PharmGKB summary

Mikkelsen, Torben Stamm; Thorn, Caroline F.; Yang, Jun J.; Ulrich, Cornelia M.; French, Deborah; Zaza, Gianluigi; Dunnenberger, Henry M.; Marsh, Sharon; McLeod, Howard L.; Giacomini, Kathy; Becker, Mara L.; Gaedigk, Roger; Leeder, J. Steven; Kager, Leo; Relling, Mary V.; Evans, William E.; Klein, Teri E.; Altman, Russ B.

doi:10.1097/fpc.0b013e328343dd93

Cited by 123 publications

(73 citation statements)

References 108 publications

(47 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Methotrexate treatment (1 μM, 2 h) resulted in a 30-fold increase of DHF and 3- to 12-fold decreases in different THF species (Figure 6), consistent with methotrexate inhibiting dihydrofolate reductase, its canonical target (42, 43). …”

Section: Resultssupporting

confidence: 70%

An LC-MS chemical derivatization method for the measurement of five different one-carbon states of cellular tetrahydrofolate

Chen

Ducker

et al. 2017

Anal Bioanal Chem

View full text Add to dashboard Cite

The cofactor tetrahydrofolate (THF) is used to reduce, oxidize and transfer one-carbon (1C) units required for the synthesis of nucleotides, glycine, and methionine. Measurement of intracellular THF species is complicated by their chemical instability, signal dilution caused by variable polyglutamation and the potential for interconversion among these species. Here we describe a method using negative mode liquid chromatography-mass spectrometry (LC-MS) to measure intracellular folate species from mammalian cells. Application of this method with isotope-labeled substrates revealed abiotic interconversion of THF and methylene-THF, which renders their separate quantitation particularly challenging. Chemical reduction of methylene-THF using deuterated sodium cyanoborohydride traps methylene-THF, which is unstable, as deuterated 5-methyl-THF, which is stable. Together with proper sample handling and LC-MS, this enables effective measurements of five active folate pools (THF, 5-methyl-THF, methylene-THF, methenyl-THF/10-formyl-THF, and 5-formyl-THF) representing the biologically important 1C oxidation states of THF in mammalian cells.

show abstract

Section: Resultssupporting

confidence: 70%

An LC-MS chemical derivatization method for the measurement of five different one-carbon states of cellular tetrahydrofolate

Chen

Ducker

et al. 2017

Anal Bioanal Chem

View full text Add to dashboard Cite

show abstract

“…Doxorubicin and MTX are also substrates of P-glycoprotein, an efflux transporter that is the product of the ABCB1 [multi-drug resistance ( MDR - 1 )] gene (reviewed in [50, 51]). Lal et al [52] found that SNPs in ABCB1 increased drug exposure by decreasing its clearance.…”

Section: Discussionmentioning

confidence: 99%

Common variants in genes coding for chemotherapy metabolizing enzymes, transporters, and targets: a case–control study of contralateral breast cancer risk in the WECARE Study

Brooks

Teraoka

Bernstein

et al. 2013

Cancer Causes Control

View full text Add to dashboard Cite

PurposeWomen who receive chemotherapy for a first primary breast cancer have been observed to have a reduced risk of contralateral breast cancer (CBC), however, whether the genetic profile of a patient modifies this protective effect is currently not understood. The purpose of this study is to investigate the impact of germline genetic variation in genes coding for drug metabolizing enzymes, transporters, and targets on the association between chemotherapy and risk of CBC.MethodsFrom the population-based Women’s Environment Cancer and Radiation Epidemiology (WECARE) Study, we included 636 Caucasian women with CBC (cases) and 1,224 women with unilateral breast cancer (controls). The association between common chemotherapeutic regimens, CMF and FAC/FEC, and risk of CBC stratified by genotype of 180 single nucleotide polymorphisms in 14 genes selected for their known involvement in metabolism, action, and transport of breast cancer chemotherapeutic agents, were determined using conditional logistic regression.ResultsCMF (RR = 0.5, 95 % CI 0.4, 0.7) and FAC/FEC (RR = 0.7, 95 % CI 0.4, 1.0) are associated with lower CBC risk relative to no chemotherapy in multivariable-adjusted models. Here we show that genotype of selected genes involved in the metabolism and uptake of these therapeutic agents does not significantly alter the protective effect of either CMF or FAC/FEC on risk of CBC.ConclusionThe results of this study show that germline genetic variation in selected gene does not significantly alter the protective effect of CMF, FAC, and FEC on risk of CBC.Electronic supplementary materialThe online version of this article (doi:10.1007/s10552-013-0237-6) contains supplementary material, which is available to authorized users.

show abstract

“…The remaining human candidate genes listed in Table S2 are not associated with publications reporting a germline genetic polymorphism impacting MTX toxicity, although they are believed to be in the pathway that processes MTX, based on biochemical studies. The role of these “pathway implicated” genes is discussed most fully in a recent review by Mikkelsen et al (2011). Glutathione S -transferase (GST) is a strong human a priori candidate gene family with known pharmogenetic polymorphisms, but Ensembl’s fly ortholog prediction seems incorrect, we define the human GST fly orthologs to be the two Drosophila regions harboring tandemly repeated GST gene families.…”

Section: Methodsmentioning

confidence: 99%

The Genetic Architecture of Methotrexate Toxicity Is Similar in Drosophila melanogaster and Humans

Kislukhin

King

Walters

et al. 2013

G3 Genes|Genomes|Genetics

View full text Add to dashboard Cite

The severity of the toxic side effects of chemotherapy varies among patients, and much of this variation is likely genetically based. Here, we use the model system Drosophila melanogaster to genetically dissect the toxicity of methotrexate (MTX), a drug used primarily to treat childhood acute lymphoblastic leukemia and rheumatoid arthritis. We use the Drosophila Synthetic Population Resource, a panel of recombinant inbred lines derived from a multiparent advanced intercross, and quantify MTX toxicity as a reduction in female fecundity. We identify three quantitative trait loci (QTL) affecting MTX toxicity; two colocalize with the fly orthologs of human genes believed to mediate MTX toxicity and one is a novel MTX toxicity gene with a human ortholog. A fourth suggestive QTL spans a centromere. Local single-marker association scans of candidate gene exons fail to implicate amino acid variants as the causative single-nucleotide polymorphisms, and we therefore hypothesize the causative variation is regulatory. In addition, the effects at our mapped QTL do not conform to a simple biallelic pattern, suggesting multiple causative factors underlie the QTL mapping results. Consistent with this observation, no single single-nucleotide polymorphism located in or near a candidate gene can explain the QTL mapping signal. Overall, our results validate D. melanogaster as a model for uncovering the genetic basis of chemotoxicity and suggest the genetic basis of MTX toxicity is due to a handful of genes each harboring multiple segregating regulatory factors.

show abstract

PharmGKB summary

Cited by 123 publications

References 108 publications

An LC-MS chemical derivatization method for the measurement of five different one-carbon states of cellular tetrahydrofolate

An LC-MS chemical derivatization method for the measurement of five different one-carbon states of cellular tetrahydrofolate

Common variants in genes coding for chemotherapy metabolizing enzymes, transporters, and targets: a case–control study of contralateral breast cancer risk in the WECARE Study

The Genetic Architecture of Methotrexate Toxicity Is Similar in Drosophila melanogaster and Humans

Contact Info

Product

Resources

About