Modulation of Therapeutic Response

为了改善癌症治疗，人们对辐射损伤的修饰给予了相当大的关注。 正在研究各种化疗和/或分子靶向药物与放射的相互作用，以确定是否可以使肿瘤对放射治疗更敏感或使正常组织对放射治疗更耐受。 中心目标是确定将导致净治疗收益的方法，从而改善癌症的放射治疗。 该项目的一个目标是定义和更好地了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。 增强肿瘤对辐射的响应而不增强给定治疗区域内的正常组织的能力是期望的。 Gugglutamine是一种由没药树（Commiphora mukul）的树脂衍生的衍生物，已被广泛报道为降血脂剂，最近被报道为NF-κ B活化的抑制剂。 Gugglutamine可抑制辐射诱导的胰腺癌细胞系PC-Sw中NF-κ B的活化并增强其辐射敏感性。Gugglutamine可降低细胞周期运动和细胞生长，降低MCF 7细胞中的ER α蛋白和结肠癌细胞及胰腺癌细胞中的IGF 1-R β蛋白，并抑制辐射后DNA双链断裂（DSB）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）基因转移到小鼠下颌下腺提供了显着的保护，对单次和分次剂量的辐射。 局部基因转移导致显着的全身水平的KGF，然而，KGF基因转移有或没有辐射对肿瘤生长没有影响。 这些数据表明潜在的临床应用。 我们还表明，氮氧化物，Tempol防止辐射引起的口腔粘膜炎（全身和局部应用）。 口腔粘膜炎是头颈部癌症放化疗（顺铂联合分次放疗）治疗的常见毒性。 Tempol还可以预防放化疗诱导的粘膜炎，但不会改变放化疗对肿瘤再生长延迟的影响，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。一种新的五元环氮氧自由基（23 C）被证明是一种有效的抗辐射保护剂，小鼠中的诱导致死性，并计划进行研究以确定是否可以在小鼠的选定正常组织中观察到保护作用，特别是脑，因为氮氧化合物穿透血脑屏障。

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.