Enhancing cancer treatment by normal tissue protection

简介(申请人提供)：背景。3，3‘-二吲哚甲烷(DIM)是一种建议的癌症防御剂，可以安全地口服给人类。我们发现，DIM可以保护正常细胞和组织免受电离辐射的损害。这种保护在一定程度上是由于ATM的激活，并有可能被用于保护放射治疗诊所的正常组织和器官。在初步研究中，DIM不保护裸鼠体内的人乳腺移植瘤，但强烈保护小鼠和大鼠免受高达13Gy超致死剂量的全身照射。假设。这里，我们假设DIM激活了ATM依赖的细胞保护性DNA损伤反应(DDR)和抗氧化反应，而本身不会造成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具有不同的保护作用，因为肿瘤已经表现出类似的结构性激活 Ddr-like通路和细胞存活通路(如AKT、NF-�B、Bcl2/Bclxl)。研究设计。我们提出了三个具体的目标来研究DIM的作用机制，并推动DIM作为癌症治疗过程中的候选临床辐射保护剂。实验计划将包括以下研究：1)通过生化、分子生物学和遗传学方法确定DIM辐射防护ATM上下游的分子机制(S)；2)测试DIM对肿瘤生长和肿瘤放射敏感性的影响；以及3)使用已建立的小鼠肺和皮肤毒性模型，测试DIM在正常组织中抵御晚期辐射效应的能力。意义重大。这项拟议的研究旨在开发一种在癌症放射治疗中对正常组织进行辐射防护的新方法。最终目标是开发DIM作为临床放射防护剂，以便通过允许更高剂量的放射来改善局部肿瘤控制和/或通过减少在任何给定剂量下限制晚期剂量的正常组织毒性来提高治疗指数。

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.