Nephrotoxicity of a novel antineoplastic platinum complex, nedaplatin: a comparative study with cisplatin in rats.
The present study was designed to characterize the nephrotoxicity induced by the antineoplastic platinum complex nedaplatin (NDP) in rats of different ages in comparison with cisplatin (CDDP). A single dose of 15 mg/kg NDP or 7.5 mg/kg CDDP was administered intravenously to 8-, 11-, or 15-week-old male and female SD rats, which were then sacrificed after ten days. Body weight decreases were observed for both drugs, in direct relation to age. CDDP treatment markedly increased urinary excretion of NAG, gamma-GTP, LDH and protein, with peaks on day 4 and complete or partial recovery on day 7; NDP increased NAG, LDH and protein excretion, but to a lesser extent, and these elevations were generally more marked for females. CDDP increased plasma creatinine and BUN in males and females of all age groups at necropsy. No apparent changes were seen following NDP treatment except in the 15-week-old rats. These results also show that NDP is less nephrotoxic than CDDP. CDDP-treated rats showed remarkable proximal tubular lesions in the renal cortex and corticomedullary region, and the papillary lesions were minor. On the other hand, the NDP-induced nephrotoxicity was morphologically characterized by hyaline droplet changes (electron microscopically, hyperplasia of lysosomes), necrosis or hyperplasia of the collecting duct epithelium in the renal papilla and the epithelium covering the papilla. Cortical lesions, indicated by slight tubular dilatation, were found only in the animals with papillary lesions. In summary, NDP is a promising second-generation platinum complex with reduced nephrotoxicity.
Uehara
Takeki
T
Developmental Research Laboratories, Shionogi and Co. Ltd, 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan. tabeki.uehara@shionogi.co.jp
Watanabe
Hiroshi
H
Itoh
Fumio
F
Inoue
Satoshi
S
Koshida
Hikaru
H
Nakamura
Masuhisa
M
Yamate
Jyoji
J
Maruyama
Toshiyuki
T
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D002945:Cisplatin / Q000633:toxicity*; D005260:Female; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology / Q000652:urine; D007677:Kidney Function Tests; D007685:Kidney Tubules, Collecting / Q000187:drug effects / Q000648:ultrastructure; D008136:Longevity / Q000187:drug effects; D008247:Lysosomes / Q000187:drug effects / Q000648:ultrastructure; D008297:Male; D009929:Organ Size / Q000187:drug effects; D009944:Organoplatinum Compounds / Q000633:toxicity*; D011507:Proteinuria / Q000139:chemically induced / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C053989:nedaplatin; D002945:Cisplatin