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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



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



Fundamental and Applied Toxicology 14(4): 706-719



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.

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Accession: 041201004

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PMID: 2163338


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