Experimental studies of the protective effect of deferoxamine mesilate on cisplatin-induced toxicity

Abstract

Cisplatin (CDDP) is an antitumor agent against several types of neoplasms. It has, however, various side effects such as nephrotoxicity and ototoxicity. Several efforts have been made to prevent these toxic side effects. On the other hand, deferoxiamine mesilate (DFO), an iron-chelating agent, has been used for iron-overloaded patients. Since the 1980s, many authors have reported DFO-associated hearing impairment. Some experimental data suggest that DFO itself was responsible for ototoxicity. In addition, it has also been recognized that DFO can act as a free radical scavenger. Experimental trials using DFO are also expected to prevent CDDP-induced toxicity because its generation mechanism is thought to be associated with free radical formation. The present study was planned to investigate whether DFO, which might be an ototoxic agent, had a protective effect against various CDDP-induced toxicities including ototoxicity. Fisher rats were used in this study and were divided into four groups: 1) Group I, a vehicle control, 2) Group II, animals receiving 100mg of DFO per kg, 3) Group III, animals administered 0.9mg of CDDP per kg alone and 4) Group IV, animals receiving 100mg of DFO per kg 60 min before 0.9mg of CDDP per kg for 10 days. First, the protective effect of DFO against CDDP-induced ototoxicity was studied. The auditory threshold was determined by using the compound action potential (CAP) from the round window membrane. CAPs were recorded on the 5th day after completion of drug administration. Then CAPs recording, cochlear sensory epithelia were observed over all the turns of the cochlea by scanning electron microscopy. There were no significant differences in CAP thresholds between Group I and IV, though the thresholds in Group III were significantly higher at 16kHz and 20kHz than those in Group IV. The rate of missing outer hair cells in Group IV was significantly lower than that in Group III. The results clearly demonstrated that DFO had a protective effect against CDDP- induced ototoxicity. Second, the protective effect of DFO against CDDP- induced nephrotoxicity was studied. Renal function was evaluated by measuring blood urea nitrogen (BUN) and serum creatinine (Cr) levels. Both BUN and Cr levels in Group IV were significantly lower than those in Group III. The data suggested that DFO preadministration prevented CDDP-induced nephrotoxicity. Third, the influence of DFO on the antitumor activity of CDDP was investigated in rats inoculated with squamous cell carcinoma cells (SCC-131) subcutaneously. The influence of drugs was determined by measuring the tumor growth rate. There was no difference in the tumor growth rate between Group III and IV. The result revealed that DFO had no influence on CDDP antitumor activity. In conclusion, the above results demonstrating that DFO preadministration can prevent both CDDP-induced ototoxicity and nephrotoxicity without attenuation of CDDP antitumor activity, suggest the usefulness of CDDP antitumor chemotherapy.