Development of Novel Tocotrienol-based Radioprotective Agents

超过50%的癌症患者将在癌症治疗过程中接受放射治疗； 然而，辐射对正常组织的损伤是放射治疗相关副反应的主要原因 这是癌症放射治疗中的一个限制因素。公众对核恐怖分子的担忧也越来越多。 袭击或工业事故。然而，目前还没有安全、有效、FDA批准的辐射防护剂 可用。两种维生素E同系物--γ-生育三烯醇(γ-T3)和δ-生育三烯醇(δ-T3)--是最多的 迄今已确定的有效低毒辐射防护剂。到目前为止，在所有测试的天然产品中，γ-T3和 研究发现，δ-T3对受到以下辐射剂量的小鼠具有最高程度的保护 否则就是致命的。尽管γ-和δ-T3有潜在的辐射防护剂，但它们的血浆相对较短 消除半衰期，如果不是静脉注射，生物利用度低，这限制了他们的暴露 在体循环中的时间和浓度，有必要大剂量给药。短小的 血浆消除半衰期是由于它们对α-生育酚转移蛋白(α-TTP)及其受体的低亲和力所致 新陈代谢速度快。γ-和δ-T3的低生物利用度至少部分是由于它们的高 亲油性和低水溶性。α-TTP亲和力低和代谢稳定性低也是导致 γ-和δ-T3的口服生物利用度低，因为口服给药受显著的首过代谢影响 肝脏。因此，为了提高γ-和δ-T3作为放射防护剂的潜在治疗效用，我们建议 设计和合成具有与之相当或更好的固有辐射防护性能的基于T3的类似物 与γ-和δ-T3相比，但亲脂性降低，α-TTP亲和力增强，代谢增加 稳定性。为此，我们将追求以下具体目标：1)设计和合成γ-和δ-T3 类似物；2)测定α-TTP结合及γ-和δ-T3类似物的肝脏代谢；3)测定 γ-和δ-T3类似物的抗氧化剂和HMG-CoA还原酶抑制性能；4)体外测定 γ-和δ-T3类似物的辐射防护性能。我们的长期目标是将这些化合物开发成 人类使用的辐射防护药物。我们预计，这些化合物也将作为研究工具 研究辐射防护的生化机制。

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.