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Reduced folate carrier polymorphism determines methotrexate uptake by B cells and CD4+ T cells
Department of Rheumatology, Rigshospitalet and the University of Copenhagen.
Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
Institute for Inflammation Research, Rigshospitalet, The University Hospital of Copenhagen, Denmark..
2008 (English)In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 47, no 4, 451-453 p.Article in journal (Refereed) Published
Abstract [en]

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

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

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

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

Place, publisher, year, edition, pages
2008. Vol. 47, no 4, 451-453 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-77610DOI: 10.1093/rheumatology/ken073PubMedID: 18316334OAI: oai:DiVA.org:liu-77610DiVA: diva2:528122
Available from: 2012-05-24 Created: 2012-05-24 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Pharmacogenetic studies in childhood acute lymphoblastic leukaemia with primary focus on methotrexate
Open this publication in new window or tab >>Pharmacogenetic studies in childhood acute lymphoblastic leukaemia with primary focus on methotrexate
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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

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

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

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

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

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

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

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

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2012. 83 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1302
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:liu:diva-77625 (URN)978-91-7519-929-0 (ISBN)
Public defence
2012-05-31, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2012-05-24 Created: 2012-05-24 Last updated: 2012-05-24Bibliographically approved

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