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.