MODULATION OF BOTH CISPLATIN NEPHROTOXICITY AND DRUG-RESISTANCE IN MURINE BLADDER-TUMOR BY CONTROLLING METALLOTHIONEIN SYNTHESIS

The role of metallothionein (MT) in cisplatin (cis-DDP) resistance and renal toxicity was investigated in C3H mice inoculated with mouse bla dder tumor (MBT-2). C3H mice were inoculated s.c. with 1 x 10(6) MBT-2 cells/mouse on day 0. Mice were given injections of propargylglycine (PPG) (500 mumol/kg s.c.) once a day for 3 days from day 7 to day 9 an d with ZnSO4 (200 mumol/kg s.c.) once a day for 2 days from day 8 to d ay 9. cis-DDP (50 mumol/kg i.p.) was administered 10 days after MBT-2 cell inoculation. Since MT contents in the tumor and kidneys were sign ificantly increased by administration of ZnSO4, both the antitumor act ivity of cis-DDP and its renal toxicity were reduced. However, coadmin istration of PPG reduced MT induction in tumor without affecting the l evel of renal MT. As a result, PPG could clearly overcome the MT-media ted cis-DDP resistance of tumors without compromising the protective e ffect exerted by renal MT on nephrotoxicity of the drug. It was sugges ted, therefore, that PPG may be a promising adjunct in cancer chemothe rapy to overcome the drug resistance of tumors caused by the elevated level of MT.