title: Clinical observations on associations between the UGT1A1 genotype and severe toxicity of irinotecan.
abstract: BACKGROUND
  Severe toxicity is commonly observed in cancer patients receiving irinotecan (CPT-11). UDP glucuronosyltransferase1A1 (UGT1A1) catalyzes the glucuronidation of the active metabolite SN-38 but the relationship between UGT1A1 and severe toxicity remains unclear. Our study aimed to assess this point to guide clinical use of CPT-11.
  
  
  METHODS
  89 cancer patients with advanced disease received CPT-11-based chemotherapy for at least two cycles. Toxicity, including GI and hematologic toxicity was recorded in detail and UGT1A1 variants were genotyped. Regression analysis was used to analyse relationships between these variables and tumor response.
  
  
  RESULTS
  The prevalence of grade III-IV diarrhea was 10.1%, this being more common in patients with the TA 6/7 genotype (5 of 22 patients, 22.7%) (p<0.05). The prevalence of grade III-IV neutropenia was 13.4%and also highest in patients with the TA 6/7 genotype (4 of 22 patients; 18.2%) but without significance (p>0.05). The retreatment total bilirubin levels were significantly higher in TA6/7 patients (mean, 12.75μmol/L) with compared to TA6/6 (mean, 9.92 μmol/L) with p<0.05.
  
  
  CONCLUSIONS
  Our study support the conclusion that patients with a UGT1A1*28 allele (s) will suffer an increased risk of severe irinotecan-induced diarrhea, whether with mid-or low-dosage. However, the UGT1A1*28 allele (s) did not increase severe neutropenia. Higher serum total bilirubin is an indication that patients UGT1A1 genotype is not wild-type, with significance for clinic usage of CPT-11.
authors.affiliation: Department of Chemotherapy, the Affiliated Jiangsu Cancer Hospital of Nanjing Medical University and Jiangsu Institute of Cancer Research, Nanjing, China E-mail : huangxinen06@aliyun.com.
authors.forename: Yan-Yan
authors.initials: YY
authors.lastname: Lu
authors.forename: Xin-En
authors.initials: XE
authors.lastname: Huang
authors.forename: Xue-Yan
authors.initials: XY
authors.lastname: Wu
authors.forename: Jie
authors.initials: J
authors.lastname: Cao
authors.forename: Jin
authors.initials: J
authors.lastname: Liu
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Jin
authors.initials: J
authors.lastname: Xiang
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects* / Q000627:therapeutic use; D001663:Bilirubin / Q000097:blood; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D003967:Diarrhea / Q000139:chemically induced; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced; D055815:Young Adult; D000099148:UGT1A1 Enzyme
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001663:Bilirubin; D002166:Camptothecin; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D000099148:UGT1A1 Enzyme