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定义和理解肿瘤生理学的这些方面，包括最终定义肿瘤本质的细胞和分子过程，以便使用特定剂量的电离辐射时更有效。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。我们目前的重点是ecteinascidin 743和halifuginone。海鞘素显示抗肿瘤活性，推测是通过鸟嘌呤N2的烷基化导致DNA修复酶的抑制、转录效应和拓扑异构酶的抑制。我们已经观察到显着增强的辐射反应时，人结肠癌细胞用相对无毒浓度的海鞘素预处理。目前正在进行体内研究。Halifuginone是TGF β的抑制剂，也使几种人类肿瘤细胞系放射增敏。这种药剂特别令人感兴趣，因为已经显示出Halifuginone在正常组织中保护免受辐射诱导的晚期效应。该项目的另一个主要目标是开发功能成像技术，以更好地表征肿瘤微环境中的重要因素，这些因素可能会阻止或减少影响辐射反应的药物。众所周知，缺氧是辐射敏感性的主要决定因素。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，以便可以在个体基础上优化患者的肿瘤治疗方案。使用放射生物学分支开发的新型磁共振成像设备，我们最近：a）采用“金标准”氧电极测量的肿瘤氧水平的经验证的非侵入性Overhauser磁共振成像，B）使用电子顺磁共振成像证明氮氧化合物到羟胺的体内还原速率可以产生包括肿瘤的各种组织的“氧化还原图”，和c）证明了使用双酯氮氧化物/羟胺前体分子的“氧化成像”的概念。该技术可以报告由于放射治疗或其他氧化过程导致的组织氧化。总的来说，这些非侵入性功能成像方法应该提高我们更好地了解肿瘤微环境的能力，并制定有效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 is to define and understand those aspects of tumor physiology, including 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. Our current focus is on ecteinascidin 743 and halifuginone. Ecteinascidin exhibits anti-tumor activity presumably by alkylation of guanine N2 resulting in inhibition of DNA repair enzymes, transcriptional effects, and inhibition of topoisomerases. We have observed significant enhancement of the radiation response when human colon carcinoma cells were pretreated with relatively non-toxic concentrations of ecteinascidin. in vivo studies are presently underway. Halifuginone, an inhibitor of TGF beta, also radiosensitizes several human tumor cell lines. This agent is of particular interest in that halifuginone has been shown to protect against radiation-induced late effects in normal tissues. 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. Using novel magnetic resonance imaging equipment developed in the Radiation Biology Branch we have recently: a) validated non-invasive Overhauser magnetic resonance imaging of tumor oxygen levels with "gold standard" oxygen electrode measurements, b) demonstrated using electron paramagnetic resonance imaging that the in vivo reduction rate of the nitroxide to the hydroxylamine can yield a "redox map" of various tissues including tumor, and c) demonstrated the concept of "oxidative imaging" using a double ester nitroxide/hydroxylamine precursor molecule. This technique can report on tissue oxidation as a result of radiation treatment or other oxidative processes. 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.