A comparison in rodents of renal and intestinal toxicity of cisplatin and a new water-soluble antitumor platinum complex: N-methyl-iminodiacetato-diaminocyclohexane platinum (II).
A new third-generation water-soluble platinum complex, N-methyliminodiacetato-1,2-diaminocyclohexane platinum (II) (MIDP) has been reported to have remarkable antitumor activity against several murine tumor model systems. In the present study, the renal and intestinal toxicity of MIDP was compared directly with that of cis-diamminedichloroplatinum (cisplatin). Measurement of renal physiologic parameters in Fischer 344 rats 3 and 5 days after receiving equitherapeutic doses of either cisplatin or MIDP (6.0 and 25 mg/kg, respectively) revealed that, whereas cisplatin significantly reduced glomerular filtration rates (GFR) and increased blood urea nitrogen (BUN) and serum creatinine values, MIDP produced no alteration in either GFR or BUN levels and only a slight rise (Day 5) in serum creatinine value. Histopathologic analyses by light and electron microscopy showed severe renal proximal tubular necrosis in cisplatin-treated rats yet no detectable lesions were produced by MIDP. Determination of elemental platinum content revealed that less platinum was retained in the kidneys of MIDP-treated rats than in cisplatin-treated animals. The degree of drug-mediated intestinal injury was determined for each drug by measurement of jejunal crypt cell regeneration in mice. Cisplatin reduced crypt survival by 1 log whereas no killing of crypt cells was seen even at MIDP doses exceeding the median lethal dose. Our data demonstrate that far less renal and intestinal toxicity results from administration of MIDP than from administration of cisplatin.
D000818:Animals; D001806:Blood Urea Nitrogen; D002945:Cisplatin / Q000378:metabolism / Q000633:toxicity*; D003404:Creatinine / Q000378:metabolism; D005919:Glomerular Filtration Rate; D007583:Jejunum / Q000187:drug effects* / Q000648:ultrastructure; D007668:Kidney / Q000187:drug effects* / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009944:Organoplatinum Compounds / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution
D009944:Organoplatinum Compounds; C049496:N-methyliminodiacetato-1,2-diaminocyclohexane platinum(II); D003404:Creatinine; D002945:Cisplatin