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 (0-342/DDP) rat ovarian tumor cells were investigated. TBL alone, at either 40 or 80 micrograms/ml, exerted higher cytotoxicity in the DDP-resistant 0-342/DDP cells than in the parental 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 micrograms/ml of TBL, respectively). TBL at 40 micrograms/ml showed an additive effect with DDP in the sensitive cells, while a synergistic cytotoxicity was observed in the resistant subline when the two drugs were used in combination, as exhibited by either % inhibition or cell viability. At 80 micrograms/ml of TBL, however, the combination effects were less than additive (infraadditive) in both lines, but still this treatment was more cytotoxic in 0-342/DDP cells. Alkaline elution assay showed that DDP induced higher 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. Combination of these two compounds resulted in a dramatic increase of DNA-SSB in 0-342/DDP cells. It is tentatively concluded that TBL might have some potential in combination with DDP to conquer the resistance in clinical use, which may result from its selective SSB-inducing activity in the resistant cells.
Chen
G
G
Institute of Toxicology and Chemotherapy, German Cancer Research Center, Heidelberg.
Zeller
W J
WJ
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology*; D001060:Aporphines / Q000008:administration & dosage / Q000494:pharmacology*; D044182:Benzylisoquinolines; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000187:drug effects; D004347:Drug Interactions; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D005260:Female; D007546:Isoquinolines / Q000008:administration & dosage / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D051381:Rats; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000972:Antineoplastic Agents, Phytogenic; D001060:Aporphines; D044182:Benzylisoquinolines; D004273:DNA, Neoplasm; D007546:Isoquinolines; C073328:thalicarpine; D002945:Cisplatin