Water-soluble /V-substituted Iminodiacetato(l,2-diaminocyclohexane)-platinum(II) Complexes as Potential Antitumor Agents1

A series of water-soluble /V-substituted iminodiacetato(l,2-diaminocyclohexane)-platinuin(H) complexes (IDP) were synthesized and tested for chemical stability, antitumor activity, and toxicity. The results ob tained suggest that these complexes are relatively stable for more than 48 h when dissolved in water or phosphate buffer. All complexes had good in vitro cytotoxicity and were not cross-resistant with cu-dichlorodiammineplatinum(II) (DDP) in a DDP-resistant cell line in vitro. When the complexes were administered as a single i.p. injection to CS7BL/6 x DBA/2 F, (hereafter called B6D2F,) mice inoculated with LI 210 leuke mia cells, a significant increase in mean survival time was observed, but there were few long-term survivors. When the complexes were adminis tered on Days 1, 5, and 9 after tumor inoculation, however, cure rates of 50 to 85% were obtained. The oncolytic activity of the IDP complexes against LI 210 ascites appeared much greater than that of DDP. The IDP complexes also had good antitumor activity when administered i.p. on Days 1,5, and 9 following i.p. inoculationof B16 melanoma to B6D2K, mice. Five of the six IDP complexes had no significant nephrotoxicity (as evidenced by lack of elevated blood urea nitrogen levels). V-lk-n/yIiminodiacetato(l,2-diaminocyclohexane)-platinum(II) resolved into three distinct peaks of UV-absorbing material that corresponded with three distinct peaks of platinum-containingmaterial. The exact chemical iden tity of the active component of this mixture is currently under investiga tion. The results obtained to date, however, suggest that the ^-substituted iminodiacetato(l,2-diaminocyclohexane)-platinum(II) complexes are good candidates for further developmental studies.