Alpha-difluoromethylornithine (DFMO) is an inhibitor of ornithine decarboxylase (ODC), a critical enzyme in the synthesis of polyamines. DFMO is an antineoplastic and antiparasitic drug that unexpectedly produced a sensorineural hearing loss in humans. Understanding the toxicity of DFMO is important because it is now the major new drug to be used against African sleeping sickness and will be given to large numbers of people in Africa. DFMO is also effective in the treatment of pneumocystis in AIDS patients. We have developed the first animal model of DFMO-induced hearing loss, and have described the brainstem audiometric and light microscopic effects of DFMO on the cochlea. we have also developed the technology to measure polyamine levels and assay ODC activity from subfractionated cochleas from a single animal. From the standpoint of cochlear physiology, the most exciting finding is that DFMO causes more loss of inner hair cells than outer hair cells in the hook and first turn. This preferential toxicity of inner hair cells may prove to be an important tool in understanding the physiology of inner versus outer hair cells. In this proposal we will 1) Extend our histologic evaluation to include the stria vascularis and eighth nerve with light and electron microscopy, 2) Determine if DFMO hearing loss is from its inhibition of ODC by administration of exogenous polyamines, 3) Apply already developed biochemical techniques to evaluate the effect - of DFMO on ODC and polyamines in the cochlea, and 4) localize ODC within the cochlea with autoradiographic techniques.
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