Polymorphisms of metabolizing enzymes and transporter proteins involved in the clearance of anticancer agents

Abstract

Background: The efficacies and toxicities of anticancer agents vary greatly among patients. This is attributable to the activities of drug-metabolizing enzymes and membrane transporters, primarily determined by polymorphisms of the functions of genes encoding these proteins.

Design: We reviewed the available literature on drug-metabolizing enzymes and membrane transporters, especially their physiological functions, genetic and functional polymorphisms, and involvement in metabolism, pharmacokinetics and toxicity of anticancer agents.

Results: Nine enzymes metabolizing anticancer agents have been shown to have genetic polymorphisms: dihydropyrimidine dehydrogenase, cytochrome P450, NAD(P)H:quinone oxidoreductase 1, N-acetyltransferase 2, thiopurine methyltransferase, glutathione S-transferase, and uridine diphosphate glucuronosyltransferase. Decreased activities of these proteins can cause not only inherited metabolic disorders, but also extraordinarily severe toxicity in cancer patients given chemothearpy. Transporter proteins mediate cellular uptake and secretion of organic anions and cations. These proteins have recently been shown to play critical roles in the clearance of anticancer agents, although relations between patients' genetics backgrounds and the clinical significance of drug actions are poorly understood.

Conclusions: Further studies should be focused on dosing and selection of anticancer agents, based on the type and extent of metabolic variation among individuals, in order to avoid adverse reactions and therapeutic failure.