Novel Genetic Variants in Carboxylesterase 1 Predict Severe Early-Onset Capecitabine-Related Toxicity.
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Hamzic S, Kummer D, Milesi S, Mueller D, Joerger M, Aebi S, Amstutz U, Largiader CR
Novel Genetic Variants in Carboxylesterase 1 Predict Severe Early-Onset Capecitabine-Related Toxicity.
Clin Pharmacol Ther. 2017 Nov;102(5):796-804. doi: 10.1002/cpt.641. Epub 2017 May 30.
- PubMed ID
- 28139840 [ View in PubMed]
- Abstract
An important concern with the anticancer drug capecitabine (Cp), an oral prodrug of 5-fluorouracil, are dose-limiting adverse effects, in particular hand-foot syndrome (HFS) and diarrhea. Here we evaluated the association of genetic variability in all enzymes of the Cp-activation pathway to 5-fluorouracil with Cp-related early-onset toxicity in 144 patients receiving Cp. We identified a haplotype encompassing five variants in the carboxylesterase 1 (CES1) gene region including an expression quantitative trait locus associated with early-onset Cp-toxicity (Haplotype A3: OR(additive) = 2.2, 95% CI 1.2-4.0, P(adjusted) = 0.012; OR(recessive) = 10.3, 95% CI 2.1-49.4, P(adjusted) = 0.0038). Furthermore, the association of two linked cytidine deaminase (CDA) promoter variants (c.1-451C>T: OR(dominant) = 4.3, 95% CI 1.3-14.2, P(adjusted) = 0.017; and c.1-92A>G: OR(dominant) = 4.4, 95% CI 1.3-14.5, P(adjusted) = 0.015) with Cp-related diarrhea was replicated. This first study identifying an association of genetic variation in CES1 with Cp-related toxicity provides further evidence for the existence of a functional noncoding CES1-variant with a possible regulatory impact.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Capecitabine Uridine phosphorylase 1 Protein Humans NoSubstrateDetails Capecitabine Uridine phosphorylase 2 Protein Humans NoSubstrateDetails