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Ammine/Amine Platinum(IV) Dicarboxylates: A Novel Class of Platinum Complex Exhibiting Selective Cytotoxicity to Intrinsically Cisplatin-resistant Human Ovarian Carcinoma Cell Lines¹

Drug Development Section, The Institute of Cancer Research, Belmont, Sutton, Surrey SM2 5NG, United Kingdom [L. R. K., G. A., P. M., K. R. H.]; Johnson Matthey Technology Centre, Sonning, Reading, United Kingdom [B. A. M.] and Johnson Matthey Biomedical Research, West Chester, Pennsylvania 19380 [C. M. G.]

Using a panel of six human ovarian carcinoma cell lines varying by two orders of magnitude in terms of cisplatin cytotoxicity, we have investigated the in vitro antitumor activity of a series of novel alkylamine ammine dicarboxylatodichloroplatinum(IV) complexes of the general formula c, t, c-[PtC]₂(OCOR₁)₂NH₃(RNH₂)]. A clear relationship existed between increasing the number of carbons in the R₁ substitutent and increasing cytotoxicity up to R₁ = C₅H₁₁. In terms of changing the R group, maximum cytotoxic effects were conferred by alicyclic substituents. Furthermore, increasing the alicyclic ring size from cyclobutane through to cycloheptane resulted in increasing cytotoxicity. The agents with longer axial chains (e.g., JM300, R = cyclohexyl, R₁ = C₆H₁₃) were significantly more cytotoxic than cisplatin and, moreover, exhibited a selective cytotoxic effect against the most intrinsically cisplatin-resistant cell lines (e.g., for HX/62, cisplatin 50% inhibitory concentration, 12.6 µM; SKOV-3, cisplatin 50% inhibitory concentration, 4.4 µM and 41 M; cisplatin 50% inhibitory concentration, 0.23 µM; JM300 was 840-, 440-, and only 34-fold more active, respectively). The dicarboxylates JM221 (R = cyclohexyl, R₁ = C₃H₇) and JM244 (R = n-propyl, R₁ = C₆H₅) also retained activity against a 4-fold cisplatin-acquired resistant variant of the 41 M cell line. At least part of the increased cytotoxicity of the dicarboxylate, JM221, over cisplatin appeared to be attributable to an increased intracellular accumulation. This novel class of platinum compound represents a valuable lead in the development of a "third-generation" agent capable of exhibiting activity against clinical disease currently resistant to cisplatin.

¹ This study was supported by grants to the Institute of Cancer Research from the Cancer Research Campaign and the Medical Research Council, the Johnson Matthey Technology Centre, and Bristol Myers Squibb Oncology.

² To whom requests for reprints should be addressed.

Received 9/ 5/91. Accepted 12/ 3/91.

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