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

Dichloro-1,2-diaminocyclohexane (DACH):platinum(ll), the pro totype DACH:platinum complex, had good antitumor activity, was not cross-resistant with c/'s-dichlorodiammineplatinum(ll) (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 c/'sbisascorbato-DACH:platinum(ll) complexes (DAP). Although the primary emphasis has been placed on the DAP complex con sisting of the isomerie 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(ll) 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-pres sure liquid chromatography of c/s-bisascorbato (mixed-isomer DACH):platinum revealed a series of platinum-containing, ultra violet-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 ¿¿g/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 c/s-bisascorbato (mixed-isomer DACH):platinum (DAP-1) was administered i.p. to C57BL x DBA/2 F, 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 investiga tions.