Cisplatin is widely used for treating of a variety of solid tumors in cancer patients. However, this drug produces dose-limiting side effects such as ototoxicity and nephrotoxicity. While the incidence of nephrotoxicity is reduced by hydrating the patients prior to cisplatin administration, ototoxicity remains a significant problem. Cisplatin ototoxicity is particularly serious in the pediatric population undergoing treatment for cancers such as neuroblastoma. Loss of hearing at this developmental stage hampers speech, cognition and social development. Thus, there is an urgent need to develop effective treatments to ameliorate ototoxicity. We have pursued hypothesis that cisplatin ototoxicity is mediated by its ability to increase reactive oxygen species (ROS) generation in cochlear cells. ROS mediate damage to the outer hair cells (OHCs), stria vascularis (SV) and spiral ganglion cells (SGCs). We and others have shown that the NOX3 isoform of NADPH oxidase is the primary source of ROS in the cochlea which is activated by cisplatin. ROS generated by NOX3 play a critical role in the regulation of cochlear genes, including NOX3 itself, transient receptor potential vanilloid (TRPV1) channel and genes involved in the inflammation and apoptosis. Knockdown of NOX3 or TRPV1 by administering short interfering (si) RNAs into the cochlea reduced damage to OHCs and attenuated cisplatin-induced hearing loss in rat. Signal transducer and activator of transcription 1 (STAT1) plays a primary role in coupling ROS to inflammation and apoptosis in the cochlea. As such, inhibition of STAT1 protected against cisplatin ototoxicity. Interestingly, transplatin, an inactive isomer of cisplatin, was able to mitigate cisplatin ototoxicity, by inhibiing TRPV1 and reducing ROS generation. Transplatin otoprotection was associated with reduced cochlear inflammation. Importantly, unlike other otoprotective agents, transplatin did not alter cisplatin-induced killing of cancer cells. These findings provide the basis for pursuing the clinicl development of transplatin for the alleviation of cisplatin oto- and nephrotoxicity. Studies outlined will provide the basis for in vivo application of transplatin against cisplatin ototoxicit. It is anticipated that such information would be used for an Investigational New Drug (IND) filing to the US Food and Drug Administration.
Six specific aims are proposed.
Aims 1 and 2 will determine the efficacy of intravenous (IV) and oral transplatin against cisplatin ototoxicity and nephrotoxicity, respectively.
Aim 3 will determine the pharmacokinetics of transplatin following IV and oral administration.
Aim 4 will determine the molecular basis of transplatin protection by gene microarray studies, focusing on stress-responsive and pro- inflammatory gene pathways activated by cisplatin in the cochlea.
Aim 5 will assess potential interference by transplatin of cisplatin antitumor efficacy in a mouse tumor model.
Aim 6 will determine potential toxicity of transplatin in rodents using good laboratory practice (GLP) and non-GLP studies. Overall, we believe that this study will provide the basis for the use of transplatin to alleviate cisplatin toxicities in cancer patients.
This proposal will test the ability of an investigational drug, transplatin, to protect against significant side effects of cisplatin, an anticancer drug. Cisplati therapy is associated with significant hearing loss and acute renal failure. We have shown that transplatin could protect against these toxicities in preliminary studies in animals. Over the tenure of this proposal, we will perform more detailed studies to examine protection against cisplatin-induced hearing loss and nephrotoxicity. The data obtained would be used for an Investigational New Drug filing to the US Food and Drug Administration for clinical trials of transplatin to alleviate these cisplatin side effects in patients.
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