Enhancing cancer treatment by normal tissue protection

描述（由申请人提供）：背景。3，3 '-二吲哚基甲烷（DIM）是一种建议的癌症预防剂，可以安全地口服给人类。我们发现，DIM保护正常细胞和组织免受电离辐射的损害。这种保护部分是由于ATM激活，并且可能可用于在放射治疗临床中保护正常组织和器官。在初步研究中，DIM不能保护裸鼠的人乳腺异种移植瘤，但能强烈保护小鼠和大鼠免受高达13-戈伊的超致死剂量全身照射。假说.在这里，我们假设，DIM激活ATM依赖的细胞保护性DNA损伤反应（DDR）和抗氧化反应，而本身不引起DNA损伤或氧化应激。我们预测在体内正常细胞相对于肿瘤细胞的差异保护，因为肿瘤已经表现出类似的 DDR样途径和细胞存活途径（例如，AKT、NF-κ B B、Bcl-2/Bcl-XL）。研究设计。我们提出了三个具体的目标，以调查DIM的作用机制，并推进DIM作为一个候选人的临床辐射保护在癌症治疗。实验计划将包括以下研究：1）通过使用生物化学、分子生物学和遗传学方法，确定DIM在ATM上游和下游的辐射防护的分子机制; 2）测试DIM对肿瘤生长和肿瘤对分次辐射治疗的辐射敏感性的影响;和3）使用已建立的小鼠肺和皮肤毒性模型，测试DIM在正常组织中保护免受晚期辐射效应的能力。意义拟议的研究解决了癌症放射治疗中正常组织辐射防护的新方法的发展。最终目标是开发DIM作为临床放射防护剂，以通过允许更高剂量的辐射来改善局部肿瘤控制和/或通过在任何给定剂量的辐射下减少晚期剂量限制性正常组织毒性来改善治疗指数。

DESCRIPTION (provided by applicant): Background. 3,3'-Diindolylmethane (DIM) is a proposed cancer prevention agent that can be given safely to humans in oral form. We showed that DIM protects normal cells and tissues from damage by ionizing radiation. The protection is due, in part, by ATM activation and is potentially exploitable for protecting normal tissues and organs in the radiotherapy clinic. In preliminary studies, DIM did not protect human breast xenograft tumors in nude mice, but strongly protected mice and rats against supralethal doses of total body irradiation up to 13-Gy. Hypothesis. Here, we hypothesize that DIM activates an ATM-dependent cytoprotective DNA damage response (DDR) and antioxidant response without itself causing DNA damage or oxidative stress. We predict differential protection of normal cells relative to tumor cells in vivo because tumors already exhibit constitutive activation of a similar DDR-like pathway and of cellular survival pathways (e.g., AKT, NF-¿B, Bcl-2/Bcl-XL). Research design. We propose three specific aims to investigate DIM's mechanism of action and to advance DIM as a candidate clinical radiation protector during cancer treatment. The experimental plan will include studies to: 1) identify the molecular mechanism(s) of DIM radioprotection up- and down-stream of ATM by the use of biochemical, molecular biologic, and genetic approaches; 2) test the effects of DIM on tumor growth and tumor radiosensitivity in response to fractionated radiation treatments; and 3) test the ability of DIM to protect against late radiation effects in normal tissues, using established mouse models for lung and skin toxicity. Significance. The proposed research addresses the development of a novel means of radioprotection of normal tissues in cancer radiation therapy. The ultimate goal is to develop DIM as a clinical radioprotector in order to improve the therapeutic index by allowing higher doses of radiation to improve locoregional tumor control and/or by reducing late dose-limiting normal tissue toxicity at any given dose of radiation.