Christen R D, Hom D K, Porter D C, Andrews P A, MacLeod C L, Hafstrom L, Howell S B
Department of Medicine, University of California, San Diego, La Jolla 92093.
J Clin Invest. 1990 Nov;86(5):1632-40. doi: 10.1172/JCI114885.
Cisplatin (DDP) is the most effective drug for the treatment of human ovarian cancer, but the mechanisms that determine sensitivity to the cytotoxic action of DDP are not well understood. Treatment of two human ovarian carcinoma cell lines with epidermal growth factor (EGF) simultaneously increased sensitivity to DDP and caused a persistent change in morphology in the absence of any mitogenic effect. Sensitization to DDP was shown to be dependent on both EGF concentration and EGF receptor number in C127 mouse fibroblasts expressing the human EGF receptor after transfection with a pBPV plasmid construct containing the human EGF receptor gene under control of the transferrin receptor 3'-inducible regulator. Sensitization of human ovarian carcinoma cells to DDP was not blocked by inhibition of protein synthesis. EGF did not enhance sensitivity to DDP or alter morphology in DDP-resistant human ovarian carcinoma cells despite the presence of functional EGF receptors on these cells. These results showed that elements of the signal transduction pathway activated by EGF determined cellular sensitivity to DDP, and that a DDP-resistant phenotype is associated with a defect in this signal transduction pathway.
顺铂（DDP）是治疗人类卵巢癌最有效的药物，但决定对DDP细胞毒性作用敏感性的机制尚不清楚。用表皮生长因子（EGF）处理两个人类卵巢癌细胞系，在没有任何促有丝分裂作用的情况下，同时增加了对DDP的敏感性，并导致形态学上的持续变化。在用含有转铁蛋白受体3'-诱导调节子控制下的人表皮生长因子受体基因的pBPV质粒构建体转染后，在表达人表皮生长因子受体的C127小鼠成纤维细胞中，对DDP的致敏作用显示出既依赖于EGF浓度又依赖于EGF受体数量。抑制蛋白质合成并未阻断人卵巢癌细胞对DDP的致敏作用。尽管这些细胞上存在功能性的EGF受体，但EGF并未增强对DDP的敏感性，也未改变耐DDP的人卵巢癌细胞的形态。这些结果表明，由EGF激活的信号转导途径的元件决定了细胞对DDP的敏感性，并且耐DDP表型与该信号转导途径中的缺陷有关。
