Genetic determinants of cancer drug efficacy and toxicity:... : Anti-Cancer Drugs (original) (raw)

REVIEW PAPERS

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

Candelaria, Myrnaa; Taja-Chayeb, Luciab; Arce-Salinas, Claudiaa; Vidal-Millan, Silviab; Serrano-Olvera, Albertoa; Dueñas-Gonzalez, Alfonsoc

Divisions of aClinical Research

bBasic Research, Instituto Nacional de Cancerología

cUnidad de Investigación Biomédica en Cancer, Instituto Nacional de Cancerología/Instituto de Investigaciones Biomédicas, UNAM, Tlalpan, Mexico

Correspondence to M. Candelaria, Instituto Nacional de Cancerología. Ave. San Fernando 22, Col. Sección XVI, CP 14080, Tlalpan, Mexico, DF Mexico

Tel: +52 55 5628 04 79; fax: +52 55 5573 46 62;

e-mail: [email protected]

Received 9 May 2005 Revised form accepted 8 July 2005

Abstract

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.