Gene expression in X-irradiated human tumour cell lines expressing cisplatin resistance and altered DNA repair capacity.

Abstract

Previous studies have indicated that excision repair genes, such as ERCC1, or early response genes, such as c-fos, may play a significant role in regulating cellular responses to cisplatin (CDDP) by mediating DNA synthesis and repair pathways. This present study aimed to determine whether altered gene expression mediated CDDP resistance expressed in two human tumour sublines following their in vitro exposure to fractionated X-irradiation, not to the drug itself. These sublines, designated SuSa/DXR10 and SKOV-3/DXR10, established respectively from a testicular teratoma cell line (SuSa) or an ovarian carcinoma cell line (SKOV-3), expressed stable 3.1- and 2-fold levels of CDDP resistance, as judged by clonogenic assay. Both sublines expressed c-fos, c-myc and thymidylate synthase (TS) RNA constitutively, but at comparable levels to their parental counterparts. Whilst the ovarian carcinoma cells inherently expressed markedly higher levels (30- to 50-fold) of the excision repair gene ERCC1 than the teratoma cells, only the teratoma DXR10 subline showed an increased level of expression of ERCC1 mRNA relative to their parental cells. Expression of the ERCC3/XPB gene encoding a repair helicase, however, was similar in all the lines tested. The results suggest that CDDP resistance may be mediated by different mechanisms in these DXR10 sublines from those previously identified in drug-selected CDDP-resistant human ovarian A2780/DDP cells.

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