Modulation of Therapeutic Response

为了改善癌症的治疗，人们对改变辐射损伤给予了相当大的关注。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。我们最近发现一种分子靶向Chk-1抑制剂对p53突变的人类肿瘤细胞系具有显著的放射增敏作用。正常的人成纤维细胞（p53野生型）对该药物不具有放射致敏性，提示有不同的肿瘤致敏性。这种药物在体内（使用异种移植物）也提供相当大的辐射增强，几乎没有正常组织毒性。虽然这种药物消除了正常的辐射诱导的细胞周期G2的延迟，但抑制辐射损伤的修复似乎是放射致敏的主要机制。我们还在评估一种CK2抑制剂，它在放射暴露后给予时具有令人印象深刻的放射致敏性。初步研究表明，p53 WT细胞比p53突变细胞系具有更大程度的放射致敏性。CK2抑制剂潜在应用的主要焦点是头颈癌。最后，我们正在评估Jak2/Stat3抑制剂在人肺癌细胞系中的作用。初步研究表明，该细胞系具有放射致敏性，机制研究正在进行中。关于正常组织对辐射的反应，我们已经确定了一种新的5元环氮氧化物（23c）作为一种有效的保护剂，可以防止小鼠辐射引起的死亡，并且计划研究是否可以在小鼠的选定正常组织中观察到保护作用，特别是大脑，因为氮氧化物可以穿透血脑屏障。最后，我们已经证明，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。

In 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. We have recently shown that a molecularly targeted Chk-1 inhibitor provides significant radiosensitization in p53 mutated human tumor cell lines. Normal human fibroblasts (p53 wild type) are not radiosensitized by this agent suggesting differential tumor sensitization. This agent also provides considerable radiation enhancement in vivo (using xenografts) with very little to no normal tissue toxicity. While this agent abrogates the normal radiation-induced delay in G2 of the cell cycle, inhibition of repair of radiation damage appears to be the major mechanism of radiosensitization. We are also evaluating a CK2 inhibitor, which provides impressive radiosensitization when administered post-radiation exposure. Preliminary studies indicate that p53 WT cells are radiosensitized to a greater extent that p53 mutated cell lines. The major focus for the potential application of the CK2 inhibitor is head and neck cancer. Finally, we are evaluating a Jak2/Stat3 inhibitor in human lung cancer cell lines. Preliminary studies have demonstrated radiosensitization of the cell lines and mechanistic studies are ongoing. With respect to normal tissue response to radiation, we have identified a novel 5-membered ring nitroxide (23c) as 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. Lastly, we have 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.