A basic fibroblast growth factor analog for protection and mitigation against acute radiation syndromes.

The effects of fibroblast growth factors and their potential as broad-spectrum agents to treat and mitigate radiation injury have been studied extensively over the past two decades. This report shows that a peptide mimetic of basic fibroblast growth factor (FGF-P) protects and mitigates against acute radiation syndromes. FGF-P attenuates both sepsis and bleeding in a radiation-induced bone marrow syndrome model and reduces the severity of gastrointestinal and cutaneous syndromes; it should also mitigate combined injuries. FGF-2 and FGF-P induce little or no deleterious inflammation or vascular leakage, which distinguishes them from most other growth factors, angiogenic factors, and cytokines. Although recombinant FGFs have proven safe in several ongoing clinical trials, they are expensive to synthesize, can only be produced in limited quantity, and have limited shelf life. FGF-P mimics the advantageous features of FGF-2 without these disadvantages. This paper shows that FGF-P not only has the potential to be a potent yet safe broad-spectrum medical countermeasure that mitigates acute radiotoxicity but also holds promise for thermal burns, ischemic wound healing, tissue engineering, and stem-cell regeneration.

A heparin-mimicking polymer conjugate stabilizes basic fibroblast growth factor.

Basic fibroblast growth factor (bFGF) is a protein that plays a crucial role in diverse cellular functions, from wound healing to bone regeneration. However, a major obstacle to the widespread application of bFGF is its inherent instability during storage and delivery. Here, we describe the stabilization of bFGF by covalent conjugation with a heparin-mimicking polymer, a copolymer consisting of styrene sulfonate units and methyl methacrylate units bearing poly(ethylene glycol) side chains. The bFGF conjugate of this polymer retained bioactivity after synthesis and was stable to a variety of environmentally and therapeutically relevant stressors--such as heat, mild and harsh acidic conditions, storage and proteolytic degradation--unlike native bFGF. Following the application of stress, the conjugate was also significantly more active than the control conjugate system in which the styrene sulfonate units were omitted from the polymer structure. This research has important implications for the clinical use of bFGF and for the stabilization of heparin-binding growth factors in general.

Antiangiogenic activity of semisynthetic biotechnological heparins: low-molecular-weight-sulfated Escherichia coli K5 polysaccharide derivatives as fibroblast growth factor antagonists.

OBJECTIVE: Low-molecular-weight heparin (LMWH) exerts antitumor activity in clinical trials. The K5 polysaccharide from Escherichia coli has the same structure as the heparin precursor. Chemical and enzymatic modifications of K5 polysaccharide lead to the production of biotechnological heparin-like compounds. We investigated the fibroblast growth factor-2 (FGF2) antagonist and antiangiogenic activity of a series of LMW N,O-sulfated K5 derivatives. METHODS AND RESULTS: Surface plasmon resonance analysis showed that LMW-K5 derivatives bind FGF2, thus inhibiting its interaction with heparin immobilized to a BIAcore sensor chip. Interaction of FGF2 with tyrosine-kinase receptors (FGFRs), heparan sulfate proteoglycans (HSPGs), and alpha(v)beta3 integrin is required for biological response in endothelial cells. Similar to LMWH, LMW-K5 derivatives abrogate the formation of HSPG/FGF2/FGFR ternary complexes by preventing FGF2-mediated attachment of FGFR1-overexpressing cells to HSPG-bearing cells and inhibit FGF2-mediated endothelial cell proliferation. However, LMW-K5 derivatives, but not LMWH, also inhibit FGF2/alpha(v)beta3 integrin interaction and consequent FGF2-mediated endothelial cell sprouting in vitro and angiogenesis in vivo in the chick embryo chorioallantoic membrane. CONCLUSIONS: LMW N,O-sulfated K5 derivatives affect both HSPG/FGF2/FGFR and FGF2/alpha(v)beta3 interactions and are endowed with FGF2 antagonist and antiangiogenic activity. These compounds may provide the basis for the design of novel LMW heparin-like angiostatic compounds.

Different molecular forms of basic fibroblast growth factor (bFGF) accelerate duodenal ulcer healing in rats.

UNLABELLED: Basic fibroblast growth factor is an angiogenic polypeptide that exhibits potent antiulcer activity without decreasing gastric acid or pepsin secretion. In this study, we investigated the effect of three acid-stable derivatives of human recombinant bFGF (hrbFGF) on the healing of chronic duodenal ulcer in rats. In Sprague-Dawley female rats, duodenal ulcers were induced by cysteamine-HCl. After laparotomy, rats were randomized to create six groups with homogeneously severe ulcers (perforated or penetrated into the liver or pancreas) and treated by gavage twice a day for 3 weeks with a) vehicle, b) cimetidine (10 mg/100 g), c) Ser78,96-hrbFGF (bioequivalent to rbFGF-CS23), d) CMC-hrbFGF, a carboxymethyl cysteine derivative of hrbFGF or e) PEG-hrbFGF, a polyethylene glycol derivative of hrbFGF. The peptides were administered at 100 ng/100 g. Autopsy was performed on the 21st day, and the ulcer size was measured. The ulcer sizes (mm2) were reduced from 10.3 +/- 1.8 in controls to 4.8 +/- 1.4* after cimetidine treatment and to 5.0 +/- 2.4, 4.2 +/- 1.1* and 0.5 +/- 0.2**, respectively, after administration of aforementioned hrbFGF derivatives (*P < .05; **P < .01 vs. vehicle group), which also significantly enhanced angiogenesis in the ulcer bed. CONCLUSIONS: 1) Oral administration of novel derivatives of hrbFGF accelerated the healing of cysteamine-induced chronic duodenal ulcer. 2) The PEG-hrbFGF derivative was more active than the other hrbFGF analogs. 3) The naturally occurring bFGF provides a good prototype to design new locally acting antiulcer drugs.

In vitro inhibition of the actions of basic FGF by a novel 16 amino acid peptide.

A composite procedure involving molecular modelling and a property-pattern algorithm, the Resonant Recognition Model (RRM), has been applied to structure-function studies with basic fibroblast growth factor (bFGF). Property-pattern characteristics for biological activity and receptor recognition for a group of FGF-related proteins were defined and then used to aid the design of a set of peptides which can act as bFGF antagonists. Molecular modelling techniques were then employed to identify the peptide within this set with the greatest conformational similarity to the putative receptor domain of bFGF. This 16 amino acid residue peptide (16mer), which exhibits no sequence homology to bFGF, antagonised the stimulatory effect of bFGF on fibroblast [3H]thymidine incorporation and cell proliferation, but exerted no effect itself in these in vitro bioassays.