期刊
ANTI-CANCER DRUGS
卷 20, 期 10, 页码 867-879出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/CAD.0b013e328330c7d2
关键词
colorectal cancer; delayed diarrhoea; drug metabolism; efficacy; gene polymorphism; irinotecan; neutropenia; racial variability; toxicity; UGT1A1
Irinotecan [Camptosar (CPT-11), Pfizer Pharmaceuticals, New York, USA] is one of the most effective chemotherapeutic agents in the treatment of metastatic colorectal cancer. In vivo, the prodrug CPT-11 is biotransformed by carboxylesterase into its active metabolite SN-38. SN-38 is inactivated by uridine disphosphate glucuronosyl transferalse 1 (UGT1A1) into the inactive compound SN-38G, which is excreted with the bile. This review concentrates on a critical evaluation of UGT1A1 gene polymorphism as a predictor of toxicity and treatment efficacy in patients who received irinotecan for metastatic colorectal cancer. Irinotecan is explained with its main toxicities as well as the underlying mechanisms. The enzyme UGT1A1 is shown in the context of other metabolic pathways and different UGT enzymes involved. We will review in detail the controversy of the current literature with regard to the significance of identifying patients carrying the homozygous genotype UGT1A1*28. Racial differences concerning UGT enzymes have to be considered when discussing a pragmatic approach to determine gene polymorphisms as a predictor of treatment efficacy and outcome in patients receiving irinotecan-based chemotherapy. Dose dependency of toxicity and the clinical relevance of various UGT1 enzymes and single nucleotide polymorphisms in different alternative metabolic pathways are clarified to put UGT1A1 genotyping in a broad context with additional and competing strategies of patient-tailored therapy. Anti-Cancer Drugs 20:867-879 (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
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