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Ascorbato(1,2-diaminocyclohexane):platinum(II) Complexes, a New Series of Water-soluble Antitumor Drugs¹

Vermont Regional Cancer Center [M. P. H., A. R. K., J. J. M., D. B. B., I. H. K.], and Departments of Pharmacology [M. P. H., J. J. M.], Chemistry [A. R. K., D. B. B.], and Medicine [I. H. K.], University of Vermont, Burlington, Vermont 05405

Dichloro-1,2-diaminocyclohexane (DACH):platinum(II), the prototype DACH:platinum complex, had good antitumor activity, was not cross-resistant with cis-dichlorodiammineplatinum(II) (DDP), but was, unfortunately, virtually insoluble in water and was, therefore, not evaluated clinically. This paper summarizes some of the chemical and biological attributes of a series of cis-bisascorbato-DACH:platinum(II) complexes (DAP). Although the primary emphasis has been placed on the DAP complex consisting of the isomeric mixture DACH, a series of complexes using the isomers of either DACH or ascorbic acid have also been synthesized. The synthetic procedure entailed reacting the water-soluble sulfato-DACH:platinum(II) with barium ascorbate, and the water-soluble product DAP was removed from the BaSO₄ precipitate by filtration. Based upon elemental analysis, all the complexes had stoichiometric composition of one DACH:one platinum and two ascorbate monoanions. High-pressure liquid chromatography of cis-bisascorbato (mixed-isomer DACH):platinum revealed a series of platinum-containing, ultraviolet-absorbing peaks. All the DAP complexes had significant in vitro cytotoxicity against L1210 leukemia cells (L1210/0) with 50%-inhibitory dose values ranging from 2 to 5 µg/ml. None of the complexes was cross-resistant with DDP when tested in vitro against L1210 cells 50-fold resistant to DDP (L1210/DDP). The cis-bisascorbato (mixed-isomer DACH):platinum (DAP-1) was administered i.p. to C57BL x DBA/2 F₁ mice inoculated i.p. with 10⁶ L1210/0 cells. When administered on Days 1, 5, and 9, the DAP-1 complex consistently produced treated:control values in excess of 200% with several long-term survivors (alive 60 days after tumor inoculation). Further, the DAP-1 complex was totally non-cross-resistant with DDP when tested in vivo against a DDP-resistant L1210 line. Toxicological investigations revealed that DAP-1 was relatively nonnephrotoxic but did cause the expected bone marrow and gastrointestinal toxicity. In summary, the DAP complexes are highly water-soluble, nonnephrotoxic platinum complexes with sufficient antitumor activity to warrant further pharmacological, biochemical, and chemical investigations.

¹ This research was supported in part by Grants CA32244 and CA23545 from the National Cancer Institute, Bethesda, MD. The results were reported in part at the American Association for Cancer Research meeting held in St. Louis, MO, 1982 (13) and at the Ninth International Pharmacology Meeting held in London, England, 1984.

² To whom requests for reprints should be addressed, at Department of Pharmacology, University of Vermont, Burlington, VT 05405.

Received 7/17/84. Revised 7/ 3/85. Accepted 7/ 8/85.