engleski

Etoposide/platinum therapy, UGT1A1 and GSTP1 polymorphisms and toxicity in childrens with solid tumors

Etoposide is a commonly used chemotherapy agent with a broad range of antitutmor activity. It stabilize the double-stranded DNA cleavage normally catalyzed by topoisomerase II and inhibit faithful relegation of DNA breaks. Glutathione and glucuronide conjugation seem to inactivate parent drug and metabolite, and are mediated by GSTT1/GSTP1 and UGT1A1. Recently, 64 genetic variants that contribute to etoposide-induced cytotoxicity were identified through a whole-genome association study. UGT1A1 gene promoter polymorphism can affect the expression level of UDP glucuronosyltransferase. The polymorphism consists of an insertion of a TA nucleotide sequence into a (TA)6 TAA sequence in the gene promoter resulting in (TA)7 TAA (UGT1A1*28). The longer TA repeats lower the enzyme expression level and glucuronidation. Decreased glucuronidation leads to severe hematotoxicity and mucositis. The SNP polymorphism GSTP1 313A>G (I105V in exon 5) has been associated with reduced enzyme activity and anticancer drug resistance and toxicity. The aim of our research was the correlation between UGT1A1 and GSTP1 polymorphisms and etoposide/platinum therapy in children with solid tumors in Croatian population. Our study was performed on 44 childrens with solid tumors treated in Children’s Hospital Zagreb. All patients received standardized adjuvant chemotherapy, etoposide (in range 100-150 mg/m2) in combination with platinum derivates. Toxicity was assessed according to the NCI Common toxicity criteria (version 2.0). The study was approved by the Ethics Committee of the Children’s Hospital Zagreb. UGT1A1 polymorphisms was analyzed by heteroduplex analysis on Elchrom Spreadex EL-300 gels stained with SYBRGreen. GSTP1 polymorphism was analysed using predeveloped real-time PCR Taqman® SNP genotyping assay. Correlation between UGT1A1 and GSTP1 genotypes and grade of hematotoxicity were found. Hematotoxicity grade 3 was more frequent in children with GSTP1 G allele and UGT1A1*28 allele. There was no correlation between GSTP1 and UGT1A1 genotypes and mucositis. These results are a part of prospective pharmacogenetic study to examine the correlation between SNPs in genes regulating chemotherapeutic metabolism and solid tumor chemotherapy in children in Croatian population. We hope that the results of this project will be used in the future for improvement of children’s solid tumors therapy.

etoposide; UGT1A1; GSTP1; pharmacogenetics

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