Cancer pharmacogenomics: powerful tools in cancer chemotherapy and drug development.
Interindividual differences in tumor response and normal tissue toxicities are consistently observed with most chemotherapeutic agents or regimens. While many clinical variables have been associated with drug responses (e.g., age, gender, diet, drug-drug interactions), inherited variations in drug disposition (metabolism and transport) genes and drug target genes also likely contribute to the observed variability in cancer treatment outcome. Pharmacogenomic studies aim to elucidate the genetic bases for interindividual differences and to use such genetic information to predict the safety, toxicity, and/or efficacy of drugs. There exist several clinically relevant examples of the utility of pharmacogenomics that associate specific genetic polymorphisms in drug metabolizing enzymes (e.g., TPMT, UGT1A1, DPD), drug transporters (MDR1), and drug target enzymes (TS) with clinical outcomes in patients treated with commonly prescribed chemotherapy drugs, such as 5-fluorouracil and irinotecan (Camptosar; Pfizer Pharmaceuticals; New York, NY http://www.pfizer.com). Techniques to discover and evaluate the functional significance of these polymorphisms have evolved in recent years and may soon be applied to clinical practice and clinical trials of currently prescribed anticancer drugs as well as new therapeutic agents. This review discusses the current and future applications of pharmacogenomics in clinical cancer therapy and cancer drug development.
Lee
Wooin
W
Department of Medicine, Division of Medical Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, USA. wooin.lee@vanderbilt.edu
Lockhart
A Craig
AC
Kim
Richard B
RB
Rothenberg
Mace L
ML
D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*; D001711:Biotransformation / Q000187:drug effects / Q000235:genetics; D016503:Drug Delivery Systems; D020536:Enzyme Activators / Q000493:pharmacokinetics; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics; D006239:Haplotypes; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D010597:Pharmacogenetics / Q000379:methods*; D011110:Polymorphism, Genetic / Q000187:drug effects / Q000235:genetics
D000964:Antimetabolites, Antineoplastic; D020536:Enzyme Activators; D004791:Enzyme Inhibitors