ENHANCEMENT OF SENSITIVITY TO PLATINUM(II)-CONTAINING DRUGS BY 12-O-TETRADECANOYL-PHORBOL-13-ACETATE IN A HUMAN OVARIAN-CARCINOMA CELL-LINE

Sensitivity to platinum-containing drugs is believed to be a function of how much drug enters the cell, the extent of DNA adduct formation a nd the rate at which DNA is repaired. Activation of protein kinase C b y 12-O-tetradecanoyl-phorbol- 13-acetate (TPA) was found to enhance th e sensitivity of human ovarian carcinoma 2008 cells to cisplatin (DDP) , carboplatin (CBDCA) and (glycolato-O,O') diammineplatinum(II) (254-S ). TPA was able to enhance the sensitivity of the DDP-resistant 2008/C 135.25 subline to each of the three drugs to the same extent as for t he 2008 cells. TPA produced no significant change in the uptake of [H- 3]cis-dichloro(ethylenediamine)-platinum(II) ([H-3]DEP) or CBDCA. It d id not alter glutathione content or glutathione-S-transferase activity , and induced rather than suppressed metallothionein IIA mRNA levels. TPA did increase the formation of intrastrand guanine-guanine cross-li nks by a factor of 1.5 +/- 0.3 (s.d.), and reduced the fraction of int rastrand adducts removed from DNA over the subsequent 24h by a factor of 1.3 +/- 0.2 (s.d.) (n = 4; P< 0.05), however, these effects were to o small to account for the degree of TPA-induced sensitisation. These results indicate that the mechanism of TPA-induced sensitisation is no t specific to any one structural form of platinum-containing drug, and that it is not readily explicable on the basis of an effect on the fo ur major parameters currently believed to regulate DDP sensitivity.