Modulation of Therapeutic Response

治疗反应的调节

• 批准号: 8554011
• 负责人: James Mitchell
• 金额: $ 66.27万
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8554011
• 关键词: Attention; Blood - brain barrier anatomy; Brain; Cell Cycle; Cell Line; Cisplatin; Clinical Data; Clinical Trials; Colon Carcinoma; Commiphora mukul; DNA Double Strand Break; Data; Dose; Double Strand Break Repair; FGF7 gene; Gene Transfer; Goals; Head and Neck Cancer; Human; Hypolipidemic Agents; IGF1 gene; Ionizing radiation; MCF7 cell; Modification; Molecular; Movement; Mucositis; Mus; NF-kappa B; Normal tissue morphology; Pancreas; Physiology; Plant Resins; Process; Proteins; Radiation; Radiation Oncology; Radiation Tolerance; Radiation-Protective Agents; Reporting; Research; Research Design; Resistance; Submandibular gland; Therapeutic; Topical application; Toxic effect; Translating; Trees; Tumor-Associated Process; cancer cell; cancer therapy; cell growth; chemotherapy; clinical application; gugulu extract; human ESR1 protein; improved; inhibitor/antagonist; interest; keratinocyte growth factor; novel; oral mucositis; pancreatic cancer cells; pre-clinical; pre-clinical research; radiation effect; response; tempol; treatment response; tumor; tumor growth

SummaryIn the interest of improving cancer treatment, considerable attention has been placed on the modification of radiation damage. The interaction of a variety of chemotherapy and/or molecularly targeted agents with radiation is under study to determine if tumors can be made more sensitive or normal tissues more resistant to radiation treatment. The central aim is to identify approaches that will result in a net therapeutic gain, thus improving cancer treatment with radiation. One goal of the project is to define and better understand those aspects of tumor physiology, including cellular and molecular processes and the influence of the tumor microenvironment on treatment response. The ability to enhance the response of the tumor to radiation, without enhancing normal tissue within a given treatment field is desirable. Gugglesterone, a derivative of the resin of guggul tree Commiphora mukul has been widely reported as a hypolipidemic agent and more recently as an inhibitor of NF-kB activation. It was found that gugglesterone inhibited radiation-induced NF-kB activation and enhanced radiosensitivity in the pancreatic cell line, PC-Sw. Gugglesterone reduced both cell cycle movement and cell growth and reduced ER alpha protein in MCF7 cells and IGF1-R beta protein in colon cancer cells and pancreatic cancer cells and inhibited DNA double strand break (DSB) repair following radiation. With respect to normal tissue response to radiation, we found that keratinocyte growth factor (KGF) gene transfer to mouse submandibular glands afforded significant protection against both single and fractionated doses of radiation. Local gene transfer resulted in significant systemic levels of KGF; however, KGF gene transfer had no effect on tumor growth with or without radiation. These data suggest potential clinical application. We have also shown that the nitroxide, Tempol protects against radiation-induced oral mucositis (both systemic and topically applied). Oral mucositis is a common toxicity associated with the chemoradiation (cisplatin combined with fractionated radiation) treatment of head and neck cancers. Tempol also protects against chemoradiation-induced mucositis yet did not alter chemoradiation with respect to tumor regrowth delay, providing sufficient pre-clinical data to introduce Tempol into human radiation oncology clinical trials.Lastly, a novel 5-membered ring nitroxide (23c) was shown to be a potent protector against radiation-induced lethality in mice and studies are planned to determine if protection can be observed in selected normal tissues in mice, particularly the brain since the nitroxide penetrates the blood brain barrier.

为了提高癌症的治疗水平，对辐射损伤的治疗已经引起了相当大的关注。目前正在研究各种化疗和/或分子靶向药物与辐射的相互作用，以确定是否可以使肿瘤更敏感或正常组织对放射治疗更有抵抗力。中心目标是确定将导致净治疗增益的方法，从而改善癌症放射治疗。该项目的一个目标是定义和更好地理解肿瘤生理学的这些方面，包括细胞和分子过程以及肿瘤微环境对治疗反应的影响。在给定的治疗范围内，增强肿瘤对辐射的反应而不增强正常组织的能力是可取的。谷谷酮是谷谷树Commiphora mukul树脂的衍生物，已被广泛报道为降血脂剂，最近作为NF-kB活化抑制剂。研究发现，谷胱甘酮抑制辐射诱导的NF-kB激活，并增强胰腺细胞系PC-Sw的放射敏感性。Gugglesterone减少了细胞周期运动和细胞生长，降低了结肠癌细胞和胰腺癌细胞中MCF7细胞中的ER α蛋白和IGF1-R β蛋白，抑制了辐射后DNA双链断裂（DSB）的修复。关于正常组织对辐射的反应，我们发现角质细胞生长因子（KGF）基因转移到小鼠颌下腺对单次和分次剂量的辐射都有显著的保护作用。局部基因转移导致KGF显著的全身性水平；然而，KGF基因转移对肿瘤生长无影响。这些数据提示了潜在的临床应用。我们还表明，氮氧化物Tempol可以防止辐射引起的口腔黏膜炎（全身和局部应用）。口腔黏膜炎是头颈癌放化疗（顺铂联合分次放疗）的常见毒性。Tempol还可以防止放化疗引起的粘膜炎，但在肿瘤再生延迟方面没有改变放化疗，这为将Tempol引入人体放射肿瘤学临床试验提供了足够的临床前数据。最后，一种新的5元环氮氧化物（23c）被证明是一种有效的保护剂，可以防止小鼠受到辐射引起的死亡，研究计划确定是否可以在小鼠的某些正常组织中观察到保护作用，特别是大脑，因为氮氧化物可以穿透血脑屏障。