Single nucleotide polymorphisms and expression of ERCC1 and ERCC2 vis-à-vis chemotherapy drug cytotoxicity in human glioma

Abstract

ERCC1 and ERCC2 have been known to belong to the nucleotide excision repair (NER) pathway and are essential to the repair of cisplatin DNA adducts. In the present study, we have examined the potential correlation of ERCC1, ERCC2 mRNA expression and single nucleotide polymorphism (SNP) to chemotherapy drug cytotoxicity from 49 human gliomas. Fresh human glioma specimens were obtained during surgery. SNPs of ERCC1 and ERCC2 was determined by single strand conformation polymorphism (SSCP) and sequencing. ERCC1 and ERCC2 expression was quantified using real-time quantitative reverse transcription-PCR. Chemotherapy drug cytotoxicity was determined by the tetrazolium (MTT) assay for cisplatin (CDDP), 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU), vincristine (VCR) and teniposide (VM26). The results show that there was no statistically significant association between the C8092A polymorphism of ERCC1 or codon 312 and codon 751 polymorphisms of ERCC2 and the chemotherapy drug cytotoxicity. However there was a strong correlation between ERCC1 and ERCC2 mRNA expression levels (Spearman r = 0.42; P < 0.003). Further more, tumor samples with low ERCC1 mRNA expression levels showed enhanced CDDP cytotoxicity (P = 0.0001) while ERCC2 expression was reversely correlated with BCNU cytotoxicity (P = 0.004). In sum, Our results indicated that ERCC1 mRNA expression is associated with CDDP cytotoxicity and ERCC2 mRNA levels is related with BCNU cytotoxicity, while there was no correlation between SNP of ERCC1, ERCC2 and in vitro cytotoxicity of four anticancer drugs, CDDP, BCNU, VCR and VM26.