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Lazaroids, a novel series of 21-aminosteroids without glucocorticoid action, have the properties of free radical scavenging and potent inhibition of lipid peroxidation. U-74389G is one of the Lazaroid compounds. These compounds have shown excellent effect on central nervous system trauma and ischemia in experimental animals. The present study was designed to investigate whether Lazaroid (U-74389G) has a protective effect on Cisplatin (CDDP)-induced toxicity. Fisher 344 rats were used in this study. The animals were divided into three groups: I) CDDP 0.9 mg/kg i.v. alone; II) CDDP 0.9 mg/kg i.v. 1 hr after the p.o. administration of U-74389G 10 mg/kg; III) physiological saline 2.5 ml/kg i.v. instead of CDDP, for 7-10 days. First, the protective effect of Lazaroid (U-74389G) on CDDP-induced ototoxicity was studied. Cochlear damage was evaluated by means of the compound action potential (CAP) and histological examination using scanning electron microscopy. The degree of elevation of CAP thresholds and the rate of missing outer hair cells were significantly reduced in Group II as compared to Group I. These results clearly demonstrate that Lazaroid (U-74389G) has a protective effect on CDDP-induced ototoxicity. Second, the protective effect of Lazaroid (U-74389G) on CDDP-induced nephrotoxicity was studied. Nephrotoxicity was evaluated by means of serum BUN level and histopathological examination. There was no significant difference in serum BUN level and little difference of renal histopathological findings between Group I and Group II. Lazaroid (U-74389G) was not found to ameliorate CDDP-induced nephrotoxicity. Third, the influence of Lazaroid (U-74389G) on the antitumor effect of CDDP was investigated in rats inoculated subcutaneously with SCC-158 squamous-cell carcinoma cells. There was no significant difference of Tumor Growth Rate (TGR) between Group I and Group II. The result suggests that the combined administration does not alter the antitumor activity of CDDP. In conclusion, the combined administration of CDDP with Lazaroid (U-74389G) ameliorates CDDP-induced ototoxicity without decreasing the antitumor activity of CDDP.

An Experimental Study of the Protective Effect of Lazaroid(U-74389G) on Cisplatin-induced Toxicity.