Enhancing cancer treatment by normal tissue protection

通过保护正常组织增强癌症治疗

• 批准号: 8671485
• 负责人: Eliot M. Rosen
• 金额: $ 41.15万
• 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/8671485
• 关键词: ATM Signaling Pathway; Address; Adverse effects; Animal Model; Antioxidants; Apoptosis; BCL2 gene; Binding; Biochemical; Biological Assay; Breast; Breast Cancer Cell; Cancer cell line; 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; Genetic; Goals; Histocompatibility Testing; 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; 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; Relative (related person); 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; diindolylmethane; improved; in vivo; irradiation; malignant breast neoplasm; mouse model; neoplastic cell; novel; preclinical study; prevent; public health relevance; radiation effect; 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（由应用程序提供）：背景。 3,3'-二丁烷基甲烷（DIM）是一种拟议的癌症预防剂，可以用口服形式安全地给予人类。我们表明，通过电离辐射保护正常细胞和组织免受损伤。保护部分是由于ATM激活的部分原因，并且有可能利用放射疗法诊所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，而是强烈保护小鼠和大鼠免受超过13-GE的全身辐射。假设。在这里，我们假设该昏暗会激活ATM依赖性的细胞保护DNA损伤反应（DDR）和抗氧化剂反应，而不会自身引起DNA损伤或氧化应激。我们预测正常细胞相对于体内肿瘤细胞的差异保护，因为肿瘤已经暴露了类似的本构激活 DDR样途径和细胞存活途径（例如Akt，NF-€，Bcl-2/bcl-XL）。研究设计。我们提出了三个特定的目的，以研究DIM的作用机理，并在癌症治疗期间作为候选临床辐射保护剂的变暗。实验计划将包括：1）通过使用生化，分子生物学和遗传方法来确定ATM的昏暗辐射保护的分子机制； 2）测试对分离放射治疗的肿瘤生长和肿瘤放射敏性的影响； 3）使用已建立的肺和皮肤毒性的小鼠模型来测试昏暗的防御正常组织中晚期辐射效应的能力。意义。拟议的研究涉及癌症放射治疗中正常组织的新型辐射方法的发展。最终目标是通过允许更高剂量的放射线来改善局部区域肿瘤控制和/或通过在任何给定剂量的放射线下降低晚期剂量限制的正常组织毒性来改善降低局部肿瘤的控制和/或来改善治疗指数。