Modulation of Therapeutic Response

为了改善癌症治疗，相当多的注意力已经放在辐射损伤的修饰上。 该项目的主要目标是继续定义和理解独特的肿瘤生理学，解剖学，细胞和分子过程的那些方面，这些方面最终定义了肿瘤的本质，使得特定剂量的电离辐射在使用时更有效。 为此目的的一种手段是研究电离辐射与各种化疗药物的相互作用，以评估是否可以使肿瘤更敏感。我们以前证明，紫杉醇治疗不同的人肿瘤细胞系诱导细胞周期的G2/M期（细胞周期的放射敏感期）阻滞，导致显着的放射增敏。因此，放射肿瘤学分支目前正在将这些临床前信息转化为放射和紫杉醇联合治疗头颈癌的临床试验。 我们已经测试了其他化疗药物，包括喜树碱衍生物，米托蒽醌，和UCN-01。 米托蒽醌和UCN-01均未被发现对多种人类肿瘤细胞系具有显著的放射增敏作用。虽然发现喜树碱衍生物具有放射增敏作用，但其固有的细胞毒性很可能会阻止其在临床中与放射一起使用。 最近的研究集中在MGI-114，一种新的烷基化倍半萜类化合物，在体外和体内模型中都显示出细胞毒性。 我们已经表明，MGI-114选择性地放射增敏人乳腺癌和结肠癌细胞系的辐射与S期的细胞周期阻滞的指示。 我们还开始了研究，使用两个间变性甲状腺癌细胞系，试图确定代理，可能放射增敏这些细胞系。 在评价的大约8种不同的药物中，只有5-碘脱氧尿苷具有放射增敏作用，剂量修正因子约为2。 因此，我们正在使用几种小鼠肿瘤模型来研究肿瘤缺氧。 我们的方法是使用当前的侵入性技术，并将这些信息扩展到正在开发的非侵入性方法，以便可以在个体基础上优化患者的肿瘤治疗方案。为此，我们正在使用体外和体内存活技术，氧探针，硝基咪唑固定，然后免疫组织化学，F-18硝基咪唑PET扫描，血氧水平测定（BOLD）NMR，电子顺磁共振（EPR）和Overhauser NMR。 目前，我们正在比较/对比这些不同的技术，最终将非侵入性EPR或Overhauser NMR功能成像带入临床试验。 我们获得的信息将教会我们如何以非侵入性方式评估肿瘤中的氧气状态，以实现最佳治疗。 正在研究肿瘤内的基因表达作为氧状态、再灌注、电离辐射暴露和一般氧化应激的函数，以使用cDNA微阵列技术确定在肿瘤细胞对单独的电离辐射或与药理学试剂组合的损伤的反应性和存活中重要的那些分子事件。其目的是扩展我们的肿瘤微环境，生理学和分子生物学的知识，并将这些知识与研究肿瘤的非侵入性方法相关联，以便我们设计出高效和有效的治疗方案，使用辐射与药理学药物相结合或串联。 同样地，我们预期研究放射治疗后的基因表达谱将潜在地提供新的分子靶点，其可以被选择性地抑制和/或增强，这将调节放射反应。

In the interest of improving cancer treatment, considerable attention has been placed on the modification of radiation damage. The major goal of this project continues to define and understand those aspects of unique tumor physiology, anatomy, cellular, and molecular processes that ultimately define the very nature of a tumor such that a particular dose of ionizing radiation, when used will be more effective. One means to that end is to investigate the interaction of ionizing radiation with a variety of chemotherapy agents to assess if tumors can be made more sensitive. We previously demonstrated that treatment of diverse human tumor cell lines with paclitaxel induced a block in G2/M of the cell cycle (radiosensitive phases of the cell cycle) which resulted in significant radiosensitization. As a consequence, translation of this pre-clinical information into a clinical trail combining radiation and paclitaxel in the treatment of head/neck cancer is currently underway in the Radiation Oncology Branch. We have tested other chemotherapeutic agents including camptothecin derivatives, mitoxantrone, and UCN-01. Neither mitoxantrone nor UCN-01 was found to significantly radiosensitize a variety of human tumor cell lines. While camptothecin derivatives were found to radiosensitize, their inherent cytotoxicity alone will most likely prevent them from being used in the clinic with radiation. Recent studies have centered on the agent MGI-114, a new alkylating sesquiterpenoid which has shown cytotoxicity in both in vitro and in vivo models. We have shown that MGI-114 selectively radiosensitizes human breast and colon cell lines to radiation with an indication that the sensitization is related to cell cycle blocks in S phase. We have also initiated studies using two anaplastic thyroid cancer cell lines in an attempt to identify agents that might radiosensitize these cell lines. Of approximately eight different agents evaluated only 5-iododeoxyuridine radiosensitized with a dose-modifying factor of approximately 2.It is well established that hypoxia is a major determinant of radiation sensitivity. Therefore, we are using several murine tumor models to study tumor hypoxia. Our approach is to use current invasive techniques and extend that information to non-invasive methods that are under development, such that patient tumor treatment profiles may be optimized on an individual basis. To that end we are using in vitro and in vivo survival techniques, oxygen probes, nitroimidazole fixation followed by immunohistochemistry, F-18 nitroimidazole PET scanning, blood oxygen level determination (BOLD) NMR, electron paramagnetic resonance (EPR), and Overhauser NMR. Presently we are comparing/contrasting these various techniques with the goal of ultimately bringing non-invasive EPR or Overhauser NMR functional imaging to clinical trial. The information we acquire will teach us how to assess oxygen status in a tumor in a non-invasive manner to effect optimum treatment. Gene expression within a tumor as a function of oxygen status, reperfusion, ionizing radiation exposure and general oxidative stress is being investigated to determine those molecular events that are important in the tumor cell responsiveness and survival to insult by ionizing radiation alone or in combination with pharmacologic agents using cDNA microarray technology. The aim is to extend our knowledge of tumor micro-environment, physiology, and molecular biology and to correlate such knowledge with non-invasive methods of studying tumors so that we design efficient and effective treatment protocols using radiation in combination or tandem with pharmacologic agents. Likewise, we anticipate that studying gene expression profiles following radiation treatment will potentially provide novel molecular targets that may be selectively inhibited and/or enhanced which will modulate the radiation response.