ANTITUMOR, NEPHROTOXIC AND CLASTOGENIC EFFECT OF CIS-DDP WITH DDTC ORNAC

Diethyldithiocarbamate (DDTC) and N-acetylcysteine (NAC) are nucleophi le sulfur-containing compounds which can protect the platinum-induced nephrotoxicity. Combinations of cis-diamminedichloroplatinum(II) (cis- DDP) and DDTC or NAC were tested on the leukemia L1210 and melanoma B 16 tumor models. Nephrotoxicity of cis-DDP alone and is combination wi th DDTC or NAC was evaluated. On both of the investigated tumor models clastogenic effects in bone marrow cells were detected. DNA synthetic and mitotic activity of L1210 cells in vivo were evaluated by H-3-thy midine incorporation and cytogenetic analysis. Amelioration of the pla tinum induced nephrotoxicity and preservation of the antitumor activit y of cis-DDP through combined application with DDTC or NAC were obtain ed at the L1210 model. Maximal inhibition of the DNA synthesis in L121 0 cells was detected with the cis-DDP treatment. The sulfurcontaining nucleophiles DDTC or NAC could modulate the inhibitory effect of cis-D DP on the incorporation of H-3- thymidine into the nuclei of L1210 cel ls. Enhanced mitotic activity was detected during cytotoxic therapy wi th cis-DDP. Cis-DDP alone and In combination with DDTC or NAC caused a significant growth inhibition on the s.c. tumor of the melanoma B16 b earing mice. Two times better therapeutic results at this model were o btained with cis-DDP alone (T/C = 234.09%, T/C = 136.36% for cis-DDP+D DTC and T/C = 151.14% for cis-DDP+NAC). The usefulness of DDTC or NAC as adjuvants in the platinum based chemotherapy of human cancers have been discussed. Clastogenic effect and antitumor activity are probably connected and it is supposed that the reduction of the genotoxicity c ould lead to a decreased antitumor activity of the platinum complex.