title: Comparative cytotoxicity of CI-973, cisplatin, carboplatin and tetraplatin in human ovarian carcinoma cell lines.
abstract: The clinical efficacy of cisplatin-based chemotherapy for ovarian cancer is frequently compromised by drug resistance or dose-limiting renal and neurologic toxicities. CI-973 (NK-121), a 2-methyl-1,4-butanediamine analogue of carboplatin, has shown little nephro- and neuro-toxicity in pre-clinical model systems and in phase-I trials. Its in vitro spectrum of activity against ovarian cancer cell lines has not been previously characterized. The in vitro activities of CI-973, cisplatin, carboplatin and tetraplatin were compared in several platinum-sensitive and -resistant human ovarian carcinoma cell lines. Cytotoxicity was assessed by inhibition of clonogenic survival in soft agar with continuous drug exposure. On a molar basis, cisplatin and tetraplatin were the most potent analogues, while carboplatin was consistently less potent. Cisplatin, carboplatin and CI-973 elicited a very similar response pattern by Spearman rank correlation, distinct from that seen with tetraplatin. The magnitude of resistance to CI-973 was comparable to cisplatin in 5 cell lines but was substantially lower in the highly cisplatin-resistant 2780-CP70 and OVCAR-10 cell lines. These results suggest that CI-973 and tetraplatin may have potential utility in some cases of cisplatin-resistant ovarian cancer. In addition, our data are consistent with the existence of at least 2 platinum-resistance phenotypes--one with moderate levels of resistance to cisplatin, carboplatin and CI-973 but highly resistant to tetraplatin, the other highly resistant to cisplatin and carboplatin but only partially cross-resistant with tetraplatin and CI-973. The recognition of different resistance phenotypes may facilitate the study of cellular resistance mechanisms to cisplatin and newer platinum analogues.
authors.affiliation: Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111.
authors.forename: R P
authors.initials: RP
authors.lastname: Perez
authors.forename: P J
authors.initials: PJ
authors.lastname: O'Dwyer
authors.forename: L M
authors.initials: LM
authors.lastname: Handel
authors.forename: R F
authors.initials: RF
authors.lastname: Ozols
authors.forename: T C
authors.initials: TC
authors.lastname: Hamilton
mesh_terms: D000970:Antineoplastic Agents; D016190:Carboplatin / Q000031:analogs & derivatives / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004351:Drug Resistance; D005260:Female; D006801:Humans; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C055425:NK 121; D016190:Carboplatin; D002945:Cisplatin; C049777:ormaplatin