Pharmacogenomics of drug metabolizing enzymes and transporters: implications for cancer therapy

Abstract

The new era of personalized medicine, which integrates the uniqueness of an individual with respect to the pharmacokinetics and pharmacodynamics of a drug, holds promise as a means to provide greater safety and efficacy in drug design and development. Personalized medicine is particularly important in oncology, whereby most clinically used anticancer drugs have a narrow therapeutic window and exhibit a large interindividual pharmacokinetic and pharmacodynamic variability. This variability can be explained, at least in part, by genetic variations in the genes encoding drug metabolizing enzymes, transporters, or drug targets. Understanding of how genetic variations influence drug disposition and action could help in tailoring cancer therapy based on individual's genetic makeup. This review focuses on the pharmacogenomics of drug metabolizing enzymes and drug transporters, with a particular highlight of examples whereby genetic variations in the metabolizing enzymes and transporters influence the pharmacokinetics and/or response of chemotherapeutic agents.

Keywords: drug; enzymes; oncology; personalized medicine; polymorphisms; transporters.

Figure 1

Pathways that affect 5-FU efficacy. Genetic polymorphisms within the genes that are involved in 5-FU metabolic activation (eg, OPRT), detoxification (eg, DPD), and target interaction (eg, TS) are important determinants of the efficacy and safety of 5-FU treatment. Copyright © 2009. Nature Publishing Group. Adapted and reprinted with permission: Walther A, Johnstone E, Swanton C, Midgley R, Tomlinson I, Kerr D. Genetic prognostic and predictive markers in colorectal cancer. Nat Rev Cancer. 2009;9:489–499. Abbreviations: 5′DFCR, 5′deoxy-5-fluorocytidine; 5′DFUR, 3′deoxy-5-fluorouridine; 5-FU, 5-fluorouracil; 5-FUR, 5-fluorouridine; CDD, cytosine deaminase; CES, carboxylesterase; DHP, dihydropyrimidinase; DPD, dihydropyrimidine dehydrogenase; FBAL, fluoro-b-alanine; FUH2, dihydro-5-fluorouracil; MTHFR, methylenetetrahydrofolate reductase; OPRT, orotate phosphoribosyltransferase; RNR, ribonucleotide reductase; TK, thymidine kinase; TP, thymidine phosphorylase; TS, thymidylate synthase; UK, uridine-cytidine kinase 2; UP, uridine phosphorylase 1.

Figure 2

Schematic illustration of irinotecan disposition pathway. Irinotecan is activated to 7-ethyl-10-hydroxycamptothecin (SN-38) by human carboxylesterase 1 and 2 (hCE1 and hCE2), and SN-38 is subsequently detoxified by UGT1A1 to a β-glucuronide derivative, SN-38G. In addition, irinotecan undergoes CYP3A4-mediated oxidation to form the inactive metabolites 7-ethyl-10-(4-N-(5-aminopentanoic acid)-1-peperidino) carbonyloxycamptothecin (APC) and 7-ethyl-10-(4-amino-1-peperidino) carbonyloxycamptothecin (NPC), and NPC also undergo a subsequent conversion by hCE2 to SN-38. Irinotecan and its metabolites (ie, SN-38 and SN-38G) are also transported by the ABC transporters including ABCB1, ABCC1/2, or ABCG2 or the organic anion transporting polypeptide 1B1 (OATP1B1). Adapted and reprinted by permission from the American Association for Cancer Research: van Erp NP, Baker SD, Zhao M, et al. Effect of milk thistle (Silybum marianum) on the pharmacokinetics of irinotecan. Clin Cancer Res. 2005;11:7800–7806.

Figure 3

Metabolism pathway of tamoxifen and its interaction with estrogen receptors. Copyright © 2009. Nature Publishing Group. Adapted and reprinted with permission; Hoskins JM, Carey LA, McLeod HL. CYP2D6 and tamoxifen: DNA matters in breast cancer. Nat Rev Cancer 2009;9:576–586. Abbreviations: CYP, cytochrome P450; ER, estrogen receptor; FMO, flavin-containing monooxygenases; SULT1A1, sulphotransferase 1A1; UGT, uridine diphosphate glucuronosyltransferase.