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Abstract
Grant Number: 1RC1AI078519-01 Project Title: A Novel Mitigation Agent for Gastrointestinal Syndrome of Acute Radiation Injury
PI Information: Name Title ZHANG, LURONG lurong_zhang@urmc.rochester.edu Abstract: DESCRIPTION (provided by applicant): Currently there are no available agents to offer to victims after radiation exposure to mitigate acute gastrointestinal syndrome (AGS). FGF-P is a powerful radiation mitigator, which relieves AGS when given after irradiation. FGF-P rescues mice in LD50/7 experiments, increases survival duration, improves crypt proliferation and number, it reduces diarrhea, bleeding, endotoxin level, and improves endocrine and exocrine function. This dimerized peptide is 17 amino acids and features an FGF receptor binding domain and a linking element. The advantages of FGF-P over native FGF-2 are: 1) it is stable under severe conditions; 2) it can be self-administrated i.m. and 3) it can be synthesized in a large quantity with high purity. Mechanistically, we have shown many benefits of FGF-P in acute GI syndrome: 1) greater preservation and increased proliferation of crypt stem cells; 2) mouse strain independent response; 3) improved recovery of bone marrow cellularity; and 4) reduced endotoximia. No deaths were seen at doses 200-fold higher than the effective dose. Based on this promising data, we hypothesize that FGF-P can be developed as a novel mitigation agent to be given after radiation exposure for acute gastrointestinal syndrome. For this, we will focus on the following aims: 1) To measure the pharmacokinetics of FGF-P (month 1-9): 3H labeled FGF-P will be injected into normal and irradiated mice. Drug uptake in the blood, bowel, and other organs will be measured in control animals and animals pre-exposed to radiation. 2) To define the optimal dose and schedule of FGF-P (month 6-18): We will test different dose, schedule and the allowable delay to the first dose in three strains of mice. A DMF >1.2 (dose modification factor) or a prolongation of survival time >50% is the minimal goal. Survival (LD50/7), GI function (stool hemoccult; gross evaluation of stool formation; plasma secretin, amylase, glucose, and insulin) as well as systemic surrogate marker (levels of endotoxin and inflammatory molecules) will be measured. 3) To measure the interspecies binding and activation of FGF receptors (month 1-15). These measurements will make it possible to determine the optimal dose for scaling to humans. The results of these pre-clinical studies will provide the basis for eventual approval through the animal rule. A preliminary drug development plan has already been discussed with the FDA.
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Institution: UNIVERSITY OF ROCHESTER 518 Hylan Bldg., Box 270140 ROCHESTER, NY 14627 Fiscal Year: 2007 Department: RADIATION ONCOLOGY Project Start: 15-SEP-2007 Project End: 28-FEB-2010 ICD: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES IRG: ZAI1