COMPARISON OF EFFECTS OF GROWTH-FACTORS AND PROTEIN-KINASE-C ACTIVATORS ON CELLULAR-SENSITIVITY TO CIS-DIAMMINEDICHLOROPLATINUM(II)

The anti-proliferative activity of the DNA-interactive anti-cancer agent cis-diamminedichloroplatinum(II) (cDDP) can be modulated by intracellular signaling systems. We have investigated the effects of growth factors on the sensitivity of human cervical carcinoma (HeLa) cells to cDDP. A 24-hr pretreatment of HeLa cells with 10 ng/ml epidermal growth factor (EGF) or transforming growth factor-alpha increased the anti-proliferative activity of cDDP by 2- to 4-fold. A similar pretreatment of HeLa cells with EGF did not alter cellular sensitivity to doxorubicin or vincristine. A brief exposure (15 min) to growth factors was not sufficient for cDDP sensitization. EGF caused a modest and transient increase in cellular diacylglycerol, the endogenous activator of protein kinase C. Bryostatin 1, a partial agonist of protein kinase C, antagonized phorbol ester-mediated cDDP sensitization but had no effect on EGF-mediated sensitization to cDDP. Both EGF and phorbol 12,13-dibutyrate (PDBu) enhanced the rate of [Pt-195m]cDDP uptake but had no effect on the rate of [Pt-195m]cDDP efflux in HeLa cells. Bryostatin 1 reversed the increase in [Pt-195m]cDDP content by PDBu but failed to block EGF-induced increase in [Pt-195m]cDDP accumulation. Therefore, although the mechanism of cDDP sensitization by both EGF and phorbol ester appears to involve enhanced drug uptake, they may utilize distinct signal transduction pathways. (C) 1994 Wiley-Liss, Inc.