Enhancing cancer treatment by normal tissue protection

背景：3,3'-二吲哚基甲烷（DIM）是一种建议的防癌剂，可以安全地口服给人。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。这种保护部分是由于ATM的激活，并且有可能用于放射治疗临床中保护正常组织和器官。在初步研究中，DIM对裸鼠的人乳腺异种移植瘤没有保护作用，但对小鼠和大鼠对高达13-Gy的超致死剂量全身照射有很强的保护作用。假设。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，而本身不会引起DNA损伤或氧化应激。我们预测正常细胞相对于肿瘤细胞在体内的差异保护，因为肿瘤已经表现出类似的组成性激活

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.