Relevance of different UGT1A1 polymorphisms in irinotecan-induced toxicity: a molecular and clinical study of 75 patients.
OBJECTIVE
We wanted to assess polymorphisms in the uridine diphosphoglucuronosyl transferase 1A1 (UGT 1A1) gene: the TATA box polymorphism and UGT 1A1 G71R and Y486D mutations in the coding sequence, the main mutations characterizing Gilbert's syndrome, as predictors of severe toxic event occurrence after irinotecan (CPT-11) administration. Therefore, we set up a rapid, sensitive, and reliable technique in routine practice to detect before CPT-11 treatment, the at-risk patients.


METHODS
Seventy-five patients with advanced colorectal cancer and treated with CPT-11 and 5-fluorouracil, entered the study. We used the Pyrosequencing technology a real-time sequencing method, to detect the UGT 1A1 TATA box polymorphisms and mutations in the coding regions. Patients were also assessed for both biochemical and clinical evaluation and tolerance to treatment.


RESULTS
No G71R and Y486D mutations were found in our population. Frequencies for UGT 1A1 TATA box polymorphisms were 41, 47, and 9% for wild-type 6/6, heterozygous 6/7, and Gilbert's syndrome 7/7, respectively. Tolerance to treatment decreased with increased number of TA repeat with 71% of the patients in 7/7 group who experienced grade 3/4 toxicity.


CONCLUSIONS
The method we set up is suitable for the detection of UGT 1A1 polymorphism in routine practice before irinotecan treatment. It could help to detect the patients homozygous or heterozygous for Gilbert's syndrome, at-risk of CPT 11-induced toxicity, and thus could help to individualize the dose to optimize efficacy and limit toxicity.
Rouits
Elisabeth
E
Laboratoire d'Oncopharmacologie-INSERM U564, ANGERS Cedex 01, France.
Boisdron-Celle
Michèle
M
Dumont
Agnès
A
Guérin
Olivier
O
Morel
Alain
A
Gamelin
Erick
E
D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000633:toxicity; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001483:Base Sequence; D002166:Camptothecin / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000633:toxicity*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D017931:DNA Primers / Q000737:chemistry / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005822:Genetic Vectors; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009362:Neoplasm Metastasis; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012306:Risk; D017422:Sequence Analysis, DNA; D000099148:UGT1A1 Enzyme
D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D017931:DNA Primers; D005472:Fluorouracil; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D000099148:UGT1A1 Enzyme