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定义和了解肿瘤生理学的那些方面，包括最终确定肿瘤本质的细胞和分子过程，以便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。我们目前的重点是儿茶素743和大黄酮酮。抗肿瘤活性可能是通过鸟嘌呤N_2的烷基化作用，从而抑制DNA修复酶、转录效应和拓扑异构酶。我们观察到，当人结肠癌细胞用相对无毒浓度的胞外杀菌素进行预处理时，辐射反应显著增强。活体研究目前正在进行中。转化生长因子β的抑制剂哈利夫吉酮也对几种人类肿瘤细胞系具有放射增敏作用。该制剂特别令人感兴趣的是，已有证据表明，在正常组织中，灯盏花素可防止辐射诱导的迟发效应。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。使用放射生物学分部开发的新型磁共振成像设备，我们最近：a)通过“金标准”氧电极测量验证了对肿瘤氧水平的非侵入性Overhauser磁共振成像，b)使用电子顺磁共振成像证明了体内氮氧化物对羟胺的还原速率可以产生包括肿瘤在内的各种组织的“氧化还原图谱”，以及c)展示了使用双酯氮氧化物/羟胺前体分子的“氧化成像”概念。这项技术可以报告由于放射治疗或其他氧化过程而导致的组织氧化。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 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.