EFFECTS OF THALIBLASTINE ON CYTOTOXICITY AND DNA DAMAGE IN DRUG-SENSITIVE AND-RESISTANT RAT OVARIAN TUMOR-CELLS TREATED WITH CISPLATIN

Combination effects of cisplatin (DDP) and thaliblastine (TBL) in DDP- sensitive (0-342) and -resistant (0-3421 DDP) rat ovarian tumor cells were investigated. TBL alone, at either 40 or 80 mug/ml, exerted highe r cytotoxicity in the DDP-resistant 0-342/DDP cells than in the parent al sensitive 0-342 cells in growth inhibition assay (% inhibitions: 12 .5 and 42.8 in 0-342 cells vs. 37.5 and 66.1 in 0-342/DDP cells, at 40 and 80 pg/ml of TBL, respectively). TBL at 40 mug/ml showed an additi ve effect with DDP in the sensitive cells, while a synergistic cytotox icity was observed in the resistant subline when the two drugs were us ed in combination, as exhibited by either % inhibition or cell viabili ty. At 80 mug/ml of TBL, however, the combination effects were less th an additive (infraadditive) in both lines, but still this treatment wa s more cytotoxic in 0-342/DDP cells. Alkaline elution assay showed tha t DDP induced higer DNA interstrand crosslings (ISCL) in 0-342 cells, while TBL produced DNA single strand breaks (SSB) in a dose-dependent manner in the resistant line but not in the sensitive cells. Combinati on of these two compounds resulted in a dramatic increase of DNA-SSB i n 0-342/DDP cells. It is tentatively concluded that TBL might have som e potential in combination with DDP to conquer the resistance in clini cal use, which may result from its selective SSB-inducing activity in the resistant cells.