Epidermal growth factor regulates the in vitro sensitivity of human ovarian carcinoma cells to cisplatin.

Cisplatin (DDP) is the most effective drug for the treatment of human ovarian cancer, but the mechanisms that determine sen- sitivity to the cytotoxic action of DDP are not well understood. Treatment of two human ovarian carcinoma cell lines with epi- dermal growth factor (EGF) simultaneously increased sensi- tivity 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 con- trol of the transferrin receptor 3'-inducible regulator. Sensiti- zation of human ovarian carcinoma cells to DDP was not blocked by inhibition of protein synthesis. EGF did not en- hance sensitivity to DDP or alter morphology in DDP-resis- tant 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. (