Kashani-Sabet M, Wang W, Scanlon K J
Department of Medical Oncology, City of Hope National Medical Center, Duarte, California 91010.
J Biol Chem. 1990 Jul 5;265(19):11285-8.
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.
顺铂耐药的A2780DDP人卵巢癌细胞在顺铂处理1小时和3小时后，癌基因c-fos和c-H-ras以及DNA合成和修复所需酶的mRNA表达增强了3.2至6.1倍。相比之下，c-myc mRNA有所下降。上述基因转录的增加导致了mRNA水平的升高，因为这种增强易受放线菌素D预处理的影响。环孢素A（CSA）已被证明可逆转对多种抗肿瘤药物的耐药性。用CSA处理18小时后，A2780DDP细胞对顺铂的敏感性提高了6倍。当A2780DDP细胞先用CSA预处理再用顺铂处理时，c-fos和c-H-ras以及胸苷合成和DNA修复相关基因的mRNA没有增加。它们的表达接近A2780S细胞中的水平。相比之下，在CSA存在的情况下，A2780DDP细胞中的c-myc mRNA升高了7.4倍。长期每周将A2780DDP细胞暴露于CSA导致了一个回复细胞系A2780DDP/CSA的产生，其c-fos和dTMP合酶mRNA水平降低。因此，A2780DDP细胞中的顺铂处理差异诱导某些核癌基因（c-fos/c-myc）以及可能参与顺铂介导的DNA损伤修复的基因的表达，而CSA处理可抑制这种诱导。
