Development of New Antitumor Platinum Complexes

Abstract

cis-Diamminedichloroplatinum(II) (DDP) is a useful antitumor platinum complex. Aiming at reducing its severe nephrotoxicity, a number of platinum complexes were synthesized and their antitumor activity was studied. As a result, the degree of antitumor activity as well as antitumor spectrum of platinum complexes seemed to depend on the nature of carrier ligand, while the leaving group influenced the solubility, stability and toxicity. A thirty-fold difference in maximum tolerated doses was observed by exchange of leaving groups. So far the most active carrier ligand is [(-)-trans-1,2-cyclohexanediamine ((—)-trans-DACH). An antitumor spectrum of [(-)-trans-1,2-cyclohexanediamine](oxalato)platinum(III) (l-OHP) against mouse tumors was compared with that of DDP. l-OHP was highly effective against L-1210 leukemia and M 5076 sarcoma, while DDP was more effective against several solid tumors such as colon 26 than l-OHP. L-1210/DDP, which is a subline of L-1210 acquired resistance to DDP showed lack of cross resistance to l-OHP, P 388/DDP, however, showed cross resistance to l-OHP. A mechanism for resistance of both sublines might be different. DNA and RNA syntheses in L-1210 cells were inhibited by about 50% with the exposure of cells to 10 μmol.dm-8 of l-OHP for 1 h, followed by further incubation without the drug, while only DNA synthesis was inhibited by DDP. A search for carrier ligands lacking cross resistance in both L-1210/DDP and P 388/DDP would be another useful way to find new promising Pt complexes. © 1988, The Chemical Society of Japan. All rights reserved.