Drug May Protect Against Harmful Effects of Radiation

[Burnham Institute]

An Agonist of Toll-Like Receptor 5 Has Radioprotective Activity in Mouse and Primate Models

Lyudmila G. Burdelya,1* Vadim I. Krivokrysenko,2* Thomas C. Tallant,3 Evguenia Strom,2 Anatoly S. Gleiberman,2 Damodar Gupta,1 Oleg V. Kurnasov,4 Farrel L. Fort,2 Andrei L. Osterman,4 Joseph A. DiDonato,3 Elena Feinstein,2{dagger} Andrei V. Gudkov1,2{dagger}

The toxicity of ionizing radiation is associated with massive apoptosis in radiosensitive organs. Here, we investigate whether a drug that activates a signaling mechanism used by tumor cells to suppress apoptosis can protect healthy cells from the harmful effects of radiation. We studied CBLB502, a polypeptide drug derived from Salmonella flagellin that binds to Toll-like receptor 5 (TLR5) and activates nuclear factor?{kappa}B signaling. A single injection of CBLB502 before lethal total-body irradiation protected mice from both gastrointestinal and hematopoietic acute radiation syndromes and resulted in improved survival. CBLB502 injected after irradiation also enhanced survival, but at lower radiation doses. It is noteworthy that the drug did not decrease tumor radiosensitivity in mouse models. CBLB502 also showed radioprotective activity in lethally irradiated rhesus monkeys.

Thus, TLR5 agonists could potentially improve the therapeutic index of cancer radiotherapy and serve as biological protectants in radiation emergencies.

1 Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
2 Cleveland BioLabs, Inc. (CBLI), Buffalo, NY14203, USA.
3 Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
4 Burnham Institute for Medical Research, :applause: La Jolla, CA 92037, USA.



* These authors contributed equally to this work.

 

[sharon sanders]

Re: Drug May Protect Against Harmful Effects of Radiation

Thank you Burnham Institute. Also -

NF-κB ACTIVATING PROTEINS AS RADIOPROTECTANTS: DERIVATIVES OF FLAGELLIN FROM SALMONELLA PROTECT MICE FROM HEMATOPOIETIC AND GASTROINTESTINAL RADIATION SYNDROMES
Burdelya, L.G., Tallant, T., DiDonato, J., Krivokrysenko, V.I., Gurova, K.V., Kogan, Y., Komarov, P.G.
and Gudkov. A.V.
Cleveland BioLabs, Inc. and Cleveland Clinic Foundation, Cleveland, Ohio, 44106
Phone: 216-445-1205; gudkov@ccf.org and yakov@cbiolabs.com
Damage induced by ionizing radiation to normal tissues involves excessive cell loss in several sensitive organs (bone marrow, lymphoid organs, epithelium of small intestine, hair follicles, etc.) through the mechanism of apoptosis. There are two major mechanisms controlling apoptosis in the cell: p53 (proapoptotic) NF-κB (anti-apoptotic) pathways. In our previous work we demonstrated that blocking p53-dependent suicidal mechanism by genetic and pharmacological approaches could rescue from lethal doses of total body gamma radiation (Komarov et al. Science 285, 1733-1777, 1999), thus validating apoptosis as a target for a radioprotectants. However, protecting effect of p53 inhibition is limited to hematopoietic system and fails to preserve from gastro-intestinal syndrome (Komarova et al., Oncogene, in press). This study is devoted to the exploration of the second branch of our concept: development of radioprotectants acting through activation of NF-κB. Many microbial parasites can effectively induce NF-kB in the host cells and their NF-kB-activating factors can be considered as potential radioprotectants.
To test this idea, we chose flagellin of Salmonella typhimurium, known as a potent activator of NF-κB acting through activation of toll-like receptor 5. We found that a single injection of purified recombinant flagellin effectively protected mice from lethal doses of γ-irradiation (Fig. 1). A series of rationally designed flagellin derivatives were generated and screened for NF-κB-inducing and radioprotecting activities. As a result, a ?mini-flagellin? was generated (named CBLB502) that is three times shorter than the original protein but retains unprecedented radioprotective efficacy of flagellin, its outstanding stability and lacks its entire immunogenic part. In addition, CBLB502 was found effective after subcutaneous injections and therefore suitable for the use as a radioprotective antidote.

Preliminary studies showed that elevating tolerable dose of radiation achievable with CBLB502 made it possible to dramatically increase the anti-tumor effect of radiotherapy of experimental tumors in mice. An important advantage of CBLB502 before any known radioprotectant is its ability to effectively protect gastrointestinal tract making it a uniquely useful as radioprotective antidote. Dose and time dependence of radioprotection
induced by flagellin and derivatives, routs of delivery, effectiveness against fractionated doses of radiation and results of radiotherapy of experimental tumors will be presented.

http://www.dsls.usra.edu/meetings/radiation2004/pdf/07/1064Gudkov.pdf
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