liu.seSearch for publications in DiVA
Change search
Link to record
Permanent link

Direct link
BETA
Lindqvist Appell, MalinORCID iD iconorcid.org/0000-0002-2809-7591
Publications (10 of 38) Show all publications
Kalman, L. V., Agundez, J. A., Lindqvist Appell, M., Black, J. L., Bell, G. C., Boukouvala, S., . . . Zanger, U. M. (2016). Pharmacogenetic allele nomenclature: International workgroup recommendations for test result reporting. Clinical Pharmacology and Therapeutics, 99(2), 172-185
Open this publication in new window or tab >>Pharmacogenetic allele nomenclature: International workgroup recommendations for test result reporting
Show others...
2016 (English)In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 99, no 2, p. 172-185Article in journal (Refereed) Published
Abstract [en]

This article provides nomenclature recommendations developed by an international workgroup to increase transparency and standardization of pharmacogenetic (PGx) result reporting. Presently, sequence variants identified by PGx tests are described using different nomenclature systems. In addition, PGx analysis may detect different sets of variants for each gene, which can affect interpretation of results. This practice has caused confusion and may thereby impede the adoption of clinical PGx testing. Standardization is critical to move PGx forward.

Place, publisher, year, edition, pages
WILEY-BLACKWELL, 2016
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-125677 (URN)10.1002/cpt.280 (DOI)000369533100020 ()26479518 (PubMedID)
Available from: 2016-03-02 Created: 2016-02-29 Last updated: 2017-11-30
Lindqvist Appell, M., Mårtensson, L.-G., Almer, S. & Peterson, C. (2015). Nyttan av farmakogenetik för en mer individualiserad behandling: Exemplet tiopuriner vid inflammatorisk tarmsjukdom och barnleukemi. Läkartidningen, 112, 1229-1233, Article ID DF7L.
Open this publication in new window or tab >>Nyttan av farmakogenetik för en mer individualiserad behandling: Exemplet tiopuriner vid inflammatorisk tarmsjukdom och barnleukemi
2015 (Swedish)In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 112, p. 1229-1233, article id DF7LArticle in journal (Refereed) Published
Abstract [en]

Thiopurines are chemotherapeutic drugs used for treatment of inflammatory bowel diseases and childhood leukemia. Thiopurine methyltransferase (TPMT) is a polymorphic enzyme involved in the metabolism of thiopurines. Individuals lacking TPMT are at increased risk for severe side effects when treated with conventional doses of thiopurines. A research group at the division of drug research at Linköping University is studying thiopurine pharmacogenetics. Since the year 2000, the lab has determined the TPMT status in over 12000 individuals, as an aid to decide thiopurine doses before starting treatment. New knowledge of how genetic factors influence thiopurine treatment effect are anticipated to improve the possibilities for individualization of thiopurine therapy.

Place, publisher, year, edition, pages
Stockholm: Läkartidningen, 2015
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-119996 (URN)26126006 (PubMedID)
Available from: 2015-07-01 Created: 2015-07-01 Last updated: 2017-12-04
Niklasson, M., Andrésen, C., Helander, S., Roth, M., Zimdahl Kahlin, A., Lindqvist Appell, M., . . . Lundström, P. (2015). Robust and convenient analysis of protein thermal and chemical stability. Protein Science, 24(12), 2055-2062
Open this publication in new window or tab >>Robust and convenient analysis of protein thermal and chemical stability
Show others...
2015 (English)In: Protein Science, ISSN 0961-8368, E-ISSN 1469-896X, Vol. 24, no 12, p. 2055-2062Article in journal (Refereed) Published
Abstract [en]

We present the software CDpal that is used to analyze thermal and chemical denaturation data to obtain information on protein stability. The software uses standard assumptions and equations applied to two-state and various types of three-state denaturation models in order to determine thermodynamic parameters. It can analyze denaturation monitored by both circular dichroism and fluorescence spectroscopy and is extremely flexible in terms of input format. Furthermore, it is intuitive and easy to use because of the graphical user interface and extensive documentation. As illustrated by the examples herein, CDpal should be a valuable tool for analysis of protein stability.

Place, publisher, year, edition, pages
WILEY-BLACKWELL, 2015
Keywords
protein stability; thermal denaturation; chemical denaturation; circular dichroism; fluorescence; curve fitting; protein stability software; protein denaturation software
National Category
Chemical Sciences Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-124648 (URN)10.1002/pro.2809 (DOI)000368292000014 ()26402034 (PubMedID)
Note

Funding Agencies|Swedish Research Council [2012-5136]; LiU Cancer

Available from: 2016-02-08 Created: 2016-02-08 Last updated: 2017-11-30
Levinsen, M., Ørskov Rotevatn, E., Rosthøj, S., Nersting, J., Abrahamsson, J., Lindqvist Appell, M., . . . Schmiegelow, K. (2014). Pharmacogenetically Based Dosing of Thiopurines in Childhood Acute Lymphoblastic Leukemia: Influence on Cure Rates and Risk of Second Cancer. Pediatric Blood & Cancer, 61(5), 797-802
Open this publication in new window or tab >>Pharmacogenetically Based Dosing of Thiopurines in Childhood Acute Lymphoblastic Leukemia: Influence on Cure Rates and Risk of Second Cancer
Show others...
2014 (English)In: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 61, no 5, p. 797-802Article in journal (Refereed) Published
Abstract [en]

Background

Previous studies have indicated that patients with thiopurine methyltransferase (TPMT) low activity (TPMTLA) have reduced risk of relapse but increased risk of second malignant neoplasm (SMN) compared to patients with TPMT wild-type (TPMTWT) when treated with 6MP maintenance therapy starting doses of 75 mg/m2/day. To reduce SMN risk, 6MP starting doses were reduced to 50 mg/m2/day for patients with TPMT heterozygosity in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2000 protocol.

Procedure

We explored the pattern of SMN and relapse in the NOPHO ALL2000 protocol (n = 674) and NOPHO ALL92 protocol (n = 601) in relation to TPMT pheno- and/or genotype.

Results

The overall risk of any event did not differ significantly between the two protocols. However, in event pattern analyses considering only the patients with TPMTLA who experienced relapse or SMN, the risk of SMN versus leukemia relapse was significantly lower in the ALL2000 cohort for patients with a 6MP starting dose <75 mg/m2/day when compared to the patients in ALL92 (relapse (n = 11) and SMN (n = 0) in ALL2000 versus relapse (n = 5) and SMN (n = 4) in ALL92, P = 0.03). Furthermore, the 8-year cumulative incidence of relapse for patients with TPMTLA was significantly higher in the ALL2000 compared to the ALL92 cohort (19.7% (11.6–33.3%) vs. 6.7% (2.9–15.5%), P = 0.03).

Conclusion

This study indicates that reducing 6MP starting dose for patients with TPMTLA may reduce SMN risk but lead to a relapse risk similar to that of patients with TPMTWT.

Place, publisher, year, edition, pages
John Wiley & Sons, 2014
Keywords
ALL; late effects of cancer treatment; outcomes research; therapy
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-107849 (URN)10.1002/pbc.24921 (DOI)000333485600006 ()24395436 (PubMedID)
Available from: 2014-06-23 Created: 2014-06-23 Last updated: 2017-12-05Bibliographically approved
Lindqvist Appell, M., Wagner, A. & Hindorf, U. (2013). A skewed thiopurine metabolism is a common clinical phenomenon that can be successfully managed with a combination of low-dose azathioprine and allopurinol. Journal of Crohn's & Colitis, 7(6), 510-513
Open this publication in new window or tab >>A skewed thiopurine metabolism is a common clinical phenomenon that can be successfully managed with a combination of low-dose azathioprine and allopurinol
2013 (English)In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 7, no 6, p. 510-513Article in journal (Refereed) Published
Abstract [en]

Background and aims: A skewed thiopurine metabolism is a phenomenon associated with both poor treatment response and toxicity. Our aim was to evaluate the frequency of this phenomenon and the relationship to thiopurine methyltransferase (TPMT) function. less thanbrgreater than less thanbrgreater thanMethods: All thiopurine metabolite measurements in adult patients (n=4033) between January 2006 and April 2012 were assessed to evaluate the occurrence of a skewed metabolism and the relationship to TPMT genotype and activity. less thanbrgreater than less thanbrgreater thanResults: A skewed metabolism was observed in 14% of all patients. It only developed in patients with a normal TPMT genotype, but was observed at all TPMT activity levels within the normal range (9.1-24.2 U/ml RBC). Two cases that illustrate typical clinical scenarios of a skewed metabolism and the effect of combination treatment with low-dose azathioprine and allopurinol are presented. less thanbrgreater than less thanbrgreater thanConclusions: A skewed metabolism is a common clinical phenomenon in patients with a normal TPMT function, which can develop at all TPMT activity levels within the normal range. We suggest that metabolite measurements should be considered in patients not responding to treatment and in those with hepatotoxicity or myelotoxicity in order to detect a skewed metabolism, since this phenomenon can be successfully managed by a combination of low-dose azathioprine and allopurinol.

Place, publisher, year, edition, pages
Elsevier, 2013
Keywords
Thiopurine methyltransferase, Thiopurines, Inflammatory bowel diseases
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-95496 (URN)10.1016/j.crohns.2012.10.016 (DOI)000319370300010 ()
Available from: 2013-07-05 Created: 2013-07-05 Last updated: 2017-12-06
Karim, H., Lindqvist Appell, M. & Fotoohi, A. (2013). Comparison of three methods for measuring thiopurine methyltransferase activity in red blood cells and human leukemia cells. Journal of chromatography. B, 939, 80-85
Open this publication in new window or tab >>Comparison of three methods for measuring thiopurine methyltransferase activity in red blood cells and human leukemia cells
2013 (English)In: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 939, p. 80-85Article in journal (Refereed) Published
Abstract [en]

Thiopurine efficacy is partly reflected by the genetic polymorphism of the thiopurine methyltransferase (TPMT) enzyme, which is responsible for variation in the metabolism, toxicity and therapeutic efficacy of the thiopurines azathioprine (AZA), 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG). Determination of TPMT activity before administration of thiopurines is thus crucial for individualized dosing in order to prevent toxicity in TPMT deficient individuals. These individuals must be treated with markedly lower (eg, 5-10% of the standard) doses of the prescribed medications. This paper describes a comparison of three different methods for the quantification of TPMT activity in red blood cells (RBC) and cultured human cell lines. We succeeded to perform the measurement of TPMT activity in a minimum amount of 1×10(6) cultured cells with an HPLC-UV system modified and optimized in our laboratory. The TPMT activity was linearly correlated with the cell concentration of the cultured cell line in a range of 1-10×10(6) cells. A significant correlation of determination of TPMT activity in RBC between radiometric detection by HPLC, classic radiochemical detection and UV detection by HPLC, was observed, correlation coefficient (r) were 0.72 and 0.73, respectively. The within-day and day-to-day coefficients of variation of the HPLC-UV-based method were 8% and 16%, respectively. The evaluation of the methods was demonstrated by studying the TPMT activity in RBC isolated from 198 patients, as well as in MOLT4 leukemic cell line and its sub-cell lines with acquired resistance to 6-MP and 6-TG.

Place, publisher, year, edition, pages
Elsevier, 2013
Keywords
6-Mercaptopurine; Thiopurine methyltransferase; High performance liquid chromatography
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-100456 (URN)10.1016/j.jchromb.2013.08.036 (DOI)000326010400012 ()24113235 (PubMedID)
Available from: 2013-11-08 Created: 2013-11-08 Last updated: 2017-12-06Bibliographically approved
Green, H., Lindqvist Appell, M. & Peterson, C. (2013). Genetiska test för optimal dosering på väg att bli klinisk rutin. Onkologi i Sverige (3), 36-40
Open this publication in new window or tab >>Genetiska test för optimal dosering på väg att bli klinisk rutin
2013 (Swedish)In: Onkologi i Sverige, no 3, p. 36-40Article in journal (Other (popular science, discussion, etc.)) Published
Place, publisher, year, edition, pages
Novartis Sverige, 2013
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-116535 (URN)
Available from: 2015-03-27 Created: 2015-03-27 Last updated: 2015-04-14
Wennerstrand, P., Mårtensson, L.-G., Söderhäll, S., Lindqvist Appell, M. & Zimdahl, A. (2013). Methotrexate binds to recombinant thiopurine S-methyltransferase and inhibits enzyme activity after high-dose infusions in childhood leukaemia. European Journal of Clinical Pharmacology, 69(9), 1641-1649
Open this publication in new window or tab >>Methotrexate binds to recombinant thiopurine S-methyltransferase and inhibits enzyme activity after high-dose infusions in childhood leukaemia
Show others...
2013 (English)In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 69, no 9, p. 1641-1649Article in journal (Refereed) Published
Abstract [en]

Purpose

Important drugs in the treatment of childhood acute lymphoblastic leukaemia (ALL) are 6-mercaptopurine (6-MP) and methotrexate (MTX). Thiopurine methyltransferase (TPMT) is a polymorphic enzyme causing variability in 6-MP response and toxicity. The aim of this study was to investigate the fluctuation in TPMT enzyme activity over time and the effect of high-dose MTX infusions on TPMT enzyme activity and 6-MP metabolites in paediatric ALL patients.

Methods

Fifty-three children with ALL treated according to the NOPHO-ALL 2000 protocol were included in the study. TPMT enzyme activity was measured at six different times starting from diagnosis until after the end of maintenance treatment. TPMT and 6-MP metabolites were measured before the initiation of high-dose MTX (HD-MTX) infusions and at 66 h post-infusion. The interaction between MTX and TPMT was investigated in vitro using recombinant TPMT protein and a leukaemic cell line.

Results

Forty percent of TPMT wild-type individuals had deceptively low TPMT enzyme activity according to genotype at the time of diagnosis. TPMT activity had decreased significantly 66 h after the start of HD-MTX infusions (−9.2 %; p = 0.013). MTX bound to recombinant TPMT protein severely inhibiting TPMT enzyme activity (remaining activity 16 %).

Conclusions

Our results show that TPMT genotyping should be performed in children with ALL, since 40 % of the children in our study who carried the wild-type TPMT gene were at risk of initial underdosing of 6-MP in cases where only TPMT enzyme activity was determined. MTX inhibits the TPMT enzyme activity after HD-MTX infusions due to protein binding.

Place, publisher, year, edition, pages
Springer Berlin/Heidelberg, 2013
Keywords
Leukaemia, 6-mercaptopurine, methotrexate, pharmacogenetics, thiopurine s-methyltransferase
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-80190 (URN)10.1007/s00228-013-1521-9 (DOI)000323429900003 ()
Available from: 2012-08-22 Created: 2012-08-22 Last updated: 2017-12-07Bibliographically approved
Lindqvist Appell, M., Berg, J., Duley, J., Evans, W. E., Kennedy, M. A., Lennard, L., . . . Coulthard, S. A. (2013). Nomenclature for alleles of the thiopurine methyltransferase gene. Pharmacogenetics & Genomics, 23(4), 242-248
Open this publication in new window or tab >>Nomenclature for alleles of the thiopurine methyltransferase gene
Show others...
2013 (English)In: Pharmacogenetics & Genomics, ISSN 1744-6872, E-ISSN 1744-6880, Vol. 23, no 4, p. 242-248Article, review/survey (Refereed) Published
Abstract [en]

The drug-metabolizing enzyme thiopurine methyltransferase (TPMT) has become one of the best examples of pharmacogenomics to be translated into routine clinical practice. TPMT metabolizes the thiopurines 6-mercaptopurine, 6-thioguanine, and azathioprine, drugs that are widely used for treatment of acute leukemias, inflammatory bowel diseases, and other disorders of immune regulation. Since the discovery of genetic polymorphisms in the TPMT gene, many sequence variants that cause a decreased enzyme activity have been identified and characterized. Increasingly, to optimize dose, pretreatment determination of TPMT status before commencing thiopurine therapy is now routine in many countries. Novel TPMT sequence variants are currently numbered sequentially using PubMed as a source of information; however, this has caused some problems as exemplified by two instances in which authors articles appeared on PubMed at the same time, resulting in the same allele numbers given to different polymorphisms. Hence, there is an urgent need to establish an order and consensus to the numbering of known and novel TPMT sequence variants. To address this problem, a TPMT nomenclature committee was formed in 2010, to define the nomenclature and numbering of novel variants for the TPMT gene. A website (http://www.imh.liu.se/tpmtalleles) serves as a platform for this work. Researchers are encouraged to submit novel TPMT alleles to the committee for designation and reservation of unique allele numbers. The committee has decided to renumber two alleles: nucleotide position 106 (Gandgt;A) from TPMT*24 to TPMT*30 and position 611 (Tandgt;C, rs79901429) from TPMT*28 to TPMT*31. Nomenclature for all other known alleles remains unchanged. Pharmacogenetics and Genomics 23: 242-248

Place, publisher, year, edition, pages
Lippincott, Williams and Wilkins, 2013
Keywords
allele, nomenclature, pharmacogenetics, thiopurine methyltransferase
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-90743 (URN)10.1097/FPC.0b013e32835f1cc0 (DOI)000316109700009 ()
Note

Funding Agencies|Swedish Childrens Cancer Foundation||Swedish Cancer Society||NHMRC||Gutsy Group||NIH|R37 CA 36401U01 GM 92666U01 HL 105918P30 CA 21765UL1 RR025747P01CA142538GM 92666HL 105918U19 GM61388RO1 GM28157RO1 CA132780R24 GM61374|ALSAC||Jim and Mary Carney Charitable Trust, Whangarei, New Zealand||Leukaemia and Lymphoma Research, London, UK||Guys and St Thomas Charity||Robert Bosch Foundation, Stuttgart||Deutsche Forschungsgemeinschaft, Germany|SFB685|Childrens Cancer Foundation, Singapore||Newcastle Healthcare Charity||Newcastle upon Tyne Hospitals NHS Charity||

Available from: 2013-04-05 Created: 2013-04-05 Last updated: 2017-12-06
Hindorf, U. & Lindqvist Appell, M. (2012). Genotyping should be considered the primary choice for pre-treatment evaluation of thiopurine methyltransferase function. Journal of Crohn's and Colitis, 6(6), 655-659
Open this publication in new window or tab >>Genotyping should be considered the primary choice for pre-treatment evaluation of thiopurine methyltransferase function
2012 (English)In: Journal of Crohn's and Colitis, ISSN 1873-9946, Vol. 6, no 6, p. 655-659Article in journal (Refereed) Published
Abstract [en]

Background and aims

A pre-treatment determination of the thiopurine S-methyltransferase (TPMT) genotype or phenotype can identify patients at risk of developing severe adverse reactions from thiopurine treatment. The risk of misclassifying a patient might be dependent on the method used. The aim of this study was to investigate the concordance between TPMT genotyping and phenotyping.

Methods

The data consist of 7195 unselected and consecutive TPMT genotype and phenotype determinations sent to the division of Clinical Pharmacology, Linköping, Sweden. TPMT activity was measured in red blood cells (RBC) and the genotype determined by pyrosequencing for the three most common TPMT variants (TPMT *2, *3A, *3C).

Results

TPMT genotyping identified 89% as TPMT wild type (*1/*1), 10% as TPMT heterozygous and 0.5% as TMPT defective. The overall concordance between genotyping and phenotyping was 95%, while it was 96% among IBD patients (n = 4024). Genotyping would have misclassified 8% of the TPMT defectives as heterozygous as compared to 11% if only TPMT activity had been measured. 11% of the heterozygous patients had a normal TPMT activity (> 8.9 U/ml RBC) and 3% of the TPMT wild-type patients had an intermediate TPMT activity (2.5–8.9 U/ml RBC).

Conclusions

There is a risk for TPMT misclassification when only genotyping or phenotyping is used, but it is not reasonable to check both in all patients. Since TPMT genotyping is the more reliable test, especially in TPMT heterozygotes, we suggest that genotyping should be considered the primary choice for the pre-treatment evaluation of TPMT function before initiation of thiopurine therapy.

Place, publisher, year, edition, pages
Elsevier, 2012
Keywords
Thiopurine methyltransferase, Thiopurines, Inflammatory bowel diseases, Genotype, Phenotype
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-79120 (URN)10.1016/j.crohns.2011.11.014 (DOI)000305874000003 ()
Available from: 2012-06-29 Created: 2012-06-29 Last updated: 2013-09-03
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-2809-7591

Search in DiVA

Show all publications