Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity:A pharmacogenetic analysis

Citation
Y. Ando et al., Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity:A pharmacogenetic analysis, CANCER RES, 60(24), 2000, pp. 6921-6926
Citations number
32
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Oncology,"Onconogenesis & Cancer Research
Journal title
CANCER RESEARCH
ISSN journal
0008-5472 → ACNP
Volume
60
Issue
24
Year of publication
2000
Pages
6921 - 6926
Database
ISI
SICI code
0008-5472(200012)60:24<6921:POUGAI>2.0.ZU;2-G
Abstract
Irinotecan unexpectedly causes severe toxicity of leukopenia or diarrhea, I rinotecan is metabolized to form active SN-38, which is further conjugated and detoxified by UDP-glucuronosyltransferase (UGT) 1A1 enzyme. Genetic pol ymorphisms of the UGT1A1 would affect an interindividual variation of the t oxicity by irinotecan via the alternation of bioavailability of SN-38. In t his case-control study, retrospective review of clinical records and determ ination of UGT1A1 polymorphisms were performed to investigate whether a pat ient with the variant UGT1A1 genotypes would be at higher risk for severe t oxicity by irinotecan, All patients previously received irinotecan against cancer in university hospitals, cancer centers, or large urban hospitals in Japan. We identified 26 patients who experienced severe toxicity and 92 pa tients who did not. The relationship was studied between the multiple varia nt genotypes (UGT1A1*28 in the promoter and UGT1A1*6, UGT1A1*27, UGT1A1*29, and UGT1A1*7 in the coding region) and the severe toxicity of grade 4 leuk openia (less than or equal to0.9 x 10(9)/liter) and/or grade 3 (watery for 5 days or more) or grade 4 (hemorrhagic or dehydration) diarrhea. Of the 26 patients with the severe toxicity, the genotypes of UGT1A1*28 were homozyg ous in 4 (15%) and heterozygous in 8 (31%), whereas 3 (3%) homozygous and 1 0 (11%) heterozygous were found among the 92 patients without the severe to xicity. Multivariate analysis suggested that the genotype either heterozygo us or homozygous for UGT1A1*28 would he a significant risk factor for sever e toxicity by irinotecan (P < 0.001; odds ratio, 7.23; 95% confidence inter val, 2.52-22.3). All 3 patients heterozygous for UGT1A1*27 encountered seve re toxicity. No statistical association of UGT1A1*6 with the occurrence of severe toxicity was observed. None had UGT1A1*29 or UGT1A1*7, We suggest th at determination of the UGT1A1 genotypes might he clinically useful for pre dicting severe toxicity by irinotecan in cancer patients. This research war rants a prospective trial to corroborate the usefulness of gene diagnosis o f UGT1A1 polymorphisms prior to irinotecan chemotherapy.