Project 1 has the final goal of identifying 2 or 3 agents that will be useful in case of a radiological event, and which might be incorporated into the National Strategic Stockpile. Agents that pass the initial development and testing in the mouse models of Project 1 would go on to testing in genotoxicity models (Projects 4 and 5) and in particle exposure models (Project 2). As specified in the original application, the Aims (milestones) defined for the first 2 years involved model development and collection of surrogate marker data in mouse models. In addition, we have also, in the last two years, made progress on aims originally scheduled mainly for years 3 to 5, namely important studies evaluating, synthesizing, and optimizing interventions with an emphasis on mitigation (agents that can be used after exposure to reduce lethality and/or prolong survival). We imagine later testing would be done in collaboration with other network CMCR. For example, in the pre-clinical models of the Seattle CMCR, the genotoxicity models in the UCLA or Harvard CMCR, and the bioresponse models in the Columbia CMCR.

IM Array: Project 1 has identified several IMs that coincide with independently discovered IMs in Project 2. Ultimately IM’s will be needed to screen for radiation exposure and for organ of exposure. The CMCR at Columbia has been performing related studies. We intend to work with them toward further confirmation of our protein patterns in order to accelerate the validation of these patterns for ultimate product generation. A validated set of cytokines should provide the surrogate marker critically needed for at least three purposes. First, they could provide a surrogate method for detecting prodromal symptoms that occur before full GI, bone marrow, or lung syndromes progress to symptomatic or lethal stages. Second, agents that alter deleterious cytokine patterns could prove therapeutic. Thus understanding the patters should help develop and test new drugs. Third, the cytokine patterns could provide a type of biodosimetry (a goal of the Columbia CMCR).

Drug Screening: We are very enthusiastic about results obtained to date with EsA. It appears to have benefit for lung, cutaneous soft tissues, and brain. We do not yet know whether it will be useful for other applications. It is logical to assume that the best agents from each CMCR could be tested using approaches featured by other CMCRs in an attempt to accelerate agent development. This is a subject that will be addressed at the Steering Committee meeting. Very importantly, our success with curcumin and its ease of availability has now encouraged two national cooperative groups to incorporate curcumin as a radiation protector in clinical studies; we have leadership in both these studies.

Project 1: Communications & Publications

• Xiao Z, Su Y, Yang S, Yin L, Wang W, Yi Y, Fenton BM, Zhang L, Okunieff P. Protective effect of esculentoside A on radiation-induced dermatitis and fibrosis. Int J Radiat Oncol Biol Phys. 2006;65(3):882-9.
• Okunieff P, Xu J, Hu D, Liu W, Zhang L, Morrow G, Pentland A, Ryan JL, Ding I. Curcumin protects against radiation-induced acute and chronic cutaneous toxicity in mice and decreases mRNA expression of inflammatory and fibrogenic cytokines. Int J Radiat Oncol Biol Phys. 2006;65(3):890-8.
• S Yang, Y Su, Z Xiao, W Wang, H Zhang, S Paoni, B Fenton, P Okunieff, L Zhang: Triptolide enhances radiation therapy and reduces radiation-induced toxicity. Proc. Ann. Am. Assoc. Cancer Res. 2006:7251
• L Zhang, Y Su, S Yang, Z Xiao, W Wang, H Zhang, P Okunieff: A Rapid and Sensitive Method for Quantitative Measurement of Radiation-Induced DNA Damage. Radiat. Res. Soc.: 06-A-274
• Z Xiao, Y Su, S Yang, W Wang, H Zhang, C Dony, S Paoni, B Fenton, L Zhang, P Okunieff: Alteration of the Inflammatory Molecule Network after Irradiation of Soft Tissue. Radiat. Res. Soc.: 06-A-265
• S Yang, Y Su, Z Xiao, W Wang, S Paoni, B Fenton, L Zhang, P Okunieff. Tumor and Normal Tissue Effects of Combination Triptolide with Radiation. Radiat. Res. Soc.: 06-A-279
• H Zhang, W Sun, S Yang, W Wang, B Zhang, C Liu, J Wang, S Swarts, M Zhang, B Fenton, P Keng, P Okunieff, L Zhang: A sensitive assay for quantitative measurement of plasma DNA: Application in radiation oncology. Proc. Ann. Am. Assoc. Cancer Res. 2007
• Okunieff P, Keng P, Sun W, Wang W, Kim J, Yanh S, Zhang H, Liu C, Williams J, Zhang L. Antioxidants Used to Reduce Consequences of Radiation Exposure. 3rd Acta Oncologica symposium, “Stereotactic Body Radiotherapy”, June 15-17, 2006, Copenhagen, Denmark.
• Okunieff P, Keng P, Sun W, Wang W, Kim J, Yanh S, Zhang H, Liu C, Williams J, Zhang L. Antioxidants Used to Reduce Consequences of Radiation Exposure. 34th Annual International Society on Oxygen Transfer to Tissue Meeting, August 12-17, 2006, Louisville, KY.

Project 1 features at least 10 potential radiation countermeasure agents at various stages of pre-clinical testing. Preliminary results have been obtained for most of the agents. All agents have targeted mechanisms and have potential for use in combinations for added effect. We are now moving forward with more sophisticated methods for determining the mechanism of action of these agents, determining optimal schedules and dose and for better assessment of potential toxicity. Liaisons have been established with industry, patents have been awarded along with STTR grants to accelerate progress. Correlative clinical studies, supported by separate grants, have been sent to CTEP to evaluate some agents in cured cancer patients with side effects of therapy. Protein expression patterns specific for radiation toxicity are an important goal, and will be measured in animals and also in the correlative clinical studies.