Experimental and Clinical Therapeutics

Monday, October 17, 2005 3:00 PM-5:00 PM Exhibit Hall

(PP154) Radiation protection by FGF-2 mimetic, multi-domain peptides.

Pena, Louis*,1, Lin, Xinhua1, Glass, John1, Crawford, Janet2, Zamora, Paul3, 1 Medical Department, Upton, NY, USA2 W.M. Keck Biotechnology Laboratory, New Haven, CT, USA3 BioSET Inc., College Park, MD, USA

ABSTRACT- Introduction: Unlike current-generation radioprotectors that must be applied immediately before irradiation, cytokines/growth factors have significant potential because some can be employed for a limited time after irradiation. However, current cytokine countermeasures suffer from an associated set of problems related to stability, cost, and availability of recombinant biologicals. Here, we report on the development of a set of synthetic analogs of basic fibroblast growth factor (bFGF, a.k.a. FGF-2) that function as FGF receptor agonists. These FGF-2 Analogs (F2As) are multi-domain peptide constructs designed to interact with heparin and with FGFR-1, and they confer radiation protection in in vitro and in vivo models. Results: Surface plasmon resonance (Biacore) studies show that binding kinetics of F2As to immobilized FGFR1 and to immobilized heparin molecules are similar to bFGF. In cell culture studies, F2As were shown to interact specifically with FGF receptors, initiate the MAPK signaling cascade, and trigger cellular responses such as cell proliferation and anti-apoptotic effects in vitro on endothelial cells. The entire 3-domain construct is required for functionality; versions of F2As lacking one or more domains fail to have any activity. A single dose (i.v.) of an F2A at the time of irradiation also mimics bFGF in vivo, increasing survival of mice in experimental models of whole body radiation toxicity (Hematopoeitic Syndrome [8-13 Gy] and Gastrointestinal Syndrome [17-23 Gy]). At least one F2A is effective when administered orally to mice (gastric gavage) up to 4 hrs post-irradiation. Conclusions: F2As, like bFGF, can confer radioprotection by activating cell survial signal transduction pathways and repressing pro-apoptotic signaling within a time window that extends several hours before and after radiation exposure. F2As, being less complex and more chemically stable than proteins, may be effective countermeasures in a broad range of radiation exposures in the clinic and in the field.

Key words: radioprotection, countermeasure, cytokine, fibroblast growth factor

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2005 RRS