© 1990 Oxford University Press
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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 Rat1,2
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*Department of Environmental Sciences and Engineering, University of North Carolina Chapel Hill, North Carolina 27599
Department of Biochemistry, University of North Carolina Chapel Hill, North Carolina 27599
Curriculum in Toxicology, University of North Carolina Chapel Hill, North Carolina 27599
Department of Pathology, University of North Carolina Chapel Hill, North Carolina 27599
Received June 20, 1989; accepted December 4, 1989
Reduction of Tetrachloro(dl-trans)l,2-diaminocyclohexaneplatinum(IV) (Tetraplatin) Toxicity by the Administration of Diethyldithiocarbamate (DDTC), 5-2(3-Aminopropylamino)eth-ylphosphorothioic acid (WR-2721), or Sodium Selenite in the Fischer 344 Rat. CARFAGNA, P. F., CHANEY, S. G., CHANG, J., AND HOLBROOK, D. J. (1990). Fundam. Appl. Toxicol. 14, 706–719. Diethyldithiocarbamate (DDTC), 5-2(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)l,2-diaminocyclohexaneplatinum(IV) (tetraplatin), a second-generation platinum compound recently approved for phase I/I I clinical trials. The dose-limiting toxic-ities 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. Histopa-thology 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.