liu.seSearch for publications in DiVA
Change search
Refine search result
12 1 - 50 of 52
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 1.
    Eriksson, Andreas C
    et al.
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Lotfi, Kourosh
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Whiss, Per A
    Linköping University, Department of Medicine and Health Sciences, Pharmacology . Linköping University, Faculty of Health Sciences.
    Enhanced platelet adhesion in essential thrombocythemia after in vitro activation2010In: TURKISH JOURNAL OF HEMATOLOGY, ISSN 1300-7777, Vol. 27, no 2, p. 82-90Article in journal (Refereed)
    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)

  • 2.
    Eriksson, Andreas
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Whiss, Per
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Correction: Enhanced platelet adhesion in essential thrombocythemia after in vitro activation (vol 27 pg 82, 2010)2010In: Turkish Journal of Hematology, ISSN 1300-7777, E-ISSN 1308-5263, Vol. 27, no 3, p. 223-223Article in journal (Other academic)
    Abstract [en]

    n/a

  • 3.
    Eriksson, Andreas
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Lotfi, Kourosh
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Whiss, Per A
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Pharmacology.
    Enhanced platelet adhesion in essential thrombocythemia assessed by a novel platelet function assay2005In: Congress of the European hematology association,2005, 2005Conference paper (Other academic)
  • 4.
    Frödin, Ulla
    et al.
    Linköping University, Department of Medical and Health Sciences, Nursing Science. Linköping University, Faculty of Health Sciences.
    Börjeson, Sussanne
    Linköping University, Department of Medical and Health Sciences, Nursing Science. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    Lyth, Johan
    Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pharmacology.
    A prospective evaluation of patients' health-related quality of life during auto-SCT: a 3-year follow-up2011In: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 46, no 10, p. 1345-1352Article in journal (Refereed)
    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.

  • 5.
    Frödin, Ulla
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Fomichov, Victoria
    Region Östergötland, Center for Health and Developmental Care, Regional Cancer Center South East Sweden.
    Juliusson, G.
    Lund University, Sweden; Lund University, Sweden.
    Börjeson, Sussanne
    Linköping University, Department of Medical and Health Sciences, Division of Nursing Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Frequent and long-term follow-up of health-related quality of life following allogeneic haematopoietic stem cell transplantation2015In: European Journal of Cancer Care, ISSN 0961-5423, E-ISSN 1365-2354, Vol. 24, no 6, p. 898-910Article in journal (Refereed)
    Abstract [en]

    Health-related quality of life (HRQL) was evaluated in 94 patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT) after myeloablative (MAC, n=18) or reduced intensity conditioning (RIC, n=76). HRQL was assessed with the EORTC QLQ C-30 during the inpatient period as well as during the following 3years, i.e. at baseline and 12 times thereafter. Functional status and global quality of life decreased from baseline to weeks 2 and 3, especially role and social functions. Symptoms increased significantly during the first 3weeks, particularly appetite loss, nausea and vomiting, diarrhoea and fatigue. It took at least 1year for HRQL to return to the baseline level. The only function that improved significantly 3years after HSCT was role function. Patients treated with MAC experienced significantly worse HRQL at baseline than patients treated with RIC, as well as more pain, sleep disturbance and appetite loss in weeks 3 and 4. Patients with extensive chronic graft-versus-host disease experienced reduced HRQL. These results provide a clinically useful overview of patients HRQL during and after HSCT and indicate when they require increased support. The results demonstrate the importance of close follow-ups during the first year after HSCT to improve preventive or supportive interventions.

  • 6.
    Frödin, Ulla
    et al.
    Linköping University, Department of Medical and Health Sciences, Nursing Science. Linköping University, Faculty of Health Sciences.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pharmacology.
    Fomichov, Victoria
    Östergötlands Läns Landsting, Centre for Health and Developmental Care, Regional Cancer Centre.
    Juliusson, Gunnar
    Department of Hematology and Coagulation, Skåne County Council, Stem Cell Center, Lund University, Lund, Sweden.
    Börjeson, Sussanne
    Linköping University, Department of Medical and Health Sciences, Nursing Science. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    Early and Long-Term Follow-Up of Health-Related Quality of Life Following Allogeneic Hematopoietic Stem-Cell Transplantation2013Manuscript (preprint) (Other academic)
    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.

  • 7.
    Fyrberg, Anna
    et al.
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences.
    Albertioni, Freidoun
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology.
    Lotfi, Kourosh
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Cell cycle effect on the activity of deoxynucleoside analogue metabolising enzymes2007In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 357, no 4, p. 847-853Article in journal (Refereed)
    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.

  • 8.
    Fyrberg, Anna
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology.
    Albertioni, Freidoun
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology.
    Lotfi, Kourosh
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Evidence of cell cycle-dependent regulation of Deoxycytidine kinase and Cytosolic 5-nucleotidase-I activity2005In: 10th European Society for the Study of Purine and Pyrimidine Metabolism in Man,2005, 2005Conference paper (Other academic)
  • 9.
    Fyrberg, Anna
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Albertioni, Freidoun
    Cancer Center Karolinska, Department of Oncology and Pathology, Karolinska University Hospital, Stockholm.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Haematology. Linköping University, Faculty of Health Sciences.
    RNAi Depletion of Deoxycytidine and Deoxyguanosine Kinase in Human Leukemic CEM Cells2008In: Nucleosides, Nucleotides & Nucleic Acids, ISSN 1525-7770, E-ISSN 1532-2335, Vol. 27, no 6-7, p. 712-719Article in journal (Refereed)
    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.

  • 10.
    Fyrberg, Anna
    et al.
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences.
    Albertioni, Freidoun
    Cancer Center Karolinska Department of Oncology and Pathology, Karolinska University Hospital, SE-171 76 Stockholm.
    Lotfi, Kourosh
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pharmacology.
    The role of deoxyguanosine kinase for nucleoside analog activation in leukemic and solid tumor cell linesManuscript (preprint) (Other academic)
    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.

  • 11.
    Fyrberg, Anna
    et al.
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Drug Research.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    NUCLEOSIDE ANALOG ACTIVITY IN MALIGNANT MELANOMA CELL LINES2015In: Nucleosides, Nucleotides & Nucleic Acids, ISSN 1525-7770, E-ISSN 1532-2335, Vol. 34, no 9, p. 639-649Article in journal (Refereed)
    Abstract [en]

    Mitochondrial deoxyguanosine kinase (dGK), is an enzyme responsible for activation of nucleoside analogs (NAs) to phosphorylated compounds which exert profound cytotoxicity, especially in hematological malignancies. Screening malignant melanoma cell lines against NAs revealed high sensitivity to several of them. This was believed to be due to the high levels of dGK expression in these cells. Downregulation of dGK in the melanoma cell line RaH5 using siRNA did not cause resistance to NAs as expected, but instead cells became more sensitive. This was probably partly due to the increased activity of another mitochondrial enzyme, thymidine kinase 2, seen in transfected cells.

  • 12.
    Fyrberg, Anna
    et al.
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences.
    Lotfi, Kourosh
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Optimization and evaluation of electroporation delivery of siRNA in the human leukemic CEM cell line2010In: CYTOTECHNOLOGY, ISSN 0920-9069, Vol. 62, no 6, p. 497-507Article in journal (Refereed)
    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.

  • 13.
    Fyrberg, Anna
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology.
    Mirzaee, S
    Lotfi, Kourosh
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Cell cycle dependent regulation of deoxycytidine kinase, deoxyguanosine kinase, and cytosolic 5′-nucleotidase I activity in MOLT-4 cells2006In: Nucleosides, Nucleotides & Nucleic Acids, ISSN 1525-7770, E-ISSN 1532-2335, Vol. 25, no 9-11, p. 1201-1204Article in journal (Refereed)
    Abstract [en]

    Activation of nucleoside analogues is dependent on kinases and 5′-nucleotidases and the balance between the activity of these enzymes. The purpose of this study was to analyze deoxycytidine kinase, deoxyguanosine kinase, and 4 different 5′-nucleotidases during cell cycle progression in MOLT-4 cells. The activity of both kinases was cell cycle dependent and increased during proliferation while the activity of cytosolic 5′-nucleotidase I decreased. We could show that the kinase activity was higher than the total nucleotidase activity, which was unchanged or decreased during cell cycle progression. These data may be important in designing modern combination therapy with nucleoside analogues. Copyright © Taylor & Francis Group, LLC.

  • 14.
    Fyrberg, Anna
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Peterson, Curt
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    Kågedal, Bertil
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Chemistry.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pharmacology.
    Induction of fetal hemoglobin and ABCB1 gene expression in 9-β-D-arabinofuranosylguanine-resistant MOLT-4 cells2011In: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 68, no 3, p. 583-591Article in journal (Refereed)
    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.

  • 15.
    Fyrberg, Anna
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Skoglund, Karin
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Wolk, M
    Israel Minist Health Central Labs, Israel .
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pharmacology.
    A potential role of fetal hemoglobin in the development of multidrug resistance2012In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 427, no 3, p. 456-460Article in journal (Refereed)
    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.

  • 16.
    Green, Henrik
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Jakobsen Falk, Ingrid
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    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 karyotype2012In: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 12, no 2, p. 111-118Article in journal (Refereed)
    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).

  • 17.
    Green, Henrik
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology .
    Lotfi, Kourosh
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology .
    Zackrisson, Anna Lena
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology .
    Peterson, Curt
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Spontaneous Reversal of P-Glycoprotein Expression in Multidrug Resistant Cell Lines2003In: Pharmacology and Toxicology, ISSN 0901-9928, E-ISSN 1600-0773, Vol. 93, no 6, p. 297-304Article in journal (Refereed)
    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.

  • 18.
    Green, Henrik
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology.
    Skoglund, Karin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology.
    Rommel, Franz
    Bertilsson, Leif
    KI, Stockholm.
    Lotfi, Kourosh
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Influence of CYP3A4 activity on imatinib response in paitents with chronic myeloid leukemia2006In: 11th congress of the European Heamtology Association,2006, 2006, p. 63-63Conference paper (Refereed)
    Abstract [en]

       

  • 19.
    Green, Henrik
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Skoglund, Karin
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Rommel, Franz
    Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Haematology UHL.
    Mirghani, Rajaa A
    Karolinska University Hospital.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    CYP3A activity influences imatinib response in patients with chronic myeloid leukemia: a pilot study on in vivo CYP3A activity2010In: EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, ISSN 0031-6970, Vol. 66, no 4, p. 383-386Article in journal (Refereed)
    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.

  • 20.
    Hjorth-Hansen, Henrik
    et al.
    St Olavs Hospital, Norway; Norwegian University of Science and Technology NTNU, Norway.
    Stenke, Leif
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Söderlund, Stina
    University of Uppsala Hospital, Sweden.
    Dreimane, Arta
    Linköping University, Department of Medical and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology. Linköping University, Faculty of Medicine and Health Sciences.
    Ehrencrona, Hans
    Skåne University Hospital, Sweden.
    Gedde-Dahl, Tobias
    University of Oslo, Norway.
    Tore Gjertsen, Bjorn
    Haukeland Hospital, Norway; University of Bergen, Norway.
    Hoglund, Martin
    University of Uppsala Hospital, Sweden.
    Koskenvesa, Perttu
    University of Helsinki, Finland; University of Helsinki, Finland.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Majeed, Waleed
    Stavanger University Hospital, Norway.
    Markevarn, Berit
    Umeå University Hospital, Sweden.
    Ohm, Lotta
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Olsson-Stromberg, Ulla
    University of Uppsala Hospital, Sweden.
    Remes, Kari
    Turku University, Finland.
    Suominen, Merja
    Kanta Hame Central Hospital, Finland.
    Simonsson, Bengt
    University of Uppsala Hospital, Sweden.
    Porkka, Kimmo
    University of Helsinki, Finland; University of Helsinki, Finland.
    Mustjoki, Satu
    University of Helsinki, Finland; University of Helsinki, Finland.
    Richter, Johan
    Skåne University Hospital, Sweden.
    Dasatinib induces fast and deep responses in newly diagnosed chronic myeloid leukaemia patients in chronic phase: clinical results from a randomised phase-2 study (NordCML006)2015In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 94, no 3, p. 243-250Article in journal (Refereed)
    Abstract [en]

    We randomised 46 newly diagnosed patients with chronic myeloid leukaemia (median age 56) to receive dasatinib 100mg QD or imatinib 400mg QD and report outcome as an intention-to-treat analysis with 36months follow-up. Early cytogenetic and molecular responses were superior in the dasatinib group, with a tendency that imatinib patients caught up with time. For instance, MR3.0 was reached at 3months in 36% vs. 8% (P=0.02), at 12months in 81% vs. 46% (P=0.02) and at 18months in 73% vs. 65% (n.s.) of the patients in the two groups. In contrast, MR4.5 was consistently superior in the dasatinib group at all time points from 6months onwards, reaching 61% vs. 21% (Pless than0.05) at 36months. Sixty-four vs. 71% of the patients in the dasatinib and imatinib arms, respectively, remained on assigned drug. Dasatinib dose was frequently reduced, but with maintained excellent effect. One imatinib patient progressed to blastic phase, but no CML-related deaths occurred. In conclusion, our data compare favourably with those of the dasatinib registration study, DASISION. The fast and deep molecular responses induced by dasatinib compared with imatinib may be exploited to increase the proportion of patients who can achieve a treatment-free remission after treatment discontinuation.

  • 21.
    Ilander, M.
    et al.
    University of Helsinki, Finland; Helsinki University Hospital, Finland.
    Olsson-Stromberg, U.
    Uppsala University Hospital, Sweden; Uppsala University, Sweden.
    Schlums, H.
    Karolinska Institute, Sweden.
    Guilhot, J.
    CHU Poitiers, France.
    Bruck, O.
    University of Helsinki, Finland; Helsinki University Hospital, Finland.
    Lahteenmaki, H.
    University of Helsinki, Finland; Helsinki University Hospital, Finland.
    Kasanen, T.
    University of Helsinki, Finland; Helsinki University Hospital, Finland.
    Koskenvesa, P.
    University of Helsinki, Finland; Helsinki University Hospital, Finland.
    Soderlund, S.
    Uppsala University Hospital, Sweden.
    Hoglund, M.
    Uppsala University Hospital, Sweden.
    Markevarn, B.
    Umeå University Hospital, Sweden.
    Sjalander, A.
    Umeå University, Sweden.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Dreimane, Arta
    Linköping University, Department of Clinical and Experimental Medicine. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology. Linköping University, Faculty of Medicine and Health Sciences.
    Lubking, A.
    Skåne University Hospital, Sweden.
    Holm, E.
    Skåne University Hospital, Sweden.
    Bjoreman, M.
    University Hospital, Sweden.
    Lehmann, S.
    Uppsala University Hospital, Sweden; Uppsala University, Sweden; Karolinska University Hospital, Sweden.
    Stenke, L.
    Karolinska University Hospital, Sweden.
    Ohm, L.
    Karolinska University Hospital, Sweden.
    Gedde-Dahl, T.
    Oslo University Hospital, Norway.
    Majeed, W.
    Stavanger University Hospital, Norway.
    Ehrencrona, H.
    Skåne University Hospital, Sweden.
    Koskela, S.
    Finnish Red Cross Blood Serv, Finland.
    Saussele, S.
    Heidelberg University, Germany.
    Mahon, F-X
    University of Bordeaux Segalen, France.
    Porkka, K.
    University of Helsinki, Finland; Helsinki University Hospital, Finland.
    Hjorth-Hansen, H.
    St Olavs University Hospital, Norway.
    Bryceson, Y. T.
    Karolinska Institute, Sweden.
    Richter, J.
    Skåne University Hospital, Sweden.
    Mustjoki, S.
    University of Helsinki, Finland; Helsinki University Hospital, Finland; University of Helsinki, Finland.
    Increased proportion of mature NK cells is associated with successful imatinib discontinuation in chronic myeloid leukemia2017In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 31, no 5, p. 1108-1116Article in journal (Refereed)
    Abstract [en]

    Recent studies suggest that a proportion of chronic myeloid leukemia (CML) patients in deep molecular remission can discontinue the tyrosine kinase inhibitor (TKI) treatment without disease relapse. In this multi-center, prospective clinical trial (EURO-SKI, NCT01596114) we analyzed the function and phenotype of T and NK cells and their relation to successful TKI cessation. Lymphocyte subclasses were measured from 100 imatinib-treated patients at baseline and 1 month after the discontinuation, and functional characterization of NK and T cells was done from 45 patients. The proportion of NK cells was associated with the molecular relapse-free survival as patients with higher than median NK-cell percentage at the time of drug discontinuation had better probability to stay in remission. Similar association was not found with T or B cells or their subsets. In non-relapsing patients the NK-cell phenotype was mature, whereas patients with more naive CD56(bright) NK cells had decreased relapse-free survival. In addition, the TNF-alpha/IFN-gamma cytokine secretion by NK cells correlated with the successful drug discontinuation. Our results highlight the role of NK cells in sustaining remission and strengthen the status of CML as an immunogenic tumor warranting novel clinical trials with immunomodulating agents.

  • 22.
    Ingelsson, Björn
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Söderberg, Daniel
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Strid, Tobias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Söderberg, Anita
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Bergh, Ann-Charlotte
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Loitto, Vesa-Matti
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Segelmark, Mårten
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology.
    Spyrou, Giannis
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Rosén, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Lymphocytes eject interferogenic mitochondrial DNA webs in response to CpG and non-CpG oligodeoxynucleotides of class C2018In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 3, p. E478-E487Article in journal (Refereed)
    Abstract [en]

    Circulating mitochondrial DNA (mtDNA) is receiving increasing attention as a danger-associated molecular pattern in conditions such as autoimmunity, cancer, and trauma. We report here that human lymphocytes [B cells, T cells, natural killer (NK) cells], monocytes, and neutrophils derived from healthy blood donors, as well as B cells from chronic lymphocytic leukemia patients, rapidly eject mtDNA as web filament structures upon recognition of CpG and non-CpG oligodeoxynucleotides of class C. The release was quenched by ZnCl2, independent of cell death (apoptosis, necrosis, necroptosis, autophagy), and continued in the presence of TLR9 signaling inhibitors. B-cell mtDNA webs were distinct from neutrophil extracellular traps concerning structure, reactive oxygen species (ROS) dependence, and were devoid of antibacterial proteins. mtDNA webs acted as rapid (within minutes) messengers, priming antiviral type I IFN production. In summary, our findings point at a previously unrecognized role for lymphocytes in antimicrobial defense, utilizing mtDNA webs as signals in synergy with cytokines and natural antibodies, and cast light on the interplay between mitochondria and the immune system.

  • 23.
    Jakobsen Falk, I. A.
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    Green, K. H. Z.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pharmacology.
    Fyrberg, Anna
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    CORRELATION BETWEEN CYTIDINE DEAMINASE SINGLE NUCLEOTIDE POLYMORPHISMS AND DNA METHYLATION IN ACUTE MYELOGENOUS LEUKEMIA in ANNALS OF ONCOLOGY, vol 23, issue , pp 14-142012In: ANNALS OF ONCOLOGY, Oxford University Press (OUP): Policy A1 , 2012, Vol. 23, p. 14-14Conference paper (Refereed)
    Abstract [en]

    n/a

  • 24.
    Jakobsen Falk, Ingrid
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Fyrberg, Anna
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Paul, Esbjorn
    Karolinska Institute, Sweden.
    Nahi, Hareth
    Karolinska Institute, Sweden.
    Hermanson, Monica
    Uppsala University, Sweden.
    Rosenquist, Richard
    Uppsala University, Sweden.
    Hoglund, Martin
    Uppsala University, Sweden.
    Palmqvist, Lars
    University of Gothenburg, Sweden.
    Stockelberg, Dick
    Sahlgrens University Hospital, Sweden.
    Wei, Yuan
    Sahlgrens University Hospital, Sweden.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. KTH Royal Institute Technology, Sweden.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Impact of ABCB1 single nucleotide polymorphisms 1236C>T and 2677G>T on overall survival in FLT3 wild-type de novo AML patients with normal karyotype2014In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 167, no 5, p. 671-680Article in journal (Refereed)
    Abstract [en]

    Drug resistance is a clinically relevant problem in the treatment of acute myeloid leukaemia (AML). We have previously reported a relationship between single nucleotide polymorphisms (SNPs) of ABCB1, encoding the multi-drug transporter P-glycoprotein, and overall survival (OS) in normal karyotype (NK)-AML. Here we extended this material, enabling subgroup analysis based on FLT3 and NPM1 status, to further elucidate the influence of ABCB1 SNPs. De novo NK-AML patients (n = 201) were analysed for 1199Ggreater thanA, 1236Cgreater thanT, 2677Ggreater thanT/A and 3435Cgreater thanT, and correlations to outcome were investigated. FLT3 wild-type 1236C/C patients have significantly shorter OS compared to patients carrying the variant allele; medians 20 vs. 49 months, respectively, P = 0.017. There was also an inferior outcome in FLT3 wild-type 2677G/G patients compared to patients carrying the variant allele, median OS 20 vs. 35 months, respectively, P = 0.039. This was confirmed in Cox regression analysis. Our results indicate that ABCB1 1236Cgreater thanT and 2677Ggreater thanT may be used as prognostic markers to distinguish relatively high risk patients in the intermediate risk FLT3 wild-type group, which may contribute to future individualizing of treatment strategies.

  • 25.
    Jakobsen Falk, Ingrid
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Fyrberg, Anna
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Paul, Esbjörn
    Karolinska Institutet, Stockholm, Sweden.
    Nahi, Hareth
    Karolinska Institutet, Stockholm, Sweden.
    Hermanson, Monica
    Uppsala University, Sweden.
    Rosenquist, Richard
    Uppsala University, Sweden.
    Höglund, Martin
    University of Gothenburg, Sweden.
    Palmqvist, Lars
    University of Gothenburg, Sweden.
    Stockelberg, Dick
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Wei, Yuan
    Sahlgrenska University Hospital, Gothenburg, Sweden.
    Gréen, Henrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Decreased survival in normal karyotype AML with single-nucleotide polymorphisms in genes encoding the AraC metabolizing enzymes cytidine deaminase and 5'-nucleotidase2013In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 88, no 12, p. 1001-1006Article in journal (Refereed)
    Abstract [en]

    De novo acute myeloid leukemia with normal karyotype (NK-AML) comprises a large group of patients with no common cytogenetic alterations and with a large variation in treatment response. Single-nucleotide polymorphisms (SNPs) in genes related to the metabolism of the nucleoside analogue AraC, the backbone in AML treatment, might affect drug sensitivity and treatment outcome. Therefore, SNPs may serve as prognostic biomarkers aiding clinicians in individualized treatment decisions, with the aim of improving patient outcomes. We analyzed polymorphisms in genes encoding cytidine deaminase (CDA 79A>C rs2072671 and −451C>T rs532545), 5′-nucleotidase (cN-II 7A>G rs10883841), and deoxycytidine kinase (DCK 3′UTR 948T>C rs4643786) in 205 de novo NK-AML patients. In FLT3-internal tandem duplication (ITD)-positive patients, the CDA 79C/C and −451T/T genotypes were associated with shorter overall survival compared to other genotypes (5 vs. 24 months, P < 0.001 and 5 vs. 23 months, P = 0.015, respectively), and this was most pronounced in FLT3-ITD-positive/NPM1-positive patients. We observed altered in vitro sensitivity to topoisomerase inhibitory drugs, but not to nucleoside analogues, and a decrease in global DNA methylation in cells carrying both CDA variant alleles. A shorter survival was also observed for the cN-II variant allele, but only in FLT3-ITD-negative patients (25 vs. 31 months, P = 0.075). Our results indicate that polymorphisms in genes related to nucleoside analog drug metabolism may serve as prognostic markers in de novo NK-AML

  • 26.
    Jakobsen Falk, Ingrid
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Drug Research.
    Willander, Kerstin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Chaireti, Roza
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine.
    Lund, Johan
    Division of hematology, Department of Medicine, Karolinska Institutet, Huddinge, Stockholm, Sweden.
    Monica, Hermanson
    Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
    Gréen, Henrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    TP53 mutations identify a subgroup of AML patients with dramatically impaired outcome2014Manuscript (preprint) (Other academic)
    Abstract [en]

    TP53 is commonly mutated in several cancers and confers treatment resistance and poor prognosis. Altered expression of MDM2 (mouse double minute 2), a negative regulator of p53, may also attenuate normal p53 signaling, thereby enhancing tumor transformation and resistance to apoptosis. The single nucleotide polymorphism (SNP) 309 has been reported to increase MDM2 expression and impair normal p53 response. We investigated the frequency and impact of TP53 mutations (TP53mut) and MDM2SNP309 on treatment outcome and overall survival (OS) in 207 Swedish AML patients. We found a high frequency (22%) of TP53mut in patients with cytogenetic aberrations, with strong association to high risk cytogenetics (p<0.001). TP53mut patients had lower response rates compared to TP53 wild-type (wt) patients (22% and 76% CR, respectively, p<0.001) and reduced OS (5 and 21 months, respectively, p<0.001). In TP53wt patients with abnormal karyotype, the MDM2SNP309 conferred an impaired outcome, with patients carrying the alternative G allele  having shorter OS compared to T/T patients (13 and 29 months, p=0.031). In conclusion, our results show that TP53mut analysis as well as MDM2SNP309 genotyping may be useful tools for prognostication, risk stratification and selection of patients most likely to benefit from new drugs targeting the p53 signaling pathway.

  • 27.
    Jakobsen Falk, Ingrid
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Willander, Kerstin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Chaireti, Roza
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine. Karolinska University Hospital, Sweden.
    Lund, Johan
    Huddinge University Hospital, Sweden.
    Nahi, Hareth
    Huddinge University Hospital, Sweden.
    Hermanson, Monica
    Uppsala University, Sweden.
    Green, Henrik
    National Board Forens Med, Department Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    TP53 mutations and MDM2(SNP309) identify subgroups of AML patients with impaired outcome2015In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 94, no 4, p. 355-362Article in journal (Refereed)
    Abstract [en]

    BackgroundTP53 is commonly mutated in several cancers and confers treatment resistance and poor prognosis. Altered expression of mouse double minute 2 (MDM2), a negative regulator of p53, may also attenuate normal p53 signaling, thereby enhancing tumor transformation and resistance to apoptosis. The single nucleotide polymorphism (SNP) 309 has been reported to increase MDM2 expression and impair normal p53 response. Experimental designWe investigated the frequency and impact of TP53 mutations (TP53mut) and MDM2(SNP309) on treatment outcome and overall survival (OS) in 189 Swedish acute myeloid leukemia patients. The genetic analyses were performed using SSCA and direct sequencing (for mutations in exon 5-8 of TP53) and Pyrosequencing (for the MDM2(SNP309)). ResultsWe found a high frequency (22%) of TP53mut in patients with cytogenetic aberrations, with association to high-risk cytogenetics (Pless than0.001). TP53mut patients had lower response rates (22% compared with 76% CR in TP53 wild-type (wt) patients, Pless than0.001) and reduced OS (2 and 16months, respectively, Pless than0.001). In TP53wt patients with high or intermediate risk cytogenetic aberrations, the MDM2(SNP309) conferred an impaired outcome, with patients carrying the alternative G-allele having shorter OS compared with T/T patients (median 9 vs. 50months, P=0.020). ConclusionsOur results show that TP53mut analysis and MDM2(SNP309) genotyping may be useful tools for prognostication, risk stratification, and selection of patients most likely to benefit from new drugs targeting the p53 signaling pathway.

  • 28.
    Jangamreddy, Jaganmohan Reddy
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Jain, Mayur V.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Hallbeck, Anna-Lotta
    Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences.
    Roberg, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Los, Marek Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Pomeranian Medical University, Szczecin, Poland.
    Glucose starvation-mediated inhibition of salinomycin induced autophagy amplifies cancer cell specific cell death2015In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 6, no 12, p. 10134-10145Article in journal (Refereed)
    Abstract [en]

    Salinomycin has been used as treatment for malignant tumors in a small number of humans, causing far less side effects than standard chemotherapy. Several studies show that Salinomycin targets cancer-initiating cells (cancer stem cells, or CSC) resistant to conventional therapies. Numerous studies show that Salinomycin not only reduces tumor volume, but also decreases tumor recurrence when used as an adjuvant to standard treatments. In this study we show that starvation triggered different stress responses in cancer cells and primary normal cells, which further improved the preferential targeting of cancer cells by Salinomycin. Our in vitro studies further demonstrate that the combined use of 2-Fluoro 2-deoxy D-glucose, or 2-deoxy D-glucose with Salinomycin is lethal in cancer cells while the use of Oxamate does not improve cell death-inducing properties of Salinomycin. Furthermore, we show that treatment of cancer cells with Salinomycin under starvation conditions not only increases the apoptotic caspase activity, but also diminishes the protective autophagy normally triggered by the treatment with Salinomycin alone. Thus, this study underlines the potential use of Salinomycin as a cancer treatment, possibly in combination with short-term starvation or starvation-mimicking pharmacologic intervention.

  • 29.
    Jangamreddy, Jaganmohan Reddy
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Panigrahi, Soumya
    Case Western Reserve University, Cleveland, OH, USA.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Yadav, Manisha
    CSIR-Central Drug Research Institute, Lucknow, India.
    Maddika, Subbareddy
    Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad, India.
    Tripathi, Anil Kumar
    King George's Medical University, Lucknow, India.
    Sanyal, Sabyasachi
    CSIR-Central Drug Research Institute, Lucknow, India.
    Los, Marek Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Pomeranian Medical University, Szczecin, Poland.
    Mapping of Apoptin interaction with BCR-ABL1, and development of apoptin-based targeted therapy2014In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 5, no 16, p. 7198-7211Article in journal (Refereed)
    Abstract [en]

    Majority of chronic myeloid leukemia patients experience an adequate therapeutic effect from imatinib however, 26-37% of patients discontinue imatinib therapy due to a suboptimal response or intolerance. Here we investigated derivatives of apoptin, a chicken anemia viral protein with selective toxicity towards cancer cells, which can be directed towards inhibiting multiple hyperactive kinases including BCR-ABL1. Our earlier studies revealed that a proline-rich segment of apoptin interacts with the SH3 domain of fusion protein BCR-ABL1 (p210) and acts as a negative regulator of BCR-ABL1 kinase and its downstream targets. In this study we show for the first time, the therapeutic potential of apoptin-derived decapeptide for the treatment of CML by establishing the minimal region of apoptin interaction domain with BCR-ABL1. We further show that the apoptin decapeptide is able to inhibit BCR-ABL1 down stream target c-Myc with a comparable efficacy to full-length apoptin and Imatinib. The synthetic apoptin is able to inhibit cell proliferation in murine (32Dp210), human cell line (K562), and ex vivo in both imatinib-resistant and imatinib sensitive CML patient samples. The apoptin based single or combination therapy may be an additional option in CML treatment and eventually be feasible as curative therapy.

  • 30.
    Kechagias, Stergios
    et al.
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology and Gastroenterology UHL.
    Hägg, Staffan
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Lofti, Kourosh
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Läkemedelsorsakad leverskada av kosttillskottet Fortodol: Manipulerat preparat försenade diagnos2010In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 107, no 4, p. 186-188Article in journal (Refereed)
    Abstract [en]

    Summary:

    Pharmaceutical preparations are serious contributors to liver disease. The diagnostic approach of drug-induced liver injury is difficult and requires a high degree of suspicion and the exclusion of alternative causes of liver damage. Adulteration of food supplements is a potential cause of serious hepatotoxicity. A case of severe jaundice after consumption of Fortodol, which according to the manufacturer contained the active substances turmeric and phenylalanine, is reported. Several months later more patients experiencing hepatotoxicity from Fortodol was reported and it was discovered that the toxicity was related to adulteration by nimesulide.

  • 31.
    Kreutzman, Anna
    et al.
    Helsinki Univ Hosp, Finland; Univ Helsinki, Finland.
    Yadav, Bhagwan
    Helsinki Univ Hosp, Finland; Univ Helsinki, Finland.
    Brummendorf, Tim H.
    Univ Klinikum RWTH Aachen, Germany.
    Gjertsen, Bjorn Tore
    Univ Bergen, Norway; Univ Bergen, Norway.
    Hee, Moon Lee
    Helsinki Univ Hosp, Finland; Univ Helsinki, Finland.
    Janssen, Jeroen
    Vrije Univ Amsterdam Med Ctr, Netherlands.
    Kasanen, Tiina
    Univ Helsinki, Finland; Helsinki Univ Hosp, Finland.
    Koskenvesa, Perttu
    Univ Helsinki, Finland; Helsinki Univ Hosp, Finland.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Markevarn, Berit
    Umea Univ Hosp, Sweden.
    Olsson-Stromberg, Ulla
    Uppsala Univ, Sweden; Uppsala Univ Hosp, Sweden.
    Stentoft, Jesper
    Aarhus Univ Hosp, Denmark.
    Stenke, Leif
    Karolinska Univ Hosp, Sweden; Karolinska Inst, Sweden.
    Soderlund, Stina
    Uppsala Univ Hosp, Sweden.
    Udby, Lene
    Zealand Univ Hosp, Denmark.
    Richter, Johan
    Skane Univ Hosp, Sweden.
    Hjorth-Hansen, Henrik
    St Olavs Hosp, Norway; Norwegian Univ Sci and Technol NTNU, Norway.
    Mustjoki, Satu
    Helsinki Univ Hosp, Finland; Univ Helsinki, Finland.
    Immunological monitoring of newly diagnosed CML patients treated with bosutinib or imatinib first-line2019In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 8, no 9, article id e1638210Article in journal (Refereed)
    Abstract [en]

    Changes in the immune system induced by tyrosine kinase inhibitors (TKI) have been shown to positively correlate with therapy responses in chronic myeloid leukemia (CML). However, only a few longitudinal studies exist and no randomized comparisons between two TKIs have been reported. Therefore, we prospectively analyzed the immune system of newly diagnosed CML patients treated with imatinib (n = 20) or bosutinib (n = 13), that participated in the randomized BFORE trial (NCT02130557). Comprehensive immunophenotyping, plasma protein profiling, and functional assays to determine activation levels of T and NK cells were performed at diagnosis, 3, and 12 months after therapy start. All results were correlated with clinical parameters such as Sokal risk and BCR-ABL load measured according to IS%. At diagnosis, low Sokal risk CML patients had a higher frequency of cytotoxic cells (CD8 + T and NK cells), increased cytotoxic potential of NK cells and lower frequency of naive and central memory CD4 + T cells. Further, soluble plasma protein profile divided patients into two distinct clusters with different disease burden at diagnosis. During treatment, BCR-ABL IS% correlated with immunological parameters such as plasma proteins, together with different memory subsets of CD4+ and CD8 + T cells. Interestingly, the proportion and cytotoxic potential of NK cells together with several soluble proteins increased during imatinib treatment. In contrast, no major immunological changes were observed during bosutinib treatment. In conclusion, imatinib and bosutinib were shown to have differential effects on the immune system in this randomized clinical trial. Increased number and function of NK cells were especially observed during imatinib therapy.

  • 32.
    Lofti, Kourosh
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology.
    Månsson, Emma
    Stockholm.
    Peterson, Curt
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology.
    Eriksson, Staffan
    Uppsala.
    Low level of mitochondrical deoxyguanosine kinase is the dominant factor in acquired resistance to 9- -D-arabinofuranosylguanine cytotoxicity2002In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 293, p. 1489-1496Article in journal (Refereed)
  • 33.
    Lotfi, Kourosh
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Pharmacology and resistance mechanisms of nucleoside analogues and topoisomerase II interactive agents: studies on human leukemia cells with a focus on cross-resistance2001Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The purpose of this thesis was to elucidate mechanisms of action and resistance of clinically relevant nucleoside analogues and topoisomerase interactive agents in human leukemia cell lines and leukernia cells isolated from peripheral blood of leukemia patients. Interactions and cross-resistance patterns of these different cytotoxic drug families were also studied since these drugs are usually administrated in combination in the clinic.

    Two novel nucleoside analogues, clofarabine (2-chloro-2'-arabino-fluoro 2'-deoxyadenosine, CAFdA) and nelarabine (9-ß-D-arabinofuranosylguanine, AraG) were studied regarding cellular activation and mechanisms of resistance. Compared to cladribine (2-chloro- 2'-deoxyadenosine, CdA), CAFdA was more effective due to better stability and more efficient phosphorylation by deoxycytidine kinase (dCK). The mechanism of resistance to CAFdA was decreased activity of dCK. The most important mechanism contributing to resistance to AraG seems to be the deficiency of the activating enzymes dCK and deoxyguanosine kinase (dGK), as measured by enzyme activity assays, Western blotting, and real-time polymerase chain reaction. Unexpected cross-resistance between topoisomerase interactive agents and nucleoside analogues was identified in CEM and MOLT-4 cell lines developed for resistance to etoposide (VP) and AraG, respectively, by means of a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide viability assay. Resistance to VP was due to a decrease in the activity and amount of topoisomerase TI. Major cause of resistance to the nucleoside analogues CdA and AraC was metabolic alterations producing increased activity of 5'-nucleotidase and higher level of endogenous deoxycytidine triphosphate. The AraG-resistant cells showed also classical multidrug resistance (MDR) phenomena. The accumulation and cytotoxicity of daunorubicin (Dnr) were studied in AraG-resistant cells and in response to the resistance modifiers, such as cyclosporin A. The level of mdr1 mRNA and its product, P-glycoprotein, was increased. The topoisomerase interactive agent, idarubicin (Ida), a semisynthetic derivative of Dnr, was more effective in inducing apoptosis as determined by the Annexin V -FITC method, and Ida-resistant cells did not show any classical MDR phenomena.

    Thus, these studies suggest that anticancer agents from the same class of cytostatics could have important differences in effectivity and mechanisms of resistance. These results confirm the possibility of coexpression of multiple mechanisms of resistance in human leukemic cells, which have been selected by exposure to a single-dmg. The generally assumed lack of crossresistance between nucleoside analogues and topoisomerase interactive agents is questionable.

    The rationale for combination therapy should be based on biological properties and cross-resistance analyses of the included drugs.

    List of papers
    1. Biochemical Pharmacology and Resistance to 2-Chloro-2′-arabino-fluoro-2′-deoxyadenosine, a Novel Analogue of Cladribine in Human Leukemic Cells
    Open this publication in new window or tab >>Biochemical Pharmacology and Resistance to 2-Chloro-2′-arabino-fluoro-2′-deoxyadenosine, a Novel Analogue of Cladribine in Human Leukemic Cells
    Show others...
    1999 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 5, no 9, p. 2438-2444Article in journal (Refereed) Published
    Abstract [en]

    The objective of the present study was to investigate the biochemical pharmacology of 2-chloro-2′-arabino-fluoro-2′-deoxyadenosine (CAFdA) — a fluorinated analogue of cladribine [2-chloro-2′-deoxyadenosine, Leustatin (CdA)] with improved acid and metabolic stability — in human leukemic cell lines and in mononuclear cells isolated from patients with chronic lymphocytic leukemia (CLL) and acute myelocytic leukemia (AML). We have also made and characterized two cell lines that are not sensitive to the growth inhibitory and cytotoxic effects of CAFdA. Incubation of cells isolated from the blood of CLL and AML patients with various concentrations of CdA or of CAFdA accumulated CdA and CAFdA nucleotides in a dose-dependent manner. A significantly higher rate of phosphorylation to monophosphates was observed for CAFdA than for CdA in cells from CLL patients (n = 14; P = 0.04). The differences in the phosphorylation were even more pronounced for the respective triphosphates in both CLL (n = 14; P = 0.001) and AML (n = 4; P = 0.04) cells. Retention of CAFdA 5′-triphosphate (CAFdATP) was also longer than that for CdA 5′-triphosphate (CdATP) in cells from leukemic patients. The relative efficacy of CAFdA as a substrate for purified recombinant deoxycytidine kinase (dCK), the key enzyme in the activation of nucleoside analogues, was very high and exceeded that of CdA as well as the natural substrate, deoxycytidine, by a factor of 2 and 8, respectively. The Km for CAFdA with dCK was also lower than that for CdA, as measured in crude extracts from the human acute lymphoblastic leukemia cell line CCRF-CEM and the promyelocytic leukemia cell line HL60. Acquired resistance to CAFdA in HL60 and in CCRF-CEM cell lines was directly correlated to the decreased activity of the nucleoside phosphorylating enzyme, dCK. Resistant cells also showed a considerable degree of cross-resistance to analogues that were activated by dCK. These observations demonstrated that dCK phosphorylates CAFdA more efficiently than CdA. Furthermore, CAFdATP is apparently more stable than CdATP and the mechanisms of resistance to CAFdA are similar to those leading to CdA resistance. These results encourage studies on the clinical effect of CAFdA in lymphoproliferative diseases.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-27106 (URN)11753 (Local ID)11753 (Archive number)11753 (OAI)
    Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
    2. Pharmacological basis for cladribine resistance in a human acute T lymphoblastic leukaemia cell line selected for resistance to etoposide
    Open this publication in new window or tab >>Pharmacological basis for cladribine resistance in a human acute T lymphoblastic leukaemia cell line selected for resistance to etoposide
    Show others...
    2001 (English)In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 113, no 2, p. 339-346Article in journal (Refereed) Published
    Abstract [en]

    Cross-resistance between different classes of anti-neoplastic agents can jeopardize successful combination cancer chemotherapy. In this study, we observed an unexpected cross-resistance between the podophyllotoxine derivative etoposide (VP) and the nucleoside analogue cladribine (CdA) in CCRF-CEM cells developed for resistance to VP. The resistant cells also displayed 14- and twofold resistance to cytarabine (ara-C) and gemcitabine respectively. Closer analysis of these cells showed that they contained lower amounts of topoisomerase (topo) IIα (P < 0·001) and β protein (P < 0·026), formed substantially lower amounts of the topo II–DNA complex, and had a markedly decreased level of Fas (CD95/APO-1)-ligand mRNA expression. Interestingly, Fas expression in the resistant cells did not differ from that in the parental cell line. No differences were observed in the accumulation/efflux of daunorubicin or in the gene expressions of P-glycoprotein, multidrug resistance-associated protein and the lung resistance-related protein. The activity of deoxycytidine kinase (dCK), responsible for activation of CdA and ara-C, was the same for resistant and wild-type cells. However, there was an increase in the activity of the cytosolic 5′-nucleotidases (5′-NT), responsible for deactivation of nucleotides, amounting to 206% (P < 0·001) for the high Km and 134% (P < 0·331) for the low Km 5′-NT in resistant cells. The high Km 5′-NT is probably responsible for the decreased amount of the active metabolite CdA 5′-triphosphate [40% decreased (P < 0·045)], as well as for other purine ribonucleosides and deoxyribonucleosides triphosphates in the resistant cells. In contrast, a significantly higher deoxycytidine triphosphate (dCTP) level (167%, P < 0·001) was observed in the resistant cells. Thus, this study suggests that the major cause of resistance to the nucleoside analogues CdA and ara-C in cells selected for resistance to VP is a result of metabolic alterations producing increased activity of 5′-NT and higher dCTP levels. Furthermore, these results indicate that there is a common factor in the regulation of nucleotide-degrading enzymes and DNA topoisomerases, which may be altered in cross-resistant cells.

    Keywords
    etoposide, cladribine, CD95, deoxycytidine kinase, 5′-nucleotidase
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-26977 (URN)10.1046/j.1365-2141.2001.02751.x (DOI)11611 (Local ID)11611 (Archive number)11611 (OAI)
    Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
    3. On the mechanism of 9-ß-D-arabinofuroanosylguanine resistance in human leukemic cells
    Open this publication in new window or tab >>On the mechanism of 9-ß-D-arabinofuroanosylguanine resistance in human leukemic cells
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The present study was undertaken to elucidate the mechanism of resistance to a relatively new nucleoside, 9-ß-D-arabinofuranosylguanine (Ara-G), which is highly toxic to T-cell malignancies. In order to do this we generated two stable resistant cell lines, MOLT-4/AraG500 (100-fold resistant) and MOLT-4/Ara-G900 (180-fold resistant). The presumed limiting step in the activation of Ara-G is catalyzed by both deoxycytidine kinase (dCK) and the mitochondrial deoxyguanosine kinase (dGK). Cross-resistance was noted to analogues such as cytosine arabinoside (Ara-C), cladribine, and fludarabine, but not to difluorodeoxycytidine. HPLC measurements of intracellular triphosphates of Ara-C and Ara-G showed that resistant cells generated significantly lower levels of metabolites. The activity of dGK (MOLT-4/AraG500, 79%, and MOLT-4/Ara-G900, 83%) and dCK (MOLT-4/Ara-G500, 54%, and MOLT- 4/Ara-G900, 73%), as well as protein and mRNA levels were significantly reduced in the resistant cell lines compared to the wild type. The resistant cells also showed decreased activity as well as decreased mRNA expression of the cytosolic 5'-nucleotidase (5'-NT), compared to the wild type. The reduced levels of enzyme activity in the resistant cells may be a consequence of reduced numbers of chromosomes carrying the genes for dGK, dCK and 5 'NT. Unexpectedly, the resistant cells showed higher activity of the mitochondrial enzyme thymidine kinase 2, probably resulting from down-regulation of dGK. No mutations were found in the dCK gene ofMOLT-4/Ara-G500 but in 2 of 13 clones ofMOLT-4/Ara-G900, we found two point mutations, one T to C and other A to G, which gave rise to changes in the amino acid sequence and affected the catalytic activity. The intracellular dNTP levels were determined and a nearly unchanged dCTP pool was observed in the resistant cells, while the other dNTP pools were significantly reduced compared to those in the wild type. These results show that altered activity of the deoxyribonucleoside kinases confer resistance to Ara-G in these cell lines.

    Keywords
    Leukemia, 9-ß-D-arabinofuroanosylguanine, deoxycytidine kinase, deoxyguanosine kinase, resistance and cytotoxicity
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-80283 (URN)
    Available from: 2012-08-23 Created: 2012-08-23 Last updated: 2012-08-23Bibliographically approved
    4. Altered expression of multidrug resistance (mDR1) gene in cells selected for resistance to 9-ß-D-Arabinofuranosylguanine
    Open this publication in new window or tab >>Altered expression of multidrug resistance (mDR1) gene in cells selected for resistance to 9-ß-D-Arabinofuranosylguanine
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    9-ß-D-Arabinofuranosylguanine (AraG) is an important and relatively new guanine nucleoside analogue that is highly toxic to T-cell maliguancies. Two resistant sublines with low activity of nucleoside phosphorylating enzymes, deoxycytidine kinase (dCK) (50-70% reduction) and deoxyguanosine kinase (dGK, 70-80% reduction), were generated from a MOLT-4 cell line with stepwise-increasing concentrations of AraG. As expected, the resistant sublines were highly cross-resistance to analogues that are activated by dCK and dGK such as cytosine arabinoside, cladribine, and fludarabine. Surprisingly, the resistant cells were siguificantly less sensitive to anthracyclines and podophyllotoxin derivatives resulting from decreased cellular drug accumulation restored by cyclosporin A, as determined by calcein uptake and flow cytometry studies. To clarify the mechanisms of this resistance, the gene expression of various multidrug resistance proteins, e.g. the multidrug resistance gene (mdr1), multidrng resistance-associated protein, lung resistance-associated protein and topoisomerase IIα or IIß were investigated. We found that the resistant cells overexpressed the mdr1 gene, as assessed by a real-time PCR, and contained higher levels of P-glycoprotein, as assessed by western blotting. The expression of other multidrug resistance proteins was not affected in the AraG-resistant sublines. These fmdings may be useful in the clinical trials of AraG singly and in combination with anthracyclines and related agents.

    Keywords
    leukaemia, 9-ß-D-arabinofuranosylguanine, multidrug resistance, cytotoxicity
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-80287 (URN)
    Available from: 2012-08-23 Created: 2012-08-23 Last updated: 2012-08-23Bibliographically approved
    5. Comparison of idarubicin and daunorubicin regarding intracellular uptake, induction of apoptosis, and resistance
    Open this publication in new window or tab >>Comparison of idarubicin and daunorubicin regarding intracellular uptake, induction of apoptosis, and resistance
    2002 (English)In: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 178, no 2, p. 141-149Article in journal (Refereed) Published
    Abstract [en]

    Anthracycline antibiotics are widely used as anticancer agents. Idarubicin (4-demethoxydaunorubicin; Ida), a semisynthetic derivative of daunorubicin (Dnr) is more potent than the parent compound in vitro and in vivo. The equitoxic dose of Ida in patients is about one-fourth of that of Dnr. We compared these drugs regarding cytotoxicity, apoptosis induction, and resistance mechanisms in human leukaemic cell lines. Cytotoxicity was studied by means of the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assay and drug-induced apoptosis by means of the Annexin V–fluorescein isothiocyanate method at similar intracellular concentrations (extracellular concentrations of 0.35 μM for Ida and 1 μM for Dnr). Ida was at least twice as potent as Dnr in MOLT-4, HL60, CEM, and K562 cell lines. It took 8 h for Ida to induce approximately 20% apoptosis, but at least 22 h for Dnr to reach 20% apoptosis at identical intracellular concentration. Ida induces a faster and higher apoptosis rate compared with Dnr. The human chronic myelogenous leukaemia cell line (K562) was selected for resistance to Dnr and Ida with and without verapamil (Ver). Continuous incubation with Dnr, but not with Ida, led to an increased mdr1 gene expression as assessed by real-time PCR. The development of mdr1 gene expression in Dnr-resistant cells could be reversed by the presence of Ver. Ver also reversed the cytotoxicity to Dnr, but not to Ida, in K562/Dnr cells. The results show that Ida is more effective than Dnr in inducing apoptosis and that there are differences in resistance mechanisms between the drugs.

    Keywords
    Idarubicin, Daunorubicin, Apoptosis, Intracellular accumulation, MOLT-4, Cytotoxicity
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-27006 (URN)10.1016/S0304-3835(01)00824-2 (DOI)11642 (Local ID)11642 (Archive number)11642 (OAI)
    Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
  • 34.
    Lotfi, Kourosh
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology .
    Juliusson, Gunnar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Oncology . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Haematology UHL.
    Albertioni, Freidoun
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology .
    Pharmacological basis for cladribine resistance2003In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 44, no 10, p. 1705-1712Article in journal (Refereed)
    Abstract [en]

    The inherent or acquired resistance of leukemic cells to cytostatic agents is a major clinical challenge. The purpose of this review was to elucidate and analyse the available data concerning mechanisms of resistance of cladribine with emphasis on recent advances in the characterization of activating and inactivating enzymes in the induction of resistance to cladribine. All available in vitro and clinical data on cladribine was undertaken. Cladribine, unlike many other drugs, is toxic to both dividing and indolent lymphoid malignancies. Cladribine is a prodrug and must be phosphorylated intracellularly to cladribine-monophosphate (MP) by the nuclear/cystosol enzyme deoxycytidine kinase (dCK) and the mitochondrial enzyme deoxyguanosine kinase. The cytotoxicity mainly depends on the accumulation of cladribine-triphosphates (TP) after phosphorylation of cladribine-MP by nucleoside monophosphate kinase and nucleoside diphosphate kinase. 5'-Nucleotidase (5'-NT) dephosphorylates cladribine-MP and the accumulation of cladribine-TP depends on the ratio of dCK and 5'-NT in the cells. The mechanisms underlying cladribine resistance are multifactorial, e.g. decreased nucleoside transport, decreased activity or deficiency of dCK, altered intracellular pools of competing nucleotides, altered regulation of ribonucleotide reductase and increased drug inactivation by 5'-NT. Finally, cladribine resistance may be a consequence of a defective induction of apoptosis. In spite of the fact that more than one mechanism can contribute to a cladribine resistance phenotype, a reduction in dCK activity is probably the major determinant of cladribine resistance. Insight into the mechanism of action and resistance to cladribine is crucial for its optimal use as well as for the development of newer analogues.

  • 35.
    Lotfi, Kourosh
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Karlsson, Karin
    Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Haematology UHL.
    Fyrberg, Anna
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Juliusson, Gunnar
    Lund University Hospital.
    Jonsson, Viggo
    Oslo University.
    Peterson, Curt
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Eriksson, Staffan
    Swedish University of Agricultural Sciences, The Biomedical Center, Uppsala.
    Albertioni, Freidoun
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    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 leukemia2006In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 71, no 6, p. 882-890Article in journal (Refereed)
    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.

  • 36.
    Lotfi, Kourosh
    et al.
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Månsson, Emma
    Department of Medicine, Division of Clinical Pharmacology, Karolinska Hospital Stockholm, Sweden.
    Chandra, Joya
    Oncology Department, Mayo Clinic, Rochester, Minnesota, USA.
    Wang, Yuyinh
    Department of Oncology-Pathology, Karolinska Hospital Stockholm, Sweden.
    Xu, Dawei
    Department of Internal Medicine, Karolinska Hospital Stockholm, Sweden.
    Knaust, Eva
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Spasokoukotskaja, Tanja
    Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University of Medicine, Budapest, Hungary.
    Liliemark, Eva
    Department of Oncology-Pathology, Karolinska Hospital Stockholm, Sweden.
    Eriksson, Staffan
    Department of Veterinary Medical Chemistry, Swedish University of Agricultural Sciences, The Biomedical Centre, Uppsala, Sweden.
    Albertioni, Freidoun
    Department of Medicine, Division of Clinical Pharmacology, Karolinska Hospital Stockholm, Sweden.
    Pharmacological basis for cladribine resistance in a human acute T lymphoblastic leukaemia cell line selected for resistance to etoposide2001In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 113, no 2, p. 339-346Article in journal (Refereed)
    Abstract [en]

    Cross-resistance between different classes of anti-neoplastic agents can jeopardize successful combination cancer chemotherapy. In this study, we observed an unexpected cross-resistance between the podophyllotoxine derivative etoposide (VP) and the nucleoside analogue cladribine (CdA) in CCRF-CEM cells developed for resistance to VP. The resistant cells also displayed 14- and twofold resistance to cytarabine (ara-C) and gemcitabine respectively. Closer analysis of these cells showed that they contained lower amounts of topoisomerase (topo) IIα (P < 0·001) and β protein (P < 0·026), formed substantially lower amounts of the topo II–DNA complex, and had a markedly decreased level of Fas (CD95/APO-1)-ligand mRNA expression. Interestingly, Fas expression in the resistant cells did not differ from that in the parental cell line. No differences were observed in the accumulation/efflux of daunorubicin or in the gene expressions of P-glycoprotein, multidrug resistance-associated protein and the lung resistance-related protein. The activity of deoxycytidine kinase (dCK), responsible for activation of CdA and ara-C, was the same for resistant and wild-type cells. However, there was an increase in the activity of the cytosolic 5′-nucleotidases (5′-NT), responsible for deactivation of nucleotides, amounting to 206% (P < 0·001) for the high Km and 134% (P < 0·331) for the low Km 5′-NT in resistant cells. The high Km 5′-NT is probably responsible for the decreased amount of the active metabolite CdA 5′-triphosphate [40% decreased (P < 0·045)], as well as for other purine ribonucleosides and deoxyribonucleosides triphosphates in the resistant cells. In contrast, a significantly higher deoxycytidine triphosphate (dCTP) level (167%, P < 0·001) was observed in the resistant cells. Thus, this study suggests that the major cause of resistance to the nucleoside analogues CdA and ara-C in cells selected for resistance to VP is a result of metabolic alterations producing increased activity of 5′-NT and higher dCTP levels. Furthermore, these results indicate that there is a common factor in the regulation of nucleotide-degrading enzymes and DNA topoisomerases, which may be altered in cross-resistant cells.

  • 37.
    Lotfi, Kourosh
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Peterson, Curt
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Juliusson, Gunnar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Haematology UHL.
    Letter: Monitoring oral cyclosporine therapy2005In: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 36, p. 367-367Article in journal (Other academic)
  • 38.
    Lotfi, Kourosh
    et al.
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Zackrisson, Anna Lena
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Peterson, Curt
    Linköping University, Department of Medicine and Care, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Comparison of idarubicin and daunorubicin regarding intracellular uptake, induction of apoptosis, and resistance2002In: Cancer Letters, ISSN 0304-3835, E-ISSN 1872-7980, Vol. 178, no 2, p. 141-149Article in journal (Refereed)
    Abstract [en]

    Anthracycline antibiotics are widely used as anticancer agents. Idarubicin (4-demethoxydaunorubicin; Ida), a semisynthetic derivative of daunorubicin (Dnr) is more potent than the parent compound in vitro and in vivo. The equitoxic dose of Ida in patients is about one-fourth of that of Dnr. We compared these drugs regarding cytotoxicity, apoptosis induction, and resistance mechanisms in human leukaemic cell lines. Cytotoxicity was studied by means of the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assay and drug-induced apoptosis by means of the Annexin V–fluorescein isothiocyanate method at similar intracellular concentrations (extracellular concentrations of 0.35 μM for Ida and 1 μM for Dnr). Ida was at least twice as potent as Dnr in MOLT-4, HL60, CEM, and K562 cell lines. It took 8 h for Ida to induce approximately 20% apoptosis, but at least 22 h for Dnr to reach 20% apoptosis at identical intracellular concentration. Ida induces a faster and higher apoptosis rate compared with Dnr. The human chronic myelogenous leukaemia cell line (K562) was selected for resistance to Dnr and Ida with and without verapamil (Ver). Continuous incubation with Dnr, but not with Ida, led to an increased mdr1 gene expression as assessed by real-time PCR. The development of mdr1 gene expression in Dnr-resistant cells could be reversed by the presence of Ver. Ver also reversed the cytotoxicity to Dnr, but not to Ida, in K562/Dnr cells. The results show that Ida is more effective than Dnr in inducing apoptosis and that there are differences in resistance mechanisms between the drugs.

  • 39.
    Lyth, Johan
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    Börjeson, Sussanne
    Linköping University, Department of Medical and Health Sciences, Nursing Science. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pharmacology.
    Frodin, U
    Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology UHL.
    Pain assessments during autologous stem cell transplantation in BONE MARROW TRANSPLANTATION, vol 46, issue , pp S450-S4512011In: BONE MARROW TRANSPLANTATION, Nature Publishing Group , 2011, Vol. 46, p. S450-S451Conference paper (Refereed)
    Abstract [en]

    n/a

  • 40. Löfgren, C
    et al.
    Hjortsberg, L
    Blennow, M
    Lotfi, Kourosh
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology.
    Paul, C
    Eriksson, S
    Albertioni, F
    Mechanisms of cross-resistance between nucleoside analogues and vincristine or daunorubicin in leukemic cells2004In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 320, no 3, p. 825-832Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to clarify the biochemical and molecular mechanisms behind the cross-resistance to nucleoside analogues (Nas) in four erythroleukemic cell lines with acquired resistance to the anthracycline daunorubicin and to the vinca alkaloid vincristine, expressing high levels of p-glycoprotein (P-gp, MDR1). All resistant strains exhibited cross-resistance to NA (cladribine and cytosine arabinoside) -induced apoptosis, assessed by caspase-3-like activation and were less sensitive to NA cytotoxicity in MTT assay. Real-time PCR and enzyme activity analysis showed reduced amounts of deoxycytidine kinase (35-80%) and elevated levels of 5′- nucleotidases (50-100%). The ratio 5′-nucleotidase to deoxycytidine kinase increased between 2.5- and 7.5-folds in resistant cells. This is in agreement with the observation that 5′-nucleotidase/ deoxycytidine kinase ratio might be an important factor in predicting resistance to Nas. Implications of this finding for combining anthracyclines or vinca alkaloids with Nas toward leukemic cells are discussed.

  • 41.
    Milovanovic, Micha
    et al.
    Linköping University, Department of Social and Welfare Studies, Division of Health, Activity and Care. Linköping University, Faculty of Health Sciences.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Lindahl, Tomas
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Hallert, Claes
    Linköping University, Department of Social and Welfare Studies, Division of Health, Activity and Care. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in East Östergötland, Department of Internal Medicine in Norrköping.
    Järemo, Petter
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in East Östergötland, Department of Internal Medicine in Norrköping.
    Platelet Density Distribution in Essential Thrombocythemia2010In: Pathophysiology of Haemostasis and Thrombosis, ISSN 1424-8832, E-ISSN 1424-8840, Vol. 37, no 1, p. 35-42Article in journal (Refereed)
    Abstract [en]

    Essential thrombocythemia (ET) is characterized by high platelet counts and a slightly increased bleeding risk. Why severe hemorrhage does not occur more frequently is not known. Variations of platelet density (kg/l) depend mainly on cell organelle content in that high-density platelets contain more alpha and dense granules. This study compares ET patients (n = 2) and healthy volunteers (n = 2) with respect to platelet density subpopulations. A linear Percoll gradient containing prostaglandin E(1) was employed to separate platelets according to density. The platelet population was subsequently divided by density into 16 or 17 subpopulations. Determination of platelet counts was carried out. In each density fraction, platelet in vivo activity, i.e. platelet-bound fibrinogen, was measured using a flow cytometer. To further characterize platelet subpopulations, we determined intracellular concentrations of CD40 ligand (CD40L) and P-selectin in all fractions. Patients and controls demonstrated similar density distributions, i.e. 1 density peak. High-density platelets had more surface-bound fibrinogen in conjunction with signs of platelet release reactions, i.e. with few exceptions they contained less CD40L and P-selectin. Peak density platelets showed less surface-bound fibrinogen. These platelets contained less CD40L and P-selectin than nearby denser populations. The light platelets had more surface-bound fibrinogen than peak platelets together with elevated concentrations of CD40L. In ET, the malignant platelet production could exist together with platelets originating from normal megakaryocytes. It is also possible that clonal megakaryocytes produce platelets covering the entire density span. The 'normal' density distribution offers a tenable explanation as to why serious bleedings do not occur more frequently.

     

  • 42.
    Mosrati, Mohamed Ali
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Willander, Kerstin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Jakobsen Falk, Ingrid
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Hermanson, Monica
    Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
    Höglund, Martin
    Division of Hematology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Stockelberg, Dick
    Section for Hematology and Coagulation, Department of Internal Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Wei, Yuan
    Section for Hematology and Coagulation, Department of Internal Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Association between TERT promoter polymorphisms and acute myeloid leukemia risk and prognosis2015In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 6, no 28, p. 25109-25120Article in journal (Refereed)
    Abstract [en]

    Telomerase reverse transcriptase gene (TERT) promoter mutations are identified in many malignancies but not in hematological malignancies. Here we analyzed TERT and protection of telomeres 1 gene (POT1) mutations, and four different TERT SNVs in 226 acute myeloid leukemia (AML) patients and 806 healthy individuals in a case referent design, where also overall survival was assessed. A significant association for increased risk of AML was found for TERT SNVs, rs2853669 (OR = 2.45, p = 0.00015) and rs2736100 (OR = 1.5, p = 0.03). The overall survival for patients with CC genotype of rs2853669 was significantly shorter compared to those with TT or TC genotypes (p = 0.036 and 0.029 respectively). The influence of TERT rs2853669 CC on survival was confirmed in multivariable Cox regression analysis as an independent risk biomarker in addition to high risk group, higher age and treatment. No hot spot TERT promoter mutations at -228Cgreater thanT or -250Cgreater thanT or POT1 mutations could be identified in this AML cohort. We show that rs2853669 CC may be a risk factor for the development of AML that may also be used as a prognostic marker to identify high risk normal karyotype -AML (NK-AML) patients, for treatment guidance.

  • 43.
    Nordigården, Amanda
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Zetterblad, Jenny
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Trinks, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Eliasson, Pernilla
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Druid, Pia
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pharmacology.
    Ronnstrand, Lars
    Lund University.
    Walz, Thomas
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Irreversible pan-ERBB inhibitor canertinib elicits anti-leukaemic effects and induces the regression of FLT3-ITD transformed cells in mice2011In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 155, no 2, p. 198-208Article in journal (Refereed)
    Abstract [en]

    Recent findings have indicated that tyrosine kinase inhibitors (TKIs) targeting the ERBB receptor family display anti-leukaemic effects, despite the lack of receptor expression on human leukaemic cells. The occurrence of activating mutations in the gene encoding FMS-like tyrosine kinase 3 (FLT3) in patients with acute myeloid leukaemia (AML) has rendered inhibition of this receptor a promising therapeutic target. Due to possibility of cross-reactivity, we investigated the effect of the irreversible pan-ERBB inhibitor canertinib (CI-1033) on leukaemic cells expressing FLT3. The drug had anti-proliferative and apoptotic effects on primary AML cells and human leukaemic cell lines expressing mutated FLT3. In several AML patient samples, a blast cell population expressing FLT3-internal tandem duplication (ITD) was eradicated by canertinib. Canertinib inhibited receptor autophosphorylation and kinase activity of both mutated and FLT3 ligand stimulated wildtype FLT3, leading to inhibition of the PI3-kinase and MAP kinase pathways. Apoptotic induction was dependent on pro-apoptotic BH3-only protein BCL2L11/BIM because siRNA silencing attenuated apoptosis. Moreover, the drug induced regression of cells expressing FLT3-ITD in a murine in vivo-transplantation model at previously described tolerated doses. These results indicate that canertinib, as an irreversible TKI, could constitute a novel treatment regimen in patients with mutated or overexpressed FLT3.

  • 44.
    Noren, Elisabeth
    et al.
    Karolinska Institute, Sweden; Regional Jonköping County, Sweden.
    Verma, Deepti
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Weisselberg, Tilman
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Gastroentorology.
    Söderman, Jan
    Regional Jönköping County, Sweden.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Almer, Sven
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Single Nucleotide Polymorphisms in MORC4, CD14, and TLR4 Are Related to Outcome of Allogeneic Stem Cell Transplantation2016In: Annals of Transplantation, ISSN 1425-9524, E-ISSN 2329-0358, Vol. 21, p. 56-67Article in journal (Refereed)
    Abstract [en]

    Background: Non-HLA genes may contribute to the prognosis after hematopoietic stem cell transplantation. We investigated associations between single nucleotide polymorphisms in regions of MORC4, CD14, TLR4, NOD2, SLC22A4, SLC22A5, CARD8, NLRP3, and CLDN2 and the outcomes of patients undergoing allogeneic stem cell transplantation. Material/Methods: Single nucleotide polymorphisms in selected regions were determined and analyzed for putative associations with overall mortality and acute graft-versus-host disease. Significant associations were further explored by logistic regression, controlling for additional variables. Results: A significant association was identified between overall mortality among recipients and a nonsynonymous coding variant of MORC4 (rs6622126) in the recipient genetic makeup (P=0.029). Since MORC4 is located on the X-chromosome, the results were also analyzed separately for males and females. The association between overall mortality for recipients and the risk allele (rs6622126; A) was confirmed for males with respect to genetic makeup of recipients (P=0.012), donor genetic makeup (P=0.004), and the combined allele composition of the donor and recipient (P=0.001). A significant association was also identified between overall mortality and the recipient risk allele of CD14 (rs2569190; P=0.031), TLR4 (rs4986790; P=0.043), and NOD2 (carriage of at least 1 mutant allele of rs2066844, rs2066845, or rs2066847; P=0.048). Among the investigated genes, only the CD14 (rs2569190) recipient risk allele was significantly associated with acute graft-versus-host disease (P=0.023). Logistic regression models confirmed these findings, except for NOD2, and also identified a significant contribution by age at stem cell transplantation (MORC4, CD14, TLR4), diagnosis (CD14, TLR4), and prophylaxis (MORC4). Conclusions: Genetic variation in MORC4, CD14, and TLR4 may affect the outcome of allogeneic stem cell transplantation.

  • 45.
    Paul, Christer
    et al.
    Karolinska University Hospital.
    Green, Henrik
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences.
    Jakobsen Falk, Ingrid
    n/a.
    Lotfi, Kourosh
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Paul, Esbjorn
    Karolinska University Hospital.
    Hermansson, Monika
    Uppsala University.
    Rosenquist, Richard
    Uppsala University.
    Jonsson-Videsater, Kerstin
    n/a.
    Nahi, Hareth
    n/a.
    Implications On Drug Resistance and Survival of ABCB1 Single Nucleotide Polymorphisms in Normal Karyotype De Novo AML in BLOOD, vol 114, issue 22, pp 1038-10392009In: BLOOD, American Society of Hematology , 2009, Vol. 114, no 22, p. 1038-1039Conference paper (Refereed)
    Abstract [en]

    n/a

  • 46.
    Paul, E.
    et al.
    Karolinska Institute.
    Lotfi, Kourosh
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Jakobsen Falk, I.
    n/a.
    Rosenquist, R.
    Uppsala Univ.
    Paul, C.
    Karolinska Institute.
    Nahi, H.
    Karolinska Institute.
    Green, Henrik
    Linköping University, Department of Medicine and Health Sciences, Clinical Pharmacology . Linköping University, Faculty of Health Sciences.
    ABCB1 SINGLE NUCLEOTIDE POLYMORPHISMS IN DE NOVO AML WITH NORMAL KARYOTYPE - IMPLICATIONS ON DRUG RESISTANCE AND SURVIVAL2009In: in HAEMATOLOGICA-THE HEMATOLOGY JOURNAL, vol 94, 2009, Vol. 94, p. 0576-Conference paper (Refereed)
    Abstract [en]

    n/a

  • 47.
    Rajala, Hanna L. M.
    et al.
    University of Helsinki, Finland; Helsinki University Hospital, Finland.
    El Missiry, Mohamed
    University of Helsinki, Finland; Helsinki University Hospital, Finland.
    Ruusila, Anniina
    University of Helsinki, Finland; Helsinki University Hospital, Finland.
    Koskenvesa, Perttu
    University of Helsinki, Finland; Helsinki University Hospital, Finland.
    Bruemmendorf, Tim H.
    University Hospital Aachen RWTH, Germany.
    Gjertsen, Bjorn T.
    University of Bergen, Norway.
    Janssen, Jeroen
    Vrije University of Amsterdam, Netherlands.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Markevarn, Berit
    University of Bergen, Norway.
    Olsson-Stromberg, Ulla
    Uppsala University Hospital, Sweden.
    Stenke, Leif
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Stentoft, Jesper
    Aarhus University Hospital, Denmark.
    Richter, Johan
    Skåne University Hospital, Sweden.
    Hjorth-Hansen, Henrik
    St Olavs Hospital, Norway; NTNU, Norway.
    Kreutzman, Anna
    University of Helsinki, Finland; Helsinki University Hospital, Finland; University of Helsinki, Finland.
    Mustjoki, Satu
    University of Helsinki, Finland; Helsinki University Hospital, Finland; University of Helsinki, Finland.
    Tyrosine kinase inhibitor therapy-induced changes in humoral immunity in patients with chronic myeloid leukemia2017In: Journal of Cancer Research and Clinical Oncology, ISSN 0171-5216, E-ISSN 1432-1335, Vol. 143, no 8, p. 1543-1554Article in journal (Refereed)
    Abstract [en]

    Purpose Tyrosine kinase inhibitors (TKIs) have well-characterized immunomodulatory effects on T and NK cells, but the effects on the humoral immunity are less well known. In this project, we studied TKI-induced changes in B cell-mediated immunity. Methods We collected peripheral blood (PB) and bone marrow (BM) samples from chronic myeloid leukemia (CML) patients before and during first-line imatinib (n = 20), dasatinib (n = 16), nilotinib (n = 8), and bosutinib (n = 12) treatment. Plasma immunoglobulin levels were measured, and different B cell populations in PB and BM were analyzed with flow cytometry. Results Imatinib treatment decreased plasma IgA and IgG levels, while dasatinib reduced IgM levels. At diagnosis, the proportion of patients with IgA, IgG, and IgM levels below the lower limit of normal (LLN) was 0, 11, and 6% of all CML patients, respectively, whereas at 12 months timepoint the proportions were 6% (p = 0.13), 31% (p = 0.042) and 28% (p = 0.0078). Lower initial Ig levels predisposed to the development of hypogammaglobulinemia during TKI therapy. Decreased Ig levels in imatinibtreated patients were associated with higher percentages of immature BM B cells. The patients, who had low Ig levels during the TKI therapy, had significantly more frequent minor infections during the follow-up compared with the patients with normal Ig values (33% vs. 3%, p = 0.0016). No severe infections were reported, except recurrent upper respiratory tract infections in one imatinib-treated patient, who developed severe hypogammaglobulinemia. Conclusions TKI treatment decreases plasma Ig levels, which should be measured in patients with recurrent infections.

  • 48.
    Richter, Johan
    et al.
    Skåne University Hospital, Sweden.
    Soderlund, Stina
    University Hospital, Uppsala, Sweden.
    Lubking, Anna
    Skåne University Hospital, Sweden.
    Dreimane, Arta
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pharmacology.
    Markevarm, Berit
    University Hospital, Umeå, Sweden.
    Sjalander, Anders
    Umeå University, Sweden.
    Saussele, Susanne
    Univ Med Mannheim, Mannheim, Germany.
    Olsson-Stromberg, Ulla
    University Hospital, Uppsala, Sweden.
    Stenke, Leif
    Karolinska University Hospital, Sweden; Karolinska Institute, Sweden.
    Letter: Musculoskeletal Pain in Patients With Chronic Myeloid Leukemia After Discontinuation of Imatinib: A Tyrosine Kinase Inhibitor Withdrawal Syndrome? in JOURNAL OF CLINICAL ONCOLOGY, vol 32, issue 25, pp 2821-28232014In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 32, no 25, p. 2821-2823Article in journal (Other academic)
    Abstract [en]

    n/a

  • 49.
    Skoglund, Karin
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences.
    Richter, J.
    Department of Hematology and Coagulation, Skåne University Hospital, Lund, Sweden.
    Olsson-Strömberg, U.
    Department of Medical Sciences, Uppsala University and Department of Hematology, University Hospital, Uppsala, Sweden.
    Bergquist, J.
    Analytical Chemistry, Department of Chemistry – Biomedical Center and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Aluthgedara, W.
    Analytical Chemistry, Department of Chemistry – Biomedical Center and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Ubhayasekera, K.
    Analytical Chemistry, Department of Chemistry – Biomedical Center and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Vikingsson, Svante
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Svedberg, A.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Söderlund, S.
    Department of Medical Sciences, Uppsala University and Department of Hematology, University Hospital, Uppsala, Sweden.
    Sandstedt, Anna
    Linköping University, Department of Social and Welfare Studies. Linköping University, Faculty of Health Sciences.
    Johnsson, A.
    Department of Internal Medicine, Motala Hospital, Motala, Sweden.
    Aagesen, J.
    Department of Medicine, Ryhov County Hospital, Jönköping, Sweden.
    Alsenhed, J.
    Department of Internal Medicine, Västervik Hospital, Västervik, Sweden.
    Hägg, Staffan
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences.
    Peterson, Curt
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pharmacology.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    In vivo CYP3A activity and pharmacokinetics of imatinib in relation to therapeutic outcome in chronic myeloid leukemia patientsManuscript (preprint) (Other academic)
    Abstract [en]

    Introduction: The hepatic enzymes CYP3A4 and CYP3A5 metabolize the tyrosine kinase inhibitor imatinib into a large number of metabolites including the pharmacologically active N-desmethyl imatinib (CGP74588). Because the metabolic activity of CYP3A varies considerably between individuals and a previous pilot study suggested an inverse association between in vivo CYP3A metabolic activity and therapeutic outcome of imatinib, the primary aim of this study was to investigate the influence of CYP3A metabolic activity on the outcome of imatinib therapy in chronic myeloid leukemia patients.

    Methods: Fifty-five patients were included and CYP3A activity was estimated in vivo using quinine as a probe drug. Imatinib and CGP74588 trough concentrations in the plasma were determined at steady state in 34 patients. Cytogenetic and molecular responses after 12 months of first-line imatinib were retrospectively collected from patients’ medical records.

    Results: Patients with optimal response to imatinib (complete cytogenetic response (CCgR) or molecular response of BCR-ABL <1%) did not have different levels of CYP3A activity compared to non-optimal responders. Similar results were found when analyzing the molecular response and CCgR separately. Neither the imatinib trough concentration nor the CGP74588/imatinib ratio were significantly associated with CYP3A activity.

    Conclusion: CYP3A enzyme activity, as measured by quinine metabolic ratio, does not correlate with the plasma concentrations of imatinib or CGP74588 and is not predictive of imatinib therapeutic outcome. These results indicate that even though imatinib is metabolized by CYP3A enzymes, this activity is not the   ratelimiting step in imatinib metabolism and excretion. Future studies should focus on other pharmacokinetic processes such as plasma protein binding or transport protein activity to look for the major contributor to patient variability in imatinib plasma concentration.

  • 50.
    Skoglund, Karin
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Richter, Johan
    Skåne University Hospital, Sweden.
    Olsson-Stromberg, Ulla
    Uppsala University, Sweden.
    Bergquist, Jonas
    Uppsala University, Sweden.
    Aluthgedara, Warunika
    Uppsala University, Sweden.
    Ubhayasekera, S. J. Kumari A.
    Uppsala University, Sweden.
    Vikingsson, Svante
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
    Svedberg, Anna
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Söderlund, Stina
    Uppsala University, Sweden.
    Sandstedt, Anna
    Linköping University, Department of Social and Welfare Studies. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Johnsson, Anders
    Region Östergötland, Local Health Care Services in West Östergötland, Department of Medical Specialist in Motala.
    Aagesen, Jesper
    Ryhov County Hospital, Sweden.
    Alsenhed, Jonas
    Vastervik Hosp, Dept Internal Med, Västervik, Sweden.
    Hägg, Staffan
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Peterson, Curt
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Green, Henrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. National Board Forens Med, Department Forens Genet and Forens Toxicol, Linkoping, Sweden.
    In Vivo Cytochrome P450 3A Isoenzyme Activity and Pharmacokinetics of Imatinib in Relation to Therapeutic Outcome in Patients With Chronic Myeloid Leukemia2016In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 38, no 2, p. 230-238Article in journal (Refereed)
    Abstract [en]

    Background: Cytochrome P450 3A (CYP3A) isoenzyme metabolic activity varies between individuals and is therefore a possible candidate of influence on the therapeutic outcome of the tyrosine kinase inhibitor imatinib in patients with chronic myeloid leukemia (CML). The aim of this study was to investigate the influence of CYP3A metabolic activity on the plasma concentration and outcome of imatinib in patients with CML. Methods: Forty-three patients with CML were phenotyped for CYP3A activity using quinine as a probe drug and evaluated for clinical response parameters. Plasma concentrations of imatinib and its main metabolite, CGP74588, were determined using liquid chromatography-mass spectrometry. Results: Patients with optimal response to imatinib after 12 months of therapy did not differ in CYP3A activity compared to nonoptimal responders (quinine metabolic ratio of 14.69 and 14.70, respectively; P = 0.966). Neither the imatinib plasma concentration nor the CGP74588/imatinib ratio was significantly associated with CYP3A activity. Conclusions: The CYP3A activity does not influence imatinib plasma concentrations or the therapeutic outcome. These results indicate that although imatinib is metabolized by CYP3A enzymes, this activity is not the rate-limiting step in imatinib metabolism and excretion. Future studies should focus on other pharmacokinetic processes so as to identify the major contributor to patient variability in imatinib plasma concentrations.

12 1 - 50 of 52
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf