jannie Gregers, Ib Jarle Christensen, Kim Dalhoff, Birgitte Lausen, Henrik Schroeder, Steen Rosthoej, Niels Carlsen, Kjeld Schmiegelow and Curt Peterson, The association of reduced folate carrier 80G>A polymorphism to outcome in childhood acute lymphoblastic leukemia interacts with chromosome 21 copy number, 2010, Blood, (115), 23, 4671-4677. http://dx.doi.org/10.1182/blood-2010-01-256958 Copyright: American Society of Hematology http://www.hematology.org/Tilgjengelig fra: 2010-08-13 Laget: 2010-08-11 Sist oppdatert: 2017-12-12bibliografisk kontrollert
    3. Polymorphisms in the ABCB1 gene affect outcome and toxicity in Childhood Acute Lymphoblastic Leukemia
    Åpne denne publikasjonen i ny fane eller vindu >>Polymorphisms in the ABCB1 gene affect outcome and toxicity in Childhood Acute Lymphoblastic Leukemia
    Vise andre…
    2012 (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    The membrane transporter P-glycoprotein, encoded by the ABCB1 gene, influences pharmacokinetics in several anti-cancer drugs. We hypothesized that 1199G>A, 1236C>T, 2677G>A/T and 3435C>T variants of ABCB1 could affect outcome and toxicity in childhood acute lymphoblastic leukemia (ALL), since treatment includes known P-glycoprotein substrates and 3435C/T may affect methotrexate therapy.

    We studied 522 Danish children with ALL treated according to NOPHO ALL92 and ALL2000 protocols, 93% of all those eligible during 1992-2007. Risk of relapse was 2.9-fold increased for 41 patients with the 1199GA variant compared to 477 with 1199GG (p=0.001), and reduced by 61% and 40%, respectively for 421 patients with the 3435CT or 3435TT variants compared to 96 with 3435CC (overall p=0.02).

    Degree of bone marrow toxicity during doxorubicin, vincristine and prednisolone induction therapy was higher in 71 patients with 3435TT variant (median nadirs: hemoglobin 3% and platelets 34/37% lower in3435CT/3435CC) compared to 160 patients with 3435CT/3435CC (Hemoglobin p=0.01 and platelets p<0.0001).

    We observed more liver toxicity after high-dose methotrexate in 109 patients with 3435CC variant versus 3435CT/TT (Median max alanineaminotransferase: 280 versus 142/111 U/L, p=0.03). In conclusion, there is a statistically significant association between ABCB1 polymorphisms and efficacy and toxicity in childhood ALL.

    Emneord
    Acute lymphoblastic leukemia; ABCB1; MDR1; P-glycoprotein; Polymorphism; Relapse; Toxicity
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-77618 (URN)
    Tilgjengelig fra: 2012-05-24 Laget: 2012-05-24 Sist oppdatert: 2012-05-24bibliografisk kontrollert
    4. Pharmacogenetic polymorphisms in folate metabolism affect toxicity after high dose methotrexate in childhood acute lymphoblastic leukemia
    Åpne denne publikasjonen i ny fane eller vindu >>Pharmacogenetic polymorphisms in folate metabolism affect toxicity after high dose methotrexate in childhood acute lymphoblastic leukemia
    Vise andre…
    2012 (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    We hypothesized that polymorphisms in folate metabolism would affect treatment effects of the folate antagonist methotrexate (MTX). We studied whether ATIC347C>T, MTHFR677C>T, MTHFR1298C>A and SHMT1-1420C>T polymorphisms influence risk of disease or efficacy and toxicity of MTX in a large population of children with acute lymphoblastic leukaemia (ALL). The children were treated after standardized Nordic protocols with 5-8 g/m2 high-dose MTX courses and long term oral maintenance therapy with weekly MTX. Ninety-four percent (n=533) of the children diagnosed during a 16 year time period were included. The study showed that the polymorphisms had no effect on risk of ALL, MTX pharmacokinetics or outcome. However after high-dose MTX treatment, patients with MTHFR677TT/MTHFR677CT had more liver toxicity than patients with MTHFR677CC (alanine transferase: 174/154 versus 115U/L, p=0.049). Patients with MTHFR1298AA had more liver toxicity than patients with MTHFR1298CC (alanine transferase: 144 versus 108 U/L, p=0.04). More bone marrow toxicity was found in patients with MTHFR1298CC compared to MTHFR1298CT / MTHFR1298AA (Nadir means: Platelets 72 versus 109/93*109/L, p=0.0001).

    In conclusion this study supports that MTHFR1298C>A and MTHFR677C>T are associated with toxicity in MTX treatment and the MTHFR variants should be considered as markers for individualization of treatment in childhood ALL in combination with other pharmacogenetic markers.

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-77622 (URN)
    Tilgjengelig fra: 2012-05-24 Laget: 2012-05-24 Sist oppdatert: 2012-05-24bibliografisk kontrollert
  • 96.
    Gregers, Jannie
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Gréen, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Jarle Christensen, Ib
    Rigshospital, Copenhagen, Denmark.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Dalhoff, Kim
    Department of Clinical Pharmacology, Bispebjerg Hospital, Copenhagen, Denmark.
    Schroeder, Henrik
    Department of Pediatric, the University Hospital in Skejby, Aarhus, Denmark.
    Carlsen, Niels
    Department of Pediatric, the University Hospital in Odense, Denmark.
    Rosthoej, Steen
    Department of Pediatric, the University Hospital in Aalborg, Denmark.
    Lausen, Birgitte
    Department of Pediatric, Rigshospitalet, the University Hospital in Copenhagen, Denmark.
    Schmiegelow, Kjeld
    Institute of Gynecology, Obstetrics, and Pediatrics, The Medical Faculty, University of Copenhagen, Denmark.
    Polymorphisms in the ABCB1 gene affect outcome and toxicity in Childhood Acute Lymphoblastic Leukemia2012Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    The membrane transporter P-glycoprotein, encoded by the ABCB1 gene, influences pharmacokinetics in several anti-cancer drugs. We hypothesized that 1199G>A, 1236C>T, 2677G>A/T and 3435C>T variants of ABCB1 could affect outcome and toxicity in childhood acute lymphoblastic leukemia (ALL), since treatment includes known P-glycoprotein substrates and 3435C/T may affect methotrexate therapy.

    We studied 522 Danish children with ALL treated according to NOPHO ALL92 and ALL2000 protocols, 93% of all those eligible during 1992-2007. Risk of relapse was 2.9-fold increased for 41 patients with the 1199GA variant compared to 477 with 1199GG (p=0.001), and reduced by 61% and 40%, respectively for 421 patients with the 3435CT or 3435TT variants compared to 96 with 3435CC (overall p=0.02).

    Degree of bone marrow toxicity during doxorubicin, vincristine and prednisolone induction therapy was higher in 71 patients with 3435TT variant (median nadirs: hemoglobin 3% and platelets 34/37% lower in3435CT/3435CC) compared to 160 patients with 3435CT/3435CC (Hemoglobin p=0.01 and platelets p<0.0001).

    We observed more liver toxicity after high-dose methotrexate in 109 patients with 3435CC variant versus 3435CT/TT (Median max alanineaminotransferase: 280 versus 142/111 U/L, p=0.03). In conclusion, there is a statistically significant association between ABCB1 polymorphisms and efficacy and toxicity in childhood ALL.

  • 97.
    Gregers, Jannie
    et al.
    University of Copenhagen, Denmark.
    Jarle Christensen, Ib
    Rigshospital, Copenhagen, Denmark.
    Dalhoff, Kim
    Bispebjerg Hospital.
    Lausen, Birgitte
    Rigshospital, Copenhagen, Denmark.
    Schroeder, Henrik
    Rigshospital, Copenhagen, Denmark.
    Rosthoej, Steen
    Rigshospital, Aalborg, Denmark.
    Carlsen, Niels
    Rigshospital, Odense, Denmark.
    Schmiegelow, Kjeld
    University of Copenhagen, Denmark.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    The association of reduced folate carrier 80G greater than A polymorphism to outcome in childhood acute lymphoblastic leukemia interacts with chromosome 21 copy number2010Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 115, nr 23, s. 4671-4677Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The reduced folate carrier (RFC) is involved in the transport of methotrexate (MTX) across the cell membrane. The RFC gene (SLC19A1) is located on chromosome 21, and we hypothesized that the RFC80 G greater than A polymorphism would affect outcome and toxicity in childhood leukemia and that this could interact with chromosome 21 copy number in the leukemic clone. A total of 500 children with acute lymphoblastic leukemia treated according to the common Nordic treatment protocols were included, and we found that the RFC AA variant was associated with a 50% better chance of staying in remission compared with GG or GA variants (P = .046). Increased copy numbers of chromosome 21 appear to improve outcome also in children with GA or GG variant. In a subset of 182 children receiving 608 high-dose MTX courses, we observed higher degree of bone marrow toxicity in patients with the RFC AA variant compared with GA/GG variants (platelet 73 vs 99/105 x 10(9)/L, P = .004, hemoglobin 5.6 vs 5.9/6.0 mmol/L, P = .004) and a higher degree of liver toxicity in patients with RFC GG variant (alanine aminotransferase 167 vs 127/124 U/L, P = .05). In conclusion, the RFC 80G greater than A polymorphism interacts with chromosome 21 copy numbers and affects both efficacy and toxicity of MTX.

  • 98.
    Gregers, Jannie
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Jarle Christensen, Ib
    The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark and Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Denmark.
    Dalhoff, Kim
    Department of Clinical Pharmacology, Bispebjerg Hospital, Copenhagen, Denmark.
    Schroeder, Henrik
    Department of Pediatric, the University Hospital in Skejby, Aarhus, Denmark.
    Carlsen, Niels
    Department of Pediatric, the University Hospital in Odense, Denmark.
    Rosthoej, Steen
    Department of Pediatric, the University Hospital in Aalborg, Denmark.
    Lausen, Birgitte
    Department of Pediatric, Rigshospitalet, the University Hospital in Copenhagen, Denmark.
    Schmiegelow, Kjeld
    Institute of Gynecology, Obstetrics, and Pediatrics, The Medical Faculty, University of Copenhagen, Denmark.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Pharmacogenetic polymorphisms in folate metabolism affect toxicity after high dose methotrexate in childhood acute lymphoblastic leukemia2012Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    We hypothesized that polymorphisms in folate metabolism would affect treatment effects of the folate antagonist methotrexate (MTX). We studied whether ATIC347C>T, MTHFR677C>T, MTHFR1298C>A and SHMT1-1420C>T polymorphisms influence risk of disease or efficacy and toxicity of MTX in a large population of children with acute lymphoblastic leukaemia (ALL). The children were treated after standardized Nordic protocols with 5-8 g/m2 high-dose MTX courses and long term oral maintenance therapy with weekly MTX. Ninety-four percent (n=533) of the children diagnosed during a 16 year time period were included. The study showed that the polymorphisms had no effect on risk of ALL, MTX pharmacokinetics or outcome. However after high-dose MTX treatment, patients with MTHFR677TT/MTHFR677CT had more liver toxicity than patients with MTHFR677CC (alanine transferase: 174/154 versus 115U/L, p=0.049). Patients with MTHFR1298AA had more liver toxicity than patients with MTHFR1298CC (alanine transferase: 144 versus 108 U/L, p=0.04). More bone marrow toxicity was found in patients with MTHFR1298CC compared to MTHFR1298CT / MTHFR1298AA (Nadir means: Platelets 72 versus 109/93*109/L, p=0.0001).

    In conclusion this study supports that MTHFR1298C>A and MTHFR677C>T are associated with toxicity in MTX treatment and the MTHFR variants should be considered as markers for individualization of treatment in childhood ALL in combination with other pharmacogenetic markers.

  • 99.
    Gréen, Anna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Sarg, Bettina
    Division of Clinical Biochemistry, Biocenter, Innsbruck Medical University, Fritz-Pregl-Strasse 3, A-6020 Innsbruck, Austria.
    Gréen, Henrik
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi.
    Lönn, Anita
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi.
    Lindner, Herbert
    Division of Clinical Biochemistry, Biocenter, Innsbruck Medical University, Fritz-Pregl-Strasse 3, A-6020 Innsbruck, Austria.
    Rundquist, Ingemar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Histone H1 interphase phosphorylation pattern becomes largely established during G1/S transition in proliferating cellsManuskript (Annet vitenskapelig)
    Abstract [en]

    Histone H1 is an important constituent of chromatin, and is believed to be involved in regulation of chromatin structure. During the cell cycle, chromatin becomes locally decondensed in S phase, highly condensed during metaphase and again decondensed before re-entry into G1. This has been connected to increasing phosphorylation of H1 histones during the cell cycle. However, many of these experiments have been performed in non-human and human cancer   cell lines, and by the use of cell synchronization techniques and cell cycle-arresting drugs. In this study, we have investigated the H1 subtype composition and phosphorylation pattern in the cell cycle. Exponentially growing normal human activated T cells and Jurkat lymphoblastoid cells were sorted by fluorescence activated cell sorting into G1, S and G2/M populations, without the use of cell cycle arresting drugs. We found that the H1.5 protein level increased after T-cell activation. Our data indicate that serine phosphorylation of H1 subtypes occurred to a large extent in late G1 phase or early S, while some additional serine phosphorylation took place during S, G2 and M phases. Furthermore, our data suggest that the newly synthesized H1 molecules during S phase also achieve a similar phosphorylation pattern as the previous ones. Jurkat cells showed more extended H1.5 phosphorylation in G1 compared with T cells, a difference that can be explained by faster cell growth and/or the presence of enhanced H1 kinase activity in G1 in Jurkat cells. In conclusion, our data is consistent with a model where a major part of interphase H1 serine phosphorylation takes place within a narrow time window during the G1/Stransition. This implies that H1 serine phosphorylation may be coupled to changes in chromatin structure necessary for DNA replication.

  • 100.
    Gréen, Anna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Sarg, Bettina
    Innsbruck Medical University.
    Green, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Lönn, Anita
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Lindner, Herbert H
    Innsbruck Medical University.
    Rundquist, Ingemar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Histone H1 interphase phosphorylation becomes largely established in G(1) or early S phase and differs in G(1) between T-lymphoblastoid cells and normal T cells2011Inngår i: EPIGENETICS and CHROMATIN, ISSN 1756-8935, Vol. 4, nr 15Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Histone H1 is an important constituent of chromatin, and is involved in regulation of its structure. During the cell cycle, chromatin becomes locally decondensed in S phase, highly condensed during metaphase, and again decondensed before re-entry into G(1). This has been connected to increasing phosphorylation of H1 histones through the cell cycle. However, many of these experiments have been performed using cell-synchronization techniques and cell cycle-arresting drugs. In this study, we investigated the H1 subtype composition and phosphorylation pattern in the cell cycle of normal human activated T cells and Jurkat T-lymphoblastoid cells by capillary electrophoresis after sorting of exponentially growing cells into G(1), S and G(2)/M populations. less thanbrgreater than less thanbrgreater thanResults: We found that the relative amount of H1.5 protein increased significantly after T-cell activation. Serine phosphorylation of H1 subtypes occurred to a large extent in late G(1) or early S phase in both activated T cells and Jurkat cells. Furthermore, our data confirm that the H1 molecules newly synthesized during S phase achieve a similar phosphorylation pattern to the previous ones. Jurkat cells had more extended H1.5 phosphorylation in G(1) compared with T cells, a difference that can be explained by faster cell growth and/or the presence of enhanced H1 kinase activity in G(1) in Jurkat cells. less thanbrgreater than less thanbrgreater thanConclusion: Our data are consistent with a model in which a major part of interphase H1 phosphorylation takes place in G(1) or early S phase. This implies that H1 serine phosphorylation may be coupled to changes in chromatin structure necessary for DNA replication. In addition, the increased H1 phosphorylation of malignant cells in G(1) may be affecting the G(1)/S transition control and enabling facilitated S-phase entry as a result of relaxed chromatin condensation. Furthermore, increased H1.5 expression may be coupled to the proliferative capacity of growth-stimulated T cells.

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