Cisplatin (CDDP) is the most potent ototoxin in common clinical use. CDDP induced hearing loss can be severe and is almost always permanent. As CDDP is used for a wider variety of cancers and with increasingly higher dosing, CDDP induced ototoxicity is of increasing clinical importance. Further, CDDP induced ototoxicity is now the most common dose limiting factor for CDDP chemotherapy. The purpose of the proposed studies is to select the most effective protective agent from each class of CDDP protective agents in a rat model. Ototoxicity will be assessed by auditory brainstem response threshold, scanning electron microscopy of the cochlear hair cells (SEM) and transmission electron microscopy (TEM) of the stria vascularis. Weight loss, as a measure of general health, will also be assessed. Because nephrotoxicity is the second most common dose limiting factor for CDDP chemotherapy, and because many protective agents are effective for both ototoxicity and nephrotoxicity, we will also measure creatinine for each animal. However the primary purpose of this grant is to develop otoprotective agents and to prevent hearing loss. The classes of agents included are: sulfur containing compounds, anti- oxidants/free radical scavengers, and steroids. Each agent selected meets the following criteria: documented evidence that the agent is protective against CDDP ototoxicity and/or nephrotoxicity, no exacerbation of other CDDP toxicities, and no inhibition of CDDP anti- tumor efficacy or no mechanism for inhibition of anti-tumor efficacy. All agents must also be suitable for use in humans. Control groups, of 11 animals each, will include a treated (16 mg/kg CDDP), and an untreated (equivalent volume of saline) control group. For animals receiving protective agents in addition to the CDDP, first dose response curves (5 animals per level) will be obtained to determine the optimal dosing level for each agent. Then the agents within each class of agents will be compared (11 animals per group at the lowest dosing level that provides optimal protection. The schedule of experiments is as follows: Year 1: Sulfur containing compounds Year 2: Anti-oxidants/free radical scavengers Year 3: Steroids. In the fourth and five year of the grant, the best agent of each of the above experiments will be tested in various combinations. The """"""""best"""""""" agent will be selected on the primary criterion of otoprotection and the secondary criterion of nephroprotection because currently ototoxicity is the primary and nephrotoxicity the secondary dose limiting toxicity for CDDP. It is hoped that these experiments will allow us to develop better protocols for patients receiving CDDP chemotherapy so that they may receive CDDP dosing high enough to cure their cancer without the side effect of hearing loss.
