In vitro investigations on induction and reversal of cisplatin resistance in a rat ovarian tumor cell line.
Resistance of a rat ovarian tumor cell line (O-342/DDP) to cisplatin was induced in vitro by stepwise increase of cisplatin concentrations. Both chemosensitive parental cells (O-342) and resistant O-342/DDP cells grow in a monolayer and enter log-phase growth about 24 h after seeding (cell population doubling time in log-phase growth is about 24 h). O-342/DDP cells show a 33-fold resistance to cisplatin as compared to O-342 cells (ID50 = 33 microM in O-342/DDP vs 1 microM in O-342 cells). The intracellular total glutathione (GSH + GSSG) of O-342/DDP cells was twice as high as that of O-342 cells (3.04 vs 1.37 nmol/10(6) cells), while the intracellular GSSG was increased by 26% in O-342/DDP cells compared to O-342 cells. DNA interstrand crosslinks were found to be 8.5 times higher in O-342 cells than in O-342/DDP cells (204 vs 24 rad equiv.), following cisplatin treatment. DNA single-strand breaks were approximately doubled in the sensitive line as compared to the resistant line following exposure to cisplatin. Chromosome analysis uncovered a change in the karyotype of O-342/DDP cell as compared to O-342 cells. In the sensitive line hyperploid (3n) clones, in the resistant line near-diploid clones predominated. Both DL-buthionine-(S,R)-sulfoximine and 3-aminobenzamide were able to sensitize the resistant line towards cisplatin. Thus, the present results suggest that mechanisms for cisplatin resistance in this tumor line apparently are multi-factorial, and include a higher intracellular GSH content and an increased repair activity.
Chen
G
G
Institute of Toxicology and Chemotherapy, German Cancer Research Center, Heidelberg.
Zeller
W J
WJ
D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D019328:Buthionine Sulfoximine; D002460:Cell Line; D002945:Cisplatin / Q000494:pharmacology*; D004247:DNA / Q000187:drug effects; D004351:Drug Resistance / Q000502:physiology; D005260:Female; D005978:Glutathione / Q000031:analogs & derivatives / Q000032:analysis; D019803:Glutathione Disulfide; D066298:In Vitro Techniques; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats
D000963:Antimetabolites; D001549:Benzamides; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; C025160:3-aminobenzamide; D004247:DNA; D005978:Glutathione; D002945:Cisplatin; D019803:Glutathione Disulfide