Modulation of Therapeutic Response

为了提高癌症的治疗水平，辐射损伤的修饰受到了极大的关注。该项目的主要目标是继续定义和了解独特的肿瘤生理学、解剖学、细胞和分子过程的那些方面，这些过程最终定义了肿瘤的本质，从而使特定剂量的电离辐射在使用时将更加有效。为此，一种方法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变得更敏感。我们以前曾证明，紫杉醇处理不同的人类肿瘤细胞系，导致细胞周期的G2/M期(细胞周期的辐射敏感期)被阻断，从而导致显着的辐射增敏。因此，放射肿瘤科目前正在将这一临床前信息转化为结合放射和紫杉醇治疗头颈部癌症的临床试验。我们已经测试了其他化疗药物，包括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。我们已经证明MGI-114选择性地增敏人乳腺和结肠细胞系对辐射的敏感性，有迹象表明这种增敏作用与细胞周期阻滞在S期有关。同样，另一种新型试剂正在评估放射增敏特性。胞苷杀菌素743是一种具有抗肿瘤活性的药物，它选择性地烷化鸟嘌呤氮，目前正在细胞培养中进行评估。该项目的另一个主要目的是开发功能成像技术，以更好地表征在肿瘤微环境中重要的因素，这些因素可能防止或减少药物对辐射反应的影响。众所周知，低氧是辐射敏感性的一个主要决定因素。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，以便患者的肿瘤治疗方案可以根据个人情况进行优化。为此，我们正在使用体外和体内存活技术、氧探针、硝基咪唑固定以及免疫组织化学、电子顺磁共振(EPR)和Overhaser MRI(OMRI)。目前，我们正在对这些不同的技术进行比较，最终将非侵入性EPR或OMRI功能成像引入临床试验。我们获得的信息将教会我们如何以非侵入性的方式评估肿瘤中的氧气状态，以实现最佳治疗。我们最近比较了OMRI收集的小鼠肿瘤中的氧分布，并将结果与传统的氧电极测量进行了比较。OMRI的氧浓度曲线与氧电极测量结果具有很好的相关性，从而验证了这种非侵入性的组织氧浓度评估技术。此外，我们正在开发一种使用EPR和稳定的顺磁性探针(氮氧化物)对组织进行无创氧化还原成像的技术。总而言之，这些非侵入性的功能成像方法应该会增强我们更好地了解肿瘤微环境的能力，并开发有效地攻击目前限制癌症治疗方式有效性的潜在障碍的策略。

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 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. Likewise, another novel agent is being evaluated for radiosensitization properties. Ecteinascidin 743, an agent with anti-tumor activity that selectively alkylates guanine N2 is currently being evaluated in cell culture. Another major thrust of this project is to develop functional imaging techniques to better characterize factors important in the tumor microenvironment that may prevent or diminish agents from impacting radiation response. 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 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, electron paramagnetic resonance (EPR), and Overhauser MRI (OMRI). Presently we are comparing/contrasting these various techniques with the goal of ultimately bringing non-invasive EPR or OMRI 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. We have recently compared oxygen profiles in mouse tumors collected by OMRI and compared the results with conventional oxygen electrode measurements. OMRI oxygen profiles correlate quite well with oxygen electrode measurements, thus validating this non-invasive technique for oxygen concentration assessment in tissues. Additionally, we are developing a technique of non-invasive redox mapping of tissues using EPR and a stable paramagnetic probe (nitroxide). Collectively, these non-invasive functional imaging approaches should enhance our ability to better understand the tumor microenvironment and develop strategies to effectively attack potential barriers that currently limit the effectiveness of cancer treatment modalities.