Radioprotectors in tumor radiotherapy: factors and settings determining therapeutic ratio

WR-2721 and DDC have been used most frequently in our studies on radioprotective agents. WR-2721 was a much more potent radioprotector of murine normal tissues, both against early and late injuries of several organs and tissues, than was DDC. Protection factors for WR-2721 usually ranged between 1.5 and 2.5. Both agents protected solid murine tumors only minimally. While WR-2721 increased therapeutic ratios commonly, DDC did so only rarely. Micrometastatic foci were amenable to radioprotection more than established solitary tumors. Additional factors that influenced the degree of therapeutic benefit included dose of WR-2721, dose of irradiation (single versus fractionated), and time of WR-2721 administration in relation to radiation delivery. The ability of WR-2721 to prevent radiation-induced immunosuppression, metastatic spread, and carcinogenesis are additional benefits in the therapeutic use of this agent. Our current research on the improvement of radioprotectors for therapeutic use is focused on (a) a search for new radioprotective agents that are equal to or better than WR-2721 but less toxic and/or more specific for normal tissue, (b) understanding the basic mechanisms of action of these radioprotective agents at the molecular level, both in cells and tissues, and thus understanding the mechanisms leading to selective or preferential radioprotection of normal tissues, and (c) in vitro testing of primary human tumor cultures for their (non)susceptibility to radioprotection.