Protective effects of dithiocarbamates against toxicity of cis-diamminedichloroplatinum in mice.
The protective effects of various dithiocarbamates such as N-benzyl-D-glucamine dithiocarbamate (BGD), N-p-hydroxymethylbenzyl-D-glucamine dithiocarbamate (HBGD), N-p-carboxybenzyl-D-glucamine dithiocarbamate (CBGD), and diethyldithiocarbamate (DDTC) on cis-diamminedichloroplatinum (DDP)-induced toxicity in mice were studied. The mice were injected i.v. with a chelating agent (1 mmol/kg) immediately or 5 min after i.v. injection of DDP (15 or 20 mg/kg). The lethal toxicity of DDP (20 mg/kg) was completely prevented by treatment with HBGD or CBGD immediately after DDP. The survival time of mice treated with HBGD or CBGD 5 min after DDP tended to be longer than that treated with BGD or DDTC. Significant increases in blood urea nitrogen (BUN) level and plasma aspartate aminotransferase (AST) activity were observed 3d after DDP injection. The increase in BUN level was completely prevented only by HBGD and CBGD among these chelating agents, while increase in AST activity was significantly prevented by treatment with these two agents. Treatment with HBGD or CBGD immediately after DDP (20 mg/kg) completely protected against DDP-induced diarrhea. These chelating agents significantly decreased the platinum (Pt) contents in the kidney and liver after DDP administration. Treatment with HBGD or CBGD was the most effective in decreasing the renal Pt content, resulting in maximum protection against DDP-induced renal damage. The antitumor efficacy of DDP (15 mg/kg) in the colon 26 carcinoma-bearing mice was not affected by HBGD administration.
Shimada
H
H
Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Kumamoto University, Japan.
Takahashi
K
K
Funakoshi
T
T
Kojima
S
S
D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001806:Blood Urea Nitrogen; D002277:Carcinoma / Q000188:drug therapy; D002614:Chelating Agents / Q000494:pharmacology; D002945:Cisplatin / Q000037:antagonists & inhibitors* / Q000627:therapeutic use / Q000633:toxicity; D003110:Colonic Neoplasms / Q000188:drug therapy; D003967:Diarrhea / Q000139:chemically induced / Q000517:prevention & control; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009368:Neoplasm Transplantation; D010984:Platinum / Q000493:pharmacokinetics; D013859:Thiocarbamates / Q000494:pharmacology*; D014018:Tissue Distribution
D002614:Chelating Agents; D013859:Thiocarbamates; D010984:Platinum; D001219:Aspartate Aminotransferases; D002945:Cisplatin