SLC28A3 genotype and gemcitabine rate of infusion affect dFdCTP metabolite disposition in patients with solid tumours

Khatri, Amit; Williams, Brent; Fisher, James E.; Brundage, Richard C.; Gurvich, Vadim J.; Lis, L. G.; Skubitz, Keith M.; Dudek, Arkadiusz Z.; Greeno, Edward; Kratzke, Robert A.; Lamba, Jatinder K.; Kirstein, Mark N.

doi:10.1038/bjc.2013.738

Cited by 22 publications

(16 citation statements)

References 32 publications

(59 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[41] However, the concentration plateau of dFdCTP was not reached within the first 4 hours after infusion. An explanation for this finding is not readily apparent as different nucleoside membrane transporter genotypes and different infusion rates (8 -50 mg/m 2 /min) affect the rate and extent of dFdCTP accumulation, [42] and these factors were not assessed in our preliminary study. We suggest the presented LC-MS/MS method to be a useful tool in future studies of the nucleotide pool and of intracellular gemcitabine pharmacology.…”

Section: Application Of the Methodsmentioning

confidence: 81%

Liquid chromatography/tandem mass spectrometry method for simultaneous quantification of eight endogenous nucleotides and the intracellular gemcitabine metabolite dFdCTP in human peripheral blood mononuclear cells

Kamčeva

Bjånes

Svardal

et al. 2015

Journal of Chromatography B

View full text Add to dashboard Cite

Section: Application Of the Methodsmentioning

confidence: 81%

Liquid chromatography/tandem mass spectrometry method for simultaneous quantification of eight endogenous nucleotides and the intracellular gemcitabine metabolite dFdCTP in human peripheral blood mononuclear cells

Kamčeva

Bjånes

Svardal

et al. 2015

Journal of Chromatography B

View full text Add to dashboard Cite

“…It should be noted that the validation material used in this study was not completely independent of the screening because the remaining non-extreme patients were used for the validation in addition to an independent patient cohort. Several studies have previously associated toxicity and response with variants of candidate genes involved in metabolism and transport of gemcitabine such as CDA, dCK, SLC28A1, SLC28A3 as well as target molecules RRM1, RRM2 and RRM2b (19)(20)(21)(22)(23)(24). In a recent metaanalysis, the genetic variant A79C in the CDA gene was associated with severe anemia, but without being able to show an effect related to neutropenia, thrombocytopenia, or response (25).…”

Section: Discussionmentioning

confidence: 99%

Using Whole-Exome Sequencing to Identify Genetic Markers for Carboplatin and Gemcitabine-Induced Toxicities

Gréen

Hasmats

Kupershmidt

et al. 2016

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: Chemotherapies are associated with significant interindividual variability in therapeutic effect and adverse drug reactions. In lung cancer, the use of gemcitabine and carboplatin induces grade 3 or 4 myelosuppression in about a quarter of the patients, while an equal fraction of patients is basically unaffected in terms of myelosuppressive side effects. We therefore set out to identify genetic markers for gemcitabine/carboplatin-induced myelosuppression.Experimental Design: We exome sequenced 32 patients that suffered extremely high neutropenia and thrombocytopenia (grade 3 or 4 after first chemotherapy cycle) or were virtually unaffected (grade 0 or 1). The genetic differences/polymorphism between the groups were compared using six different bioinformatics strategies: (i) whole-exome nonsynonymous single-nucleotide variants association analysis, (ii) deviation from Hardy-Weinberg equilibrium, (iii) analysis of genes selected by a priori biologic knowledge, (iv) analysis of genes selected from gene expression meta-analysis of toxicity datasets, (v) Ingenuity Pathway Analysis, and (vi) FunCoup network enrichment analysis.Results: A total of 53 genetic variants that differed among these groups were validated in an additional 291 patients and were correlated to the patients' myelosuppression. In the validation, we identified rs1453542 in OR4D6 (P ¼ 0.0008; OR, 5.2; 95% CI, 1.8-18) as a marker for gemcitabine/carboplatin-induced neutropenia and rs5925720 in DDX53 (P ¼ 0.0015; OR, 0.36; 95% CI, 0.17-0.71) as a marker for thrombocytopenia. Patients homozygous for the minor allele of rs1453542 had a higher risk of neutropenia, and for rs5925720 the minor allele was associated with a lower risk for thrombocytopenia.Conclusions: We have identified two new genetic markers with the potential to predict myelosuppression induced by gemcitabine/carboplatin chemotherapy. Clin Cancer Res; 22(2); 366-73.Ó2015 AACR.

show abstract

“…The variants are associated with altered risk of disease progression and progression-free survival [27][28][29][30][31][32][33][34][35] . The NT5C2 gene codes for an enzyme involved in dephosphorylation of monophosphorylated gemcitabine and the particular variant included is associated with decreased clearance of intravenous gemcitabine 36,37 . NUDT15 was selected as it is important in metabolism of thiopurines and variants in NUDT15 are associated with increased risk of thiopurineinduced toxicity.…”

Section: Selection Of Variantsmentioning

confidence: 99%

Analytical Validation of Variants to Aid in Genotype-Guided Therapy for Oncology

Swart

Stansberry

Pratt

et al. 2019

The Journal of Molecular Diagnostics

View full text Add to dashboard Cite

The Clinical Laboratory Improvement Amendments (CLIA) of 1988 requires that pharmacogenetic genotyping methods need to be established according to technical standards and laboratory practice guidelines before testing can be offered to patients. Testing methods for variants in ABCB1, CBR3, COMT, CYP3A7, C8ORF34, FCGR2A, FCGR3A, HAS3, NT5C2, NUDT15, SBF2, SEMA3C, SLC16A5, SLC28A3, SOD2, TLR4, and TPMT were validated in a CLIA-accredited laboratory. As no known reference materials were available, DNA samples that were from Coriell Cell Repositories (Camden, NJ) were used for the analytical validation studies. Pharmacogenetic testing methods developed here were shown to be accurate and 100% analytically sensitive and specific. Other CLIA-accredited laboratories interested in offering pharmacogenetic testing for these genetic variants, related to genotype-guided therapy for oncology, could use these publicly available samples as reference materials when developing and validating new genetic tests or refining current assays.

show abstract

SLC28A3 genotype and gemcitabine rate of infusion affect dFdCTP metabolite disposition in patients with solid tumours

Abstract: Background: Gemcitabine is used for the treatment of several solid tumours and exhibits high inter-individual pharmacokinetic variability. In this study, we explore possible predictive covariates on drug and metabolite disposition.

Cited by 22 publications

References 32 publications

Liquid chromatography/tandem mass spectrometry method for simultaneous quantification of eight endogenous nucleotides and the intracellular gemcitabine metabolite dFdCTP in human peripheral blood mononuclear cells

Liquid chromatography/tandem mass spectrometry method for simultaneous quantification of eight endogenous nucleotides and the intracellular gemcitabine metabolite dFdCTP in human peripheral blood mononuclear cells

Using Whole-Exome Sequencing to Identify Genetic Markers for Carboplatin and Gemcitabine-Induced Toxicities

Analytical Validation of Variants to Aid in Genotype-Guided Therapy for Oncology

Contact Info

Product

Resources

About