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 micrograms/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 10(6) 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.