UGT1A1 genotyping: a predictor of irinotecan-associated side effects and drug efficacy?
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 transferase 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.
Schulz
Christoph
C
Department of Haematology, Ludwig-Maximilians University of Munich, Campus Grosshadern, Munich, Germany.
Boeck
Stefan
S
Heinemann
Volker
V
Stemmler
Hans-Joachim
HJ
D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000627:therapeutic use; D001663:Bilirubin / Q000097:blood; D054316:Biomarkers, Pharmacological; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000208:ethnology; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics; D000077146:Irinotecan; D008954:Models, Biological; D009362:Neoplasm Metastasis; D011110:Polymorphism, Genetic; D057285:Precision Medicine / Q000379:methods; D044469:Racial Groups / Q000235:genetics
D000972:Antineoplastic Agents, Phytogenic; D054316:Biomarkers, Pharmacological; D000077146:Irinotecan; D014453:Glucuronosyltransferase; D001663:Bilirubin; D002166:Camptothecin