Part 2: Pharmacogenetic Variability in Drug Transport and Phase I Anticancer Drug Metabolism

Abstract

After completing this course, the reader will be able to:1. List currently identified candidate genes involved in phase I metabolism that are potential pharmacogenetic markers in anticancer therapy.2. Describe the general effect on standard treatment of allelic variants of the candidate genes and the implications for individualized treatment.This article is available for continuing medical education credit at CME.TheOncologist.com. CME CME ABSTRACTEquivalent drug doses in anticancer chemotherapy may lead to wide interpatient variability in drug response reflected by differences in treatment response or in severity of adverse drug reactions. Differences in the pharmacokinetic (PK) and pharmacodynamic (PD) behavior of a drug contribute to variation in treatment outcome among patients. An important factor responsible for this variability is genetic polymorphism in genes that are involved in PK/PD processes, including drug transporters, phase I and II metabolizing enzymes, and The Oncologist CME Program is located online at http://cme.theoncologist.com/.To take the CME activity related to this article, you must be a registered user. ClinicalPharmacology:Pharmacogenetics:OpportunitiesforPatient-TailoredAnticancerTherapyThe Oncologist 2011;16:820 -834 www.TheOncologist.com by guest on May 12, 2018http://theoncologist.alphamedpress.org/ Downloaded from drug targets, and other genes that interfere with drug response. In order to achieve personalized pharmacotherapy, drug dosing and treatment selection based on genotype might help to increase treatment efficacy while reducing unnecessary toxicity. We present a series of four reviews about pharmacogenetic variability in anticancer drug treatment. This is the second review in the series and is focused on genetic variability in genes encoding drug transporters (ABCB1 and ABCG2) and phase I drug-metabolizing enzymes (CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, DPYD, CDA and BLMH) and their associations with anticancer drug treatment outcome. Based on the literature reviewed, opportunities for patient-tailored anticancer therapy are presented. The Oncologist 2011;16:820 -834

Pharmacogenomics of Gemcitabine Metabolism: Functional Analysis of Genetic Variants in Cytidine Deaminase and Deoxycytidine Kinase

“…However, conflicting data exist on the association of the CDA 79A.C mutation with response. In comparison with the C-allele (Gln27) carriers, the CDA79A allele (Lys27) has been associated with significantly decreased, increased, or comparable deaminase activity, suggested by clinical outcomes or dFdC pharmacokinetics (Deenen et al, 2011). On the other hand, the Pro122Ser variant of DCK was not associated with the dFdC treatment outcomes in 107 malignant mesothelioma patients (Er culj et al, 2012), although it was associated with decreased DCK expression and activity in vitro (Kocabas et al, 2008).…”

“…These polymorphisms include two nonsynonymous SNPs in CDA [79A.C (Lys27Gln) and 208G.A (Ala70Thr)] and three nonsynonymous SNPs in DCK (Ile24Val, Ala119Gly, and Pro122Ser) (Kocabas et al, 2008;Deenen et al, 2011). The haplotypes harboring 79A.C and 208G.A were designated CDA*2 and CDA*3, respectively.…”

“…The haplotypes harboring 79A.C and 208G.A were designated CDA*2 and CDA*3, respectively. The effects of the 208G.A mutation on clinical outcomes to dFdC treatment have been demonstrated (Deenen et al, 2011). However, conflicting data exist on the association of the CDA 79A.C mutation with response.…”

Analytical Methods for Quantification of Drug Metabolites in Biological Samples

“…Other typical phase I oxidation enzymes are monoamineoxidase (MAO), diamineoxidase (DAO), cyclooxygenase (COX), alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), molybdenum hydroxylase (include aldehyde oxidase, xanthine oxidase and xanthine dehydrogenase). In addition to promoting oxidative metabolism, cytochrome P450 enzymes may also catalyze reductive biotransformation reactions for the reduction of azo and nitro compounds to primary amines [10,12]. Hydrolytic enzymes that consist of non-specific esterases and amidases are also a member of phase I enzymes of metabolism [6,10].…”

Lack of ABCG2 Shortens Latency of BRCA1-Deficient Mammary Tumors and This Is Not Affected by Genistein or Resveratrol

“…Our data suggest that functional ABCG2 polymorphisms might influence tumorigenesis in women with a familiar breast cancer predisposition. Of the ABCG2 single nucleotide polymorphisms (SNP) identified, only a few influence drug transport efficiency and, therefore, pharmacokineticsrelated side effects in patients (33). The common SNP rs2231142 (421C>A), which encodes a Q141K loss of function mutation, causes at least 10% of all gout cases in the Caucasian American population of the United States (34).…”