Gilbert's Syndrome and irinotecan toxicity: combination with UDP-glucuronosyltransferase 1A7 variants increases risk
| Autor: | Tim O. Lankisch, Thomas Zwingers, Volker Heinemann, Christoph Schulz, Michael P. Manns, Christian P. Strassburg, Thomas J. Erichsen |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Oncology
Male Risk medicine.medical_specialty Genotype Epidemiology Single-nucleotide polymorphism Biology Irinotecan Polymorphism Single Nucleotide Statistics Nonparametric Internal medicine medicine SNP Humans Genetic Predisposition to Disease Glucuronosyltransferase Adverse effect Alleles Chi-Square Distribution Middle Aged medicine.disease Gilbert's syndrome Antineoplastic Agents Phytogenic Endocrinology Haplotypes Toxicity Camptothecin Female Gilbert Disease Pharmacogenetics medicine.drug |
| Zdroj: | Cancer epidemiology, biomarkersprevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 17(3) |
| ISSN: | 1055-9965 |
| Popis: | Background: Gilbert's syndrome is characterized by a functional promoter single nucleotide polymorphism (SNP) of the UDP-glucuronosyltransferase (UGT) 1A1 gene and represents a pharmacogenetic risk factor for irinotecan toxicity, but study data remain controversial. The active CPT-11 metabolite 7-ethyl-10-hydroxycamptothecin is detoxified by several UGT1A proteins, which include UGT1A7 with a high specific activity that may contribute to the risk of irinotecan toxicity in Gilbert's syndrome patients.Methods: Genotyping of the UGT1A1*28, UGT1A7 N129K/R131K, and UGT1A7-57T/G variants was done in 105 irinotecan-treated patients with metastatic colorectal cancer; adverse events were documented during all 297 treatment cycles and analyzed by Cochran-Mantel-Haenszel, Mann-Whitney, and χ2 tests.Results: The presence of UGT1A7 but not UGT1A1 variants was associated with at least one adverse event. In patients combining all three variants, thrombocytopenia and leukopenia were significantly more frequent. The overall incidence of adverse events was significantly higher (P = 0.0035) in carriers of the UGT1A risk alleles, who also had significantly higher rate of dose reductions.Conclusions: Irinotecan toxicity is more likely in patients with Gilbert's syndrome carrying the UGT1A1*28 allele combined with reduced function UGT1A7 N129K/R131K and UGT1A7-57T/G SNP. Based on the ability of UGT1A7 to metabolize and eliminate the active irinotecan metabolite 7-ethyl-10-hydroxycamptothecin, the UGT1A1/UGT1A7 SNP combination haplotype appears to be a superior risk predictor than Gilbert's syndrome alone. (Cancer Epidemiol Biomarkers Prev 2008;17(3):695–701) |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|