Background: This proposal is based on the fundamental radiobiological principle, Bergonie¿s Law, that the most sensitive tissues of the human body are those with high turnover rates, i.e., high rates of cell cycling (e.g., blood-forming tissues, gastrointestinal tissues, reproductive tissues, etc.). If rapidly cycling cells can be either slowed down in their rate of cycling or pushed out of cycle entirely for short periods, a degree of resistance can be achieved by these normally radiosensitive cells to the damaging effects of ionizing radiation, regardless of whether the damage is potentially lethal, mutagenic, or patently neoplastically transforming. Through novel chemical engineering, a new class of small molecular protectants has been discovered that appears to be highly promising for radioprotection.

Objectives and Hypothesis: The proposal is based on research advances in mammalian cell cycle regulation made by Dr. E.P. Reddy and colleagues of Fels Institute of Temple University, Philadelphia. This research has demonstrated that Onconova¿s synthetic small molecule drugs, collectively called Novonex/Ex-Rad, have the ability to arrest normal human cells at the G1 and G2 checkpoints of cell cycle. This temporary arrest can afford protection to normal cells against the deleterious effects of ionizing radiation. Further, a drug, ON 01210, has been developed that counteracts the harmful effects of high-dose irradiation. The data suggest that (a) these ¿designer-type¿ compounds are uniquely specific cell checkpoints of targeted mammalian cells, (b) that they are safe, and very well tolerated by treated animals, and (c) provide substantial protection of mice against lethal radiation.

Specific Aims: Specific objectives of this project are: (1) Elucidate the cellular, biochemical, and molecular mechanism(s) by which the Novonex/Ex-Rad drug ON 01210 exerts its radioprotective effect(s). (2) Develop genomic and proteomic response profiles for relevant, radiation-targeted blood and progenitor cell types under/not under the protective effects the ON 01210 drug. (3) Expand the chemical structure activity relationship (SAR) of the drug leading to improvements in activity, potency, and pharmacological properties of ON 01210. (4) Develop preclinical toxicity, pharmacology, and efficacy profiles for the ON 01210 drug in small rodents and in large canines. (5) Develop processes and manufacture Kilo quantities of the drug for animal and future human studies. (6) Develop optimal formulations for the delivery of the drug by oral, topical, subcutaneous, and intravenous routes of administration.

Study Design: The study design is based on the time-dependent monitoring, metering, and characterizations of biological response profiles of vital molecular and cellular biotargets within radiation-sensitive tissues of the body and, in turn, of the whole animal at large. Response profiles will be developed and interpreted in terms of the protection afforded by Novonex/Ex-Rad drug following various regimens of ionizing radiation exposure.

Relevance: Nuclear/radiological agents are a major and significant component of the NBC (Nuclear, Biological, Chemical) threat triad. The threat of exposure or actual occurrence of exposures to ionizing radiation has the potential to significantly impact the planning and execution of a military operation. Despite the six or so decades since the dawn of the nuclear age, the US military still lacks safe and effective pharmaceuticals to preventive radiation-associated injuries in its current arsenal of medicinals. This study addresses these issues and proposes to deliver a novel class of radioprotectants for military purposes. Due to the nature of the threat posed by the radioactive hazards and the current global circumstances, this proposal is aimed at rapid development of the Novonex/Ex-Rad radioprotectant.