Development of Novel Tocotrienol-based Radioprotective Agents

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More than 50% of all cancer patients will receive radiotherapy during the course of their cancer treatments; however, radiation-induced injury to normal tissues is the major cause of radiation treatment–related side effects and is a limiting factor in cancer radiotherapy. There is also growing public concern of nuclear terrorist attacks or industrial accidents. However, no safe, effective, FDA-approved radioprotectants are currently available. Two vitamin E homologues—γ-tocotrienol (γ-T3) and δ-tocotrienol (δ-T3)—are some of the most effective low-toxic radioprotective agents identified to date. Among all natural products tested to date, γ-T3 and δ-T3 were found to give the highest degree of protection to mice exposed to radiation doses that were otherwise lethal. Despite their potential as radioprotectants, γ- and δ-T3 have relatively short plasma elimination half-lives and, if not given by intravenous injection, low bioavailability, which limits their exposure time and concentration in systemic circulation and necessitates administration in large doses. The short plasma elimination half-lives are a result of their low affinity for α-tocopherol transfer protein (α-TTP) and their high rates of metabolism. The low bioavailability of γ- and δ-T3 is caused, at least in part, by their high lipophilicity and low water solubility. Low α-TTP affinity and low metabolic stability are also responsible for the low oral bioavailability of γ- and δ-T3 because oral dosing is subject to significant first-pass metabolism through the liver. Thus, to improve the potential therapeutic utility of γ- and δ-T3 as radioprotective agents, we propose to design and synthesize T3-based analogues with intrinsic radioprotective properties comparable to or better than those of γ- and δ-T3 but with reduced lipophilicity, increased α-TTP affinity, and increased metabolic stability. For this purpose, we will pursue the following Specific Aims: 1) design and synthesize γ- and δ-T3 analogues; 2) determine α-TTP binding and liver metabolism of γ- and δ-T3 analogues; 3) determine antioxidant and HMG-CoA reductase inhibitory properties of γ- and δ-T3 analogues; and 4) determine in vitro radioprotective properties of γ- and δ-T3 analogues. Our long-term goal is to develop these compounds into radioprotective drugs for human use. We expect that such compounds will also serve as research tools for studying biochemical mechanisms of radiation protection.