Enhancing cancer treatment by normal tissue protection

通过保护正常组织增强癌症治疗

• 批准号: 9207750
• 负责人: Albert J Fornace
• 金额: $ 39.76万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9207750
• 关键词: Address; Adverse effects; Animal Model; Antioxidants; Apoptosis; BCL2 gene; Binding; Biochemical; Biological Assay; Breast; Breast Cancer Cell; Breast Cancer cell line; Breast Cancer therapy; Cell Aging; Cell Culture Techniques; Cell Survival; Chromatin; Clinic; Clinical; Comet Assay; Complex; Cultured Cells; DNA; DNA Damage; DNA Double Strand Break; DNA Repair; Data; Development; Dose; Dose-Limiting; End Point Assay; Exhibits; Fibrosis; Gamma Rays; Goals; Human; Inflammation; Ionizing radiation; Late Effects; Lung; MDA MB 231; Maintenance; Malignant Neoplasms; Mediating; Molecular; Mus; NBS1 gene; Normal Cell; Normal tissue morphology; Nude Mice; Oral; Organ; Oxidative Stress; Pathway interactions; Phosphorylation; Physiological; Protein Phosphatase 2A Regulatory Subunit PR53; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Radiation; Radiation Tolerance; Radiation therapy; Radiation-Protective Agents; Radioprotection; Radioresistance; Rattus; Research; Research Design; Role; Series; Signal Pathway; Signal Transduction; Skin; Stream; Structure; Testing; Therapeutic Index; Time; Tissues; Toxic effect; Whole-Body Irradiation; Xenograft procedure; ataxia telangiectasia mutated protein; base; cancer prevention; cancer radiation therapy; cancer therapy; clinical candidate; diindolylmethane; genetic approach; improved; in vivo; irradiation; malignant breast neoplasm; mouse model; neoplastic cell; novel; preclinical study; prevent; public health relevance; radiation effect; radiosensitive; response; sensor; tumor; tumor growth; tumor xenograft

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.

描述（由申请人提供）：背景。 3,3'-二吲哚甲烷 (DIM) 是一种拟议的癌症预防剂，可以安全地以口服形式给予人类。我们证明 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 激活所致，并且可用于保护放射治疗诊所中的正常组织和器官。在初步研究中，DIM 并不能保护裸鼠体内的人类乳腺异种移植肿瘤，但可以有效保护小鼠和大鼠免受高达 13 Gy 的超致死剂量的全身照射。假设。在这里，我们假设 DIM 激活 ATM 依赖性细胞保护性 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。我们预测体内正常细胞相对于肿瘤细胞的差异性保护，因为肿瘤已经表现出类似的组成性激活 DDR 样途径和细胞生存途径（例如 AKT、NF-κB、Bcl-2/Bcl-XL）。研究设计。我们提出了三个具体目标来研究 DIM 的作用机制，并推动 DIM 作为癌症治疗期间的候选临床辐射保护剂。实验计划将包括以下研究： 1) 利用生化、分子生物学和遗传学方法确定 ATM 上游和下游 DIM 辐射防护的分子机制； 2) 测试 DIM 对肿瘤生长和肿瘤放射敏感性对分段放射治疗的影响； 3) 使用已建立的小鼠肺和皮肤毒性模型测试 DIM 保护正常组织免受后期辐射影响的能力。意义。拟议的研究致力于开发一种在癌症放射治疗中保护正常组织的新方法。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/或通过减少任何给定放射剂量下的后期剂量限制性正常组织毒性来提高治疗指数。