Cyclosporin A suppresses cisplatin-induced c-fos gene expression in ovarian carcinoma cells.

Cisplatin-resistant A2780DDP human ovarian carcinoma cells, 1 and 3 h following cisplatin treatment, display 3.2-6.1-fold enhancement of mRNA expression for oncogenes c-fos and c-H-ras and for enzymes necessary for DNA synthesis and repair. In contrast, c-myc mRNA was partially decreased. Increased transcription for the aforementioned genes accounts for the higher levels of mRNA since the enhancement is susceptible to actinomycin D pretreatment. Cyclosporin A (CSA) has been shown to reverse resistance to a variety of antineoplastic agents. An 18-h treatment with CSA yielded a 6-fold improved sensitivity to cisplatin in A2780DDP cells. When A2780DDP cells are pretreated with CSA followed by cisplatin, there is no increase in mRNA for c-fos and c-H-ras and the genes for thymidine synthesis and DNA repair. Their expression approaches the levels demonstrated in A2780S cells. In contrast, c-myc mRNA was elevated 7.4-fold in the presence of CSA in A2780DDP cells. Long term weekly exposures of A2780DDP cells to CSA resulted in the evolution of a revertant cell line, A2780DDP/CSA, with decreased c-fos and dTMP synthase mRNA. Thus, cisplatin treatment in A2780DDP cells differentially induces expression of certain nuclear oncogenes (c-fos/c-myc), as well as genes possibly involved in the repair of cisplatin-mediated DNA damage, an induction suppressed by CSA treatment.