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.
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