Cisplatin-induced ototoxicity: the effect of pigmentation and inhibitory agents

Cis-diamminedichloroplatinum II (cisplatin), a divalent platinum compound and potent cell-cycle nonspecific chemotherapeutic agent, produces a dose-limiting, permanent, high-frequency sensori-neural hearing loss and peripheral neuropathy, and a dose-related cumulative renal insufficiency with tubular necrosis and interstitial nephritis. The potential for dose-limiting and permanent cochlear (neuro) toxicity remains despite present methods of hypertonic saline, prehydration, and mannitol diuresis prior to drug administration. The exact mechanism(s) of ototoxicity and/or nephrotoxicity are still unknown. Continued aggressive high-dose cisplatin chemotherapy necessitates the investigation of ways to decrease the dose-limiting side effects that inhibit the administration of cisplatin at therapeutic and tumoricidal doses. This multifaceted project investigates two categories of potential inhibitors of cisplatin toxicity that, when coadministered with a known tumoricidal and ototoxic dose of cisplatin, will decrease or inhibit the ototoxicity: 1. phosphonic acid antibiotics (fosfomycin; 1,2 epoxypropylphosphonic acid); 2. nonglucocorticoid 21-aminosteroids, which are free oxygen radical scavengers (LAZAROIDS: U74006F and U78517F). This project also investigates the role of pigmentation as a variable affecting the evaluation of platinum-induced ototoxicity in the guinea pig animal model. Identification of an optimal animal model for future cisplatin toxicity research should be based on previously established species-specific differences in total drug dose, systemic toxicity, and morphological and functional evidence of cochlear toxicity, as affected by differences in pigmentation and drug tolerance. Cytocochleography, brainstem auditory evoked response (BSER), scanning and transmission electron microscopy of organ of Corti and the stria vascularis, double-blind light microscopy of renal, small intestine, and peripheral nerve tissue, and gamma-emission analysis of 195Mplatinum localization in inner ear neuroepithelium and the stria vascularis are used in the global evaluation of the ototoxic effects of cisplatin in both the adult albino and pigmented guinea pig.