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The Cancer Chemoprotection Program

Vitamin E Metabolism and Mechanisms for Chemoprotection and Chemotherapy

Principal Investigator: Debbie J. Mustacich, Ph.D.

Our research is focused on determining the role of oxidative stress and antioxidant status in chemical and mechanical insults and the mechanisms by which antioxidants and nutrients protect the body from these insults and the subsequent development of disease and/or debilitating physical conditions. We use preclinical models that replicate the whole-body response to chemical and mechanical insults in order to identify correlations between events at the cell and tissue level with clinically relevant biomarkers in blood and urine.

We have found that vitamin E supplementation provides protection from the ubiquitous environmental and occupational carcinogen benzo[a]pyrene (BP) by both antioxidant and non-antioxidant mechanisms. Vitamin E decreased BP-induced oxidative stress, altered gene and protein expression of specific metabolic enzymes and transporters, decreased production of DNA-damaging BP metabolites, increased production of nondamaging BP metabolites, and increased BP excretion from the body. Interestingly, vitamin E protection was greater in females than males. Defining the mechanism by which vitamin E protects from BP exposure, including the role of gender, will provide future research directions for determining the possible use of vitamin E for improving human health in both occupational and non-occupational exposures, including in utero.

Cisplatin is one of the most active anticancer agents against solid tumors. Unfortunately, development of peripheral sensory neuropathy often limits the dose and duration of cisplatin treatment. The mechanism of cisplatin neurotoxicity is unknown. We have found that therapeutic doses of cisplatin increase plasma indices of oxidative stress and decrease nervous tissue vitamin E levels. Importantly, vitamin E supplementation prevented cisplatin-induced oxidative stress and depletion of vitamin E. Studies are under way to develop improved treatment regimens that maintain anticancer efficacy while preventing neuropathy, thus improving quality of life for patients and their families.

A new and exciting research interest is that of mechanical injury mechanisms. Our recent spinal cord injury study suggests that administration of nutrients improves functional neurologic outcomes by preventing the secondary biochemical tissue damage that occurs following a mechanical injury to the spine. Based on our findings, and in collaboration with clinicians at the OSU Veterinary Hospital, we plan to initiate clinical trials for improved functional outcomes in dogs suffering from spinal cord injuries.

Knowledge provided by our current and future studies is essential for support of OSUís One Health Initiative to formulate public health recommendations and to develop preventive and therapeutic regimens that include reduction of unwanted side effects, while improving health and extending healthy lifespans for both humans and animals.