DIFFERENTIAL ANTITUMOR-ACTIVITY AND TOXICITY OF ISOMERIC 1,2-DIAMINOCYCLOHEXANE PLATINUM (II) COMPLEXES

Acquired resistance is a main drawback of using cisplatin in cancer ch emotherapy; however, analogs containing the 1,2-diaminocyclohexane (DA CH) ligand can overcome this resistance. Because DACH can exist as the trans-1R,2R, trans-1S,2S or cis isomer, the antitumor activity and to xicity of individual isomers of both DACH(sulfato)Pt(II) and DACH(1,1- cyclobutanedicarboxylato)Pt(II) complexes have been examined. At optim al doses, differences in antitumor activities among the three isomers were moderately dependent on the in vivo tumor models (L1210/0, L1210/ DDP, B16 and M5076). However. differences in efficacy among these isom ers were greatly modulated by the sulfate or 1,1-cyclobutanedicarboxyl ate (CBDCA) leaving ligands. Thus, the trans isomers (R,R and/or S,S) of the sulfate complex generally had greater activities than the corre sponding cis form, while the cis configuration appeared to be superior in the complex containing the CBDCA ligand. The isomers were also com pared for their potential to elicit myelosuppression and kidney toxici ty. Of the six isomers investigated, cis-DACH(CBDCA)Pt(II) was myelosu ppressive, and the corresponding R,R and S,S isomers were mildly nephr otoxic. No such toxicities were apparent with any of the sulfate compl exes. From these studies, particularly with the cisplatin-resistant L1 210/DDP cell line, the R,R isomers are evidently the most interesting. However, it is possible that other leaving ligands or tumor models ma y indicate either S,S- or cis-DACH as the isomer worthy of greater int erest.