Comparative cytotoxicity of CI‐973, cisplatin, carboplatin and tetraplatin in human ovarian carcinoma cell lines

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 teatraplatin 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.