The toxic side effects of many commonly used therapeutic agents can result in drug dose reduction or discontinuation, limiting the use of these effective and inexpensive agents in the clinic. Protecting against dose limiting toxicities would improve patient quality of life and has the potential to improve therapeutic outcomes by increasing compliance with treatment regimens and allowing increased treatment times and doses. With previous VA funding, we have been investigating mechanisms to decrease or eliminate the toxic side effects of cancer chemotherapy for two decades and have moved from basic research to Phase III clinical trials. Our research has demonstrated that delayed administration of the thiol chemoprotective agents sodium thiosulfate (STS) and N-acetylcysteine (NAC) is an effective strategy to reduce the cochlear, renal and bone marrow toxicities of the platinum-based chemotherapy agents cisplatin and carboplatin without decreasing their anti- tumor efficacy. This proposal will expand our chemoprotection strategy to aminoglycoside antibiotics that are commonly used in the VA patient population for the treatment of serious infections. Additionally, we will test the hypothesis that inflammation following activation of the innate immune response in the cochlea will enhance the ototoxic side effects of cisplatin chemotherapy and aminoglycoside antibiotics. To investigate the mechanisms underlying toxicity and chemoprotection, we will test novel magnetic resonance imaging (MRI) techniques using the iron oxide nanoparticle contrast agent ferumoxytol. Ferumoxytol is taken up by macrophages and activated microglial cells over the course of 24 hours, providing a non-invasive marker of inflamed tissues. We hypothesize that ferumoxytol enhancement on MRI will provide a quantifiable biomarker to measure inflammation in the cochlea and the impact of inflammation on ototoxic stimuli, as well as the impact of chemoprotection on these processes.
In Aim 1 we will evaluate innate immune system enhancement of cisplatin ototoxicity using generalized systemic inflammation versus localized acute neuroinflammation. We will evaluate the magnitude of ototoxicity and inflammatory cell infiltration into the cochlea, and determine whether thiol chemoprotection blocks the enhanced cisplatin toxicity. We will investigate high-resolution MRI with ferumoxytol to assess inflammation and cisplatin ototoxicity and determine the impact of STS and NAC on these processes.
In Aim 2 we will assess chemoprotection for endotoxemia-potentiated aminoglycoside ototoxicity. We will use ferumoxytol MRI to assess cochlear vessel permeability and inflammation. Our overall goals are to develop chemoprotection strategies against the side effects of therapeutics and imaging biomarkers to improve detection and management of inflammation, ultimately improving long-term outcomes for VA patients.

Public Health Relevance

We hypothesize that hearing loss caused by two different classes of agents, platinum chemotherapy and aminoglycoside antibiotics, is due to free radical damage in the ear, and that inflammation will exacerbate these effects. We will perform preclinical studies to determine if chemoprotection with the thiols sodium thiosulfate and/or N-acetylcysteine decreases inflammation-enhanced ototoxicity. We will also evaluate high- resolution neuroimaging with ferumoxytol iron oxide nanoparticles as a biomarker for cochlear inflammation and ototoxicity.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Neurobiology B (NURB)
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Portland VA Medical Center
United States
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Brock, Penelope R; Maibach, Rudolf; Childs, Margaret et al. (2018) Sodium Thiosulfate for Protection from Cisplatin-Induced Hearing Loss. N Engl J Med 378:2376-2385