AUTHOR=Greenberger Joel S., Clump David , Kagan Valerian , Bayir Hulya , Lazo John S., Wipf Peter , Li Song , Gao Xiang , Epperly Michael W. TITLE=Strategies for Discovery of Small Molecule Radiation Protectors and Radiation Mitigators JOURNAL=Frontiers in Oncology VOLUME=1 YEAR=2012 URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2011.00059 DOI=10.3389/fonc.2011.00059 ISSN=2234-943X ABSTRACT=

Mitochondrial targeted radiation damage protectors (delivered prior to irradiation) and mitigators (delivered after irradiation, but before the appearance of symptoms associated with radiation syndrome) have been a recent focus in drug discovery for (1) normal tissue radiation protection during fractionated radiotherapy, and (2) radiation terrorism counter measures. Several categories of such molecules have been discovered: nitroxide-linked hybrid molecules, including GS-nitroxide, GS-nitric oxide synthase inhibitors, p53/mdm2/mdm4 inhibitors, and pharmaceutical agents including inhibitors of the phosphoinositide-3-kinase pathway and the anti-seizure medicine, carbamazepine. Evaluation of potential new radiation dose modifying molecules to protect normal tissue includes: clonogenic radiation survival curves, assays for apoptosis and DNA repair, and irradiation-induced depletion of antioxidant stores. Studies of organ specific radioprotection and in total body irradiation-induced hematopoietic syndrome in the mouse model for protection/mitigation facilitate rational means by which to move candidate small molecule drugs along the drug discovery pipeline into clinical development.