engleski

Pharmacogenetic database of colon cancer patients in Croatia

Pharmacogenetics deals with inherited differences in the response to drugs. A major limitation that moderates the use of pharmacogenetic testing is the lack of prospective clinical trials demonstrating that such testing can improve the benefit/risk ratio of drug therapy. Significant heterogenity in the efficacy and toxicity of chemotherapy agents is consistently observed. Administration of the same dose of a given anti-cancer drug to a population of patients results in a range of toxicity, from unaffected to lethal events. The aim of our research is a prospective pharmacogenetic study to examine the frequency of SNPs in genes regulating chemotherapeutic metabolism and the correlation between known polymorphisms and colon cancer therapy in Croatian population. Pharmacogenetic markers that were used in our study were: TSER 5’ UTR VNTR, IVS14+1G>A (DPYD*2A), UGT1A1 and XRCC1 R399Q. Acquired resistance to 5-FU has been associated with an increased TS expression and TS genotype 3R/3R is associated with high TS mRNA and protein levels. DPD is the initial and rate-limiting enzyme in the catabolism of 5-FU and IVS14+1G>A mutation (DPYD*2A genotype) is associated with DPD deficiency and severe toxicity after the administration of 5-FU. UGT1A1 is involved in glucuronidation of a prodrug of irinotecan and UGT1A1*28 variant is associated with the risk of severe diarrhea and/or neutropenia in patients receiving the drug. XRCC1 polymorphism R399Q is known to influence outcome after platinum-based treatment and Gln/Gln genotype is associated with non responding to therapy. Our study performed on 45 colon cancer patients using PCR-RFLP method and real-time PCR Taqman® ; ; ; SNP genotyping assays showed 40, 0% TSER*3/*3 homozygotes, 4, 4% homozygotes for DPYD*2A , 37, 8% heterozygotes and 20% homozygotes for UGT1A1*28 and 8, 9% homozygotes for XRCC1 R399Q mutation. The results obtained in this research will be essential to our future work because they will be correlated with clinicopathological data and will be summarized in newly established pharmacogenetic profiles database of Croatian population. We hope that the results of this project will be used in the future for improvement of colon cancer therapy in Croatia.

pharmacogenetics; colon cancer; Croatia

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