Abstract |
We studied whether common polymorphisms in genes involved in folate metabolism affect methotrexate (MTX) sensitivity. Ex vivo MTX sensitivity of lymphoblasts obtained from pediatric patients with acute lymphoblastic leukemia (ALL; n = 157) was determined by the in situ thymidylate synthase inhibition assay after either continuous (21 hours; TSI(50, cont)) or short-term (3 hours; TSI(50, short)) MTX exposure. DNA was isolated from lymphoblasts obtained from cytospin slides. Polymorphisms in methylenetetrahydrofolate reductase (MTHFR 677C>T, MTHFR 1298A>C), methionine synthase (MTR 2756A>G), methionine synthase reductase (MTRR 66A>G), methylenetetrahydrofolate dehydrogenase (MTHFD1 1958G>A), serine hydroxymethyl transferase (SHMT1 1420C>T), thymidylate synthase (TS 2R3R), and the reduced folate carrier (RFC 80G>A) were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or real-time PCR. Patients with the MTHFR 1298AC variant or the MTRR 66 G-allele showed decreased in vitro MTX sensitivity measured under both test conditions. SHMT1 1420TT homozygotes only showed decreased MTX sensitivity in the TSI(50, cont). In conclusion, polymorphisms in the folate-related genes MTHFR, MTRR, and SHMT1 are related to MTX resistance in pediatric patients with ALL.
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Authors | Robert de Jonge, Jan Hendrik Hooijberg, Bertrand D van Zelst, Gerrit Jansen, Gerritz Jansen, Christina H van Zantwijk, Christine H van Zantwijk, Gertjan J L Kaspers, Gert Jan L Kaspers, Godefridus J Peters, Frits G J Peters, Yaddanapudi Ravindranath, Rob Pieters, Jan Lindemans |
Journal | Blood
(Blood)
Vol. 106
Issue 2
Pg. 717-20
(Jul 15 2005)
ISSN: 0006-4971 [Print] United States |
PMID | 15797993
(Publication Type: Journal Article)
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Chemical References |
- Antimetabolites, Antineoplastic
- Folic Acid
- methionine synthase reductase
- Ferredoxin-NADP Reductase
- Methylenetetrahydrofolate Reductase (NADPH2)
- Glycine Hydroxymethyltransferase
- Methotrexate
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Topics |
- Antimetabolites, Antineoplastic
(pharmacology)
- Child
- Drug Resistance, Neoplasm
(genetics)
- Ferredoxin-NADP Reductase
(genetics)
- Folic Acid
(genetics, metabolism)
- Genetic Variation
- Glycine Hydroxymethyltransferase
(genetics)
- Humans
- In Vitro Techniques
- Methotrexate
(pharmacology)
- Methylenetetrahydrofolate Reductase (NADPH2)
(genetics)
- Polymorphism, Genetic
- Precursor Cell Lymphoblastic Leukemia-Lymphoma
(drug therapy, genetics, metabolism)
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