期刊
RADIATION RESEARCH
卷 177, 期 5, 页码 628-642出版社
RADIATION RESEARCH SOC
DOI: 10.1667/RR2657.1
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资金
- U.S. Department of Defense Threat Reduction Agency [H.10004_09_AR_R]
- Defense Advanced Research Projects Agency (DARPA) [W911NF-05-C-0001]
- Veterinary Sciences Department
- Cobalt Radiation Facility
To date, there are no safe and effective drugs available for protection against ionizing radiation damage. Therefore, a great need exists to identify and develop non-toxic agents that will be useful as radioprotectors or postirradiation therapies under a variety of operational scenarios. We have developed a new pharmacological agent, CBLB613 (a naturally occurring Mycoplasma-derived lipopeptide ligand for Toll-like receptor 2/6), as a novel radiation countermeasure. Using CD2F1 mice, we investigated CBLB613 for toxicity, immunogenicity, radioprotection, radiomitigation and pharmacokinetics. We also evaluated CBLB613 for its effects on cytokine induction and radiation-induced cytopenia in unirradiated and irradiated mice. The no-observable-adverse-effect level of CBLB613 was 1.79 mg/kg and 1 mg/kg for single and repeated doses, respectively. CBLB613 significantly protected mice against a lethal dose of Co-60 gamma radiation. The dose reduction factor of CBLB613 as a radioprotector was 1.25. CBLB613 also mitigated the effects of Co-60 gamma radiation on survival in mice. In both irradiated and unirradiated mice, the drug stimulated induction of interleukin-1 beta (IL-1 beta), IL-6, IL-10, IL-12, keratinocyte-derived chemokine, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor-1 alpha. CBLB613 also reduced radiation-induced cytopenia and increased bone marrow cellularity in irradiated mice. Our immunogenicity study demonstrated that CBLB613 is not inununogenic in mice, indicating that it could be developed as a radioprotector and radiomitigator for humans against the potentially lethal effects of radiation exposure. (C) 2012 by Radiation Research Society
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