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: R P Perez, P J O'Dwyer, L M Handel, R F Ozols, T C Hamilton
• Journal: International journal of cancer (Int J Cancer) Vol. 48 Issue 2 Pg. 265-9 (May 10 1991) ISSN: 0020-7136 [Print] United States
• PMID: 2019469 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Organoplatinum Compounds
• NK 121
• Carboplatin
• Cisplatin
• ormaplatin

Topics

• Antineoplastic Agents
• Carboplatin (analogs & derivatives, pharmacology)
• Cell Survival (drug effects)
• Cisplatin (pharmacology)
• Drug Resistance
• Female
• Humans
• Organoplatinum Compounds (pharmacology)
• Ovarian Neoplasms (drug therapy)
• Tumor Cells, Cultured
• Tumor Stem Cell Assay