Recent advances in pharmacogenetic approaches to anticancer drug development

A great deal of effort has been spent in defining the pharmacokinetics and pharmacodynamics of investigational and registered anticancer agents. There is often a marked variability in drug handling between individual patients, which contributes to variability in the pharmacodynamic effects of a given dose of a drug. A combination of physiological variables, genetic characteristics (pharmacogenetics), and environmental factors are known to alter the relationship between the absolute dose and the concentration-time profile in plasma. A variety of strategies is now being evaluated in patients with cancer to improve the therapeutic index of anticancer drugs, by implementation of pharmacogenetic imprinting through genotyping or phenotyping individual patients. The efforts have mainly focused on variants in genes encoding the drug-metabolizing enzymes thiopurine S-methyltransferase, dihydropyrimidine dehydrogenase, members of the cytochrome P450 family, including the CYP2B, 2C, 2D, and 3A subfamilies, members of the UGT family, as well as the ATP-binding cassette transporters ABCB1 (P-glycoprotein) and ABCG2 (breast-cancer resistance protein). Several of these genotyping strategies have been shown to have substantial impact on therapeutic outcome and should eventually lead to improved anticancer chemotherapy.