Polymorphic characteristics of enzymes that metabolize anticancer drugs

POLYMORPHIC CHARACTERISTICS OF ENZYMES THAT METABOLIZE ANTICANCER DRUGS Arsalan AMİRFALLAH Dokuz Eylul University, Institute of Oncology, 35340 Inciraltı İzmir/TURKEY Correspondence address: arsalan.amirfallah@gmail.com Objective: 5-Fluorouracil (5-FU), the mainstay of solid tumor chemotherapy over the last 40 years, induces grade III?IV toxicities in up to 15% of patients with polymorphisms in the dihydropyrimidine dehydrogenase (DPYD), thymidylate synthase (TS), and methylenetetrahydrofolate reductase (MTHFR) genes. These toxicities include mucositis, neutropenia, nausea, diarrhea, myelosuppression, hand-foot syndrome. Aim of this study was to analyse polymorphisims charecteristics of enzymese that include in 5-FU metabolic pathway, identification of population-specific gene polymorphisms and investigation the results of treatment and observed toxicities associated with related polymophisms. Method: Eighty five pateints getting 5-FU chemotherapy were included to the study. The enzymes (DPYD, TS, MTHFR) taking place in the metabolic processes of the 5-FU, scanned at SNP level with new genaration Sequenom MassARRAY Analyzer 4 in terms of single nucleotide polymorphisms. Results: Six patients had no toxicity. Toxicities types in 79 patients were: 47 patients with hematopoietic toxicities, 18 with hand and foot syndrome, 11gastrointestinal toxicities and 3 patients with skin toxicites. MTHFR 677 C>T mutation status was; 47,1% wild type, 43,5% heterozygot, 9,4% homozygot mutant. TS 1494 ins/del mutation status was; 36,5% wild type, 38,4% heterozygot, 24,7% homozygot mutant. Allelic frequency of DIVS14G>A/G was 0.6%. DPYD 85T>C mutation status was; 47,1% wild type, 43,5% heterozygot, 9,4% homozygot mutant. There were no mutation in DPYD 2846A>T and D1679T>G/T polumorphisims. Conclusion:, Foot and hand syndrome was detected more in the patients who had MTHFR 677 C>T mutation also hematopoitik toxcities were in high range in patients with TS 1494 ins/del mutation . Determination of selected enymes polymorphic charecterestics are important in order to predict the risk of toxicity of 5-FU. To verify the relationship between toxicity and genotype population based stydies among diffrent etnic groups should be done. Key Words: 5-FU metabolic pathway, MTHFR, TS, DPYD, pharmacogenetics polymorphism