Reduction of tetrachloro(dl-trans)1,2-diaminocyclohexaneplatinum(IV) (tetraplatin) toxicity by the administration of diethyldithiocarbamate (DDTC), S-2(3-aminopropylamino)ethylphosphorothioic acid (WR-2721), or sodium selenite in the Fischer 344 rat.
Diethyldithiocarbamate (DDTC), S-2(3-aminopropylamino)ethylphosphorothioic acid (WR-2721), and sodium selenite have all been shown to effectively reduce cisplatin toxicity. As a result, we have investigated the efficacy of these compounds to reduce the toxicity associated with tetrachloro(dl-trans)1,2-diaminocyclohexaneplatinum(IV) (tetraplatin), a second-generation platinum compound recently approved for phase I/II clinical trials. The dose-limiting toxicities associated with tetraplatin (16.5 mg/kg) in the Fischer 344 male rat were nephrotoxicity, myelosuppression, and gastrointestinal toxicity. The nephrotoxicity in Fischer 344 rats was effectively reduced by treatment with either DDTC (750 mg/kg ip) 0.5 hr after tetraplatin or WR-2721 (200 mg/kg ip) 0.5 hr before tetraplatin as determined by blood urea nitrogen and creatinine values. Diarrhea was evident in 95% of the rats treated with tetraplatin alone while it was not evident in any of the DDTC- or WR-2721-protected rats. Only DDTC was moderately effective in preventing tetraplatin-induced decreases in platelet and lymphocyte counts. Histopathology confirmed DDTC protection of renal, intestinal, and lymphoid tissues and WR-2721 protection of renal and intestinal tissues. Sodium selenite was ineffective in reducing tetraplatin-induced damage when administered 4 hr before tetraplatin at doses of 0.5, 1.0, or 2.0 mg/kg. The results suggest that DDTC may allow for increased dosages of tetraplatin by ameliorating the toxic side effects of the drug. WR-2721 may also have some usefulness in tetraplatin therapy, but it does not reduce as wide a variety of toxic side effects as DDTC.
Carfagna
P F
PF
Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill 27599.
Chaney
S G
SG
Chang
J
J
Holbrook
D J
DJ
D004999:Amifostine / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D000998:Antiviral Agents / Q000494:pharmacology*; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D004050:Ditiocarb / Q000494:pharmacology*; D005767:Gastrointestinal Diseases / Q000139:chemically induced / Q000517:prevention & control; D007420:Intestine, Large / Q000166:cytology / Q000187:drug effects; D007421:Intestine, Small / Q000166:cytology / Q000187:drug effects; D007674:Kidney Diseases / Q000139:chemically induced / Q000517:prevention & control; D007958:Leukocyte Count / Q000187:drug effects; D008297:Male; D009944:Organoplatinum Compounds / Q000633:toxicity*; D009946:Organothiophosphorus Compounds / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D012643:Selenium / Q000494:pharmacology*; D018038:Sodium Selenite; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D009944:Organoplatinum Compounds; D009946:Organothiophosphorus Compounds; D004050:Ditiocarb; D003404:Creatinine; D012643:Selenium; D018038:Sodium Selenite; D004999:Amifostine; C049777:ormaplatin