Time Domian Electron Paramagnetic Resonance Imaging

A)评价TH-302作为体内辐射增敏剂的作用。TH-302是一种低氧激活的前药，它有一个与氮芥末相连的硝基咪唑触发器。当硝基咪唑部分氧化还原激活时，在低氧条件下，TH-302裂解并释放具有显著的低氧特异性细胞毒性的氮芥酸部分。由于硝基咪唑部分本身可以作为放射增敏剂，我们在体外和体内考察了TH-302和辐射的联合作用。我们使用了两种肿瘤模型：SCCVII肿瘤和HT29肿瘤。体外研究表明，将这些细胞与10M水平的TH-302孵育，可产生类似于众所周知的放射增敏剂咪唑硝唑的放射增敏作用。体内研究表明，与TH-302单独或单独照射相比，TH-302+3Gy射线联合照射导致肿瘤生长明显延迟。这些结果提示放化疗与TH-302联合治疗的益处。B)抗肿瘤药物CG-0321作用模式的机理研究：CG-0321是一种磺基糖脂，已被证明能使肿瘤对电离辐射敏感。然而，机制细节尚不清楚，一些研究指出，给药后肿瘤氧合一过性增加。体外研究表明，在几个被测试的细胞系中没有放射增敏的证据。活体成像研究表明，在给予CG-0321后30-60分钟，肿瘤的PO2有一个上升的时间窗口。肿瘤氧分压的增加幅度与肿瘤类型有关。更多的影像研究表明，给药后肿瘤的血流灌注增加。体内肿瘤生长动力学研究监测治疗反应的SCCVII和A549细胞显示，放射治疗后约30min给予CG-0321有明显的生长延迟。这些研究表明，分子成像技术探测肿瘤微环境在了解药物作用的机制方面以及使用此类成像方式来计划治疗方面具有价值。

a) Evaluation of TH-302 as an in vivo radiation sensitizer. TH-302 is a hypoxia activated prodrug which has a nitroimidazole trigger linked to a nitrogen mustard covalntly. Upon redox-activation of the nitroimidazole moiety, in hypoxic conditions, TH-302 fragments and releases the nitrogen mustard moiety exerting significant hypoxia specific cytotoxicity. Since the nitroimidazole moiety can itself act as a radiosensitizer, we examined the combined effect of TH-302 and radiation in vitro and in vivo. We used the two tumor models: The SCCVII tumor and the HT29 tumor in mice. In vitro studies show that incubation of these cells with TH-302 at 10 M level results in radiosensitzation similar to the well-known radiosensitizer, misonidazole. In vivo studies show that, the combined TH-302 + 3 Gy radiation resulted in a significant tumor growth delay compared to ether TH-302 alone or radiation alone. These results suggest the benefits of combination chemoradiation therapy with TH-302. b) Mechanistic studies of the mode of action of the anti-tumor agent CG-0321: CG-0321 is a sulfoglycolipid which has been shown to sensitize tumors to ionizing radiation. However the mechanistic details are not clearly established with some studies pointing to transient increases in tumor oxygenation after drug administration. In vitro studies show no evidence of radiosensitization in several cell lines tested. In vivo imaging studies show that there is a time window of increased tumor pO2 30 - 60 mins after CG-0321 administration. The magnitude increase in tumor pO2 was tumor type dependent. Additional imaging studies show that there is increased tumor perfusion after drug administration. In vivo tumor growth kinetics studies monitoring treatment response in SCCVII and A549 cells show that there is a significant growth delay when radiation treatment was administered at about 30 mins after CG-0321 administration. These studies show the value of molecular imaging techniques probing the tumor microenvironment in understanding the mechanistic aspects of drug action and also the use of such imaging modalities to plan treatments.