Time Domian Electron Paramagnetic Resonance Imaging

a) TH-302作为体内辐射增敏剂的评价。TH-302是一种缺氧激活的前药，它有一个与氮芥共价连接的硝基咪唑触发器。在缺氧条件下，通过氧化还原活化硝基咪唑片段，TH-302分裂并释放氮芥片段，产生明显的缺氧特异性细胞毒性。由于硝基咪唑部分本身可以作为放射增敏剂，我们在体外和体内研究了TH-302和辐射的联合作用。我们采用小鼠SCCVII肿瘤和HT29肿瘤两种肿瘤模型。体外研究表明，将这些细胞与TH-302以10 M水平孵育可产生与著名的放射增敏剂米索硝唑相似的放射增敏作用。体内研究表明，与单独TH-302或单独放疗相比，TH-302 + 3gy联合放疗可显著延缓肿瘤生长。这些结果提示放化疗联合TH-302的益处。b)抗肿瘤剂CG-0321作用方式的机理研究：CG-0321是一种巯基糖脂，已被证明可使肿瘤对电离辐射敏感。然而，其机制细节尚不清楚，一些研究指出给药后肿瘤氧合会短暂增加。体外研究表明，在几种细胞系测试中没有放射致敏的证据。体内影像学研究显示，CG-0321给药后30 - 60分钟存在肿瘤pO2增高的时间窗。肿瘤pO2的升高幅度与肿瘤类型有关。另外的影像学研究显示，给药后肿瘤灌注增加。监测SCCVII和A549细胞治疗反应的体内肿瘤生长动力学研究表明，在CG-0321给药后约30分钟进行放射治疗时，存在显著的生长延迟。这些研究显示了分子成像技术探测肿瘤微环境在理解药物作用机制方面的价值，以及使用这种成像方式来计划治疗。

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.