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.
Kashani-Sabet
M
M
Department of Medical Oncology, City of Hope National Medical Center, Duarte, California 91010.
Wang
W
W
Scanlon
K J
KJ
D002945:Cisplatin / Q000494:pharmacology*; D003524:Cyclosporins / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis; D003609:Dactinomycin / Q000494:pharmacology; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D007700:Kinetics; D010051:Ovarian Neoplasms / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016760:Proto-Oncogene Proteins c-fos; D011519:Proto-Oncogenes; D012333:RNA, Messenger / Q000096:biosynthesis; D013940:Thymidylate Synthase / Q000378:metabolism; D014407:Tumor Cells, Cultured
D003524:Cyclosporins; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D003609:Dactinomycin; D004247:DNA; D013940:Thymidylate Synthase; D002945:Cisplatin