Genetic determinants of cancer drug efficacy and toxicity:: practical considerations and perspectives

Drug-metabolizing enzymes are responsible for the activation or detoxification of cytotoxic drugs. Allelic variants are present with a variable frequency in different populations around the world and have an important role in the therapeutic index of such drugs. It is known that polymorphisms in thiopurine methyltransferase and dihydropyrimidine dehydrogenase have been associated with altered drug metabolism and increased risk of severe toxicity from 6-mercaptopurine and 5-fluorouracil, respectively. Additionally, a variant number of dinucleotide-repeat sequences in the promotor for uridine 5'-diphosphate glucuronosyltransferase 1A1 influences the glucuronidation of SN-38, the active metabolite of irinotecan, which is associated with severe toxicity, including diarrhea and neutropenia. In the same way, polymorphisms in thymidylate synthase have been associated with pyrimidine-associated toxicity and also with response to chemotherapy. The examples shown in this review demonstrate the usefulness of pre-screening patients for well-characterized polymorphism to identify the best-tolerated and most-effective treatment.