Enhancing cancer treatment by normal tissue protection

通过保护正常组织增强癌症治疗

基本信息

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
项目类别：
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

项目摘要

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）是一种可以安全地口服给人类的抗癌药物，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。保护作用部分是由于 ATM 激活，并且可用于在放射治疗临床中强有力地保护正常组织和器官。在初步研究中，DIM 不能保护裸鼠中的人类乳腺异种移植肿瘤，但可以保护。小鼠和大鼠抵抗高达 13 Gy 的超致死剂量的全身照射假设，我们预测 DIM 会激活 ATM 依赖性细胞保护性 DNA 损伤反应 (DDR) 和抗氧化反应，而不会引起 DNA 损伤或氧化应激。体内肿瘤中正常细胞相对于肿瘤细胞的差异性保护，因为已经表现出类似的组成性激活 DDR 样途径和细胞存活途径（例如 AKT、NF-κB、Bcl-2/Bcl-XL）我们提出了三个具体目标来研究 DIM 的作用机制并推动 DIM 作为候选临床。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次放射治疗的影响；以及3）使用已建立的小鼠肺和皮肤毒性模型测试DIM对正常组织免受晚期辐射影响的能力。拟议的研究致力于开发癌症放射治疗中正常组织放射防护的新方法，最终目标是将 DIM 开发为临床放射防护剂，以便通过允许更高剂量的放射来改善局部肿瘤控制来提高治疗指数。和/或通过减少任何给定辐射剂量下的后期剂量限制性正常组织毒性。