POTENTIATION OF CISPLATIN AND CARBOPLATIN CYTOTOXICITY BY AMPHOTERICIN-B IN DIFFERENT HUMAN OVARIAN-CARCINOMA AND MALIGNANT PERITONEAL MESOTHELIOMA CELLS

An in vitro study of the combined cytotoxicity of either cisplatin (CD DP) or carboplatin and amphotericin B (AmB) was undertaken on a set of different ovarian carcinoma (IGROVI, IGROVI-C10, OAW42) and peritonea l malignant mesothelioma (CFB-CARPI) cell lines and ascitic cells fres hly obtained from ovarian cancer patients so as to investigate the pos sibility of overcoming their resistance to platinum compounds. Growth- inhibition curves obtained 6 days after a 2-h period of exposure to th e drugs showed that AmB at 5-10 mg/l allowed a 5- to 10-fold decrease in the 50% growth-inhibitory concentrations (IC50) of CDDP and carbopl atin on either sensitive or resistant cells. Intracellular platinum as says with IGROVI cells showed that AmB acted by increasing dramaticall y the platinum uptake at a proportion that accounted for the increase in cytotoxicity. In the subline IGROVI-C10, a 10-fold resistant sublin e of IGROVI, AmB at 10 mg/l allowed recovery to the level of sensitivi ty seen in the parental cell line in the absence of AmB but not to the level observed in the presence of AmB. Acquisition of resistance mech anisms that are independent of the regulation of platinum uptake might be involved in this cell line. Thus, AmB might act by increasing the intracellular concentration of platinum without modifying the resistan ce mechanism involved downstream. However, in our models an increase i n the intracellular level of platinum was always sufficient for the re covery of chemosensivity in vitro. We also show that the phosphodieste rase inhibiting methylxanthines act synergistically with AmB. The latt er drugs are weakly toxic and could also attenuate the nephrotoxicity of AmB.