Fibroblast Growth Factors

The FGF family represents a large class (23 members) of structurally related proteins that share the ability to bind to heparin with high affinity (26-28). In addition, some members of the FGF family (i.e., FGF-2) have been shown to be expressed as multiple forms from a single mRNA through the use of alternate translation start sites (29). FGF-1 to FGF-10 bind and activate the four-member family of fibroblast growth factor receptors (FGFRs), which are single-pass transmembrane receptor tyrosine kinases (30). Alternate mRNA splicing gives rise to a large number of FGFR forms providing an additional level of ligand selectivity. The other FGF family members either do not bind and activate the canonical FGFR members or have yet to be fully characterized.

FGFs have been demonstrated to play critical roles in tissue morphogenesis and repair in a number of organisms. While an extensive range of biological activities have been attributed to FGFs, the well-characterized ability of FGF-1 and FGF-2 to stimulate the growth of new blood vessels from preexisting ones (angiogenesis) has produced considerable interest in their use to stimulate wound healing and relieve myocardial and peripheral ischemia. Indeed, initial small-scale trials using the direct administration of recombinant FGF-2 protein, naked DNA, and viral expression vectors produced promising results. However, the results of larger, randomized, placebo-controlled trials have revealed less impressive clinical benefit (31). The disconnect between the larger doubleblind trials and the smaller initial studies may reflect the significant placebo effect observed. Even so, there also appear to be considerable pharmacological issues that may be partly responsible. For example, studies with FGF-2 in rats revealed an extremely short half-life (~3 minutes) for intravenously administered protein that reflected both fast clearance and significant tissue deposition (15). This complex pharmacokinetics most likely relates to the interaction of FGF-2 with the heparan sulfate (HS) class of complex polysaccharides, which can, somewhat paradoxically, enhance clearance, increase stability, and prolong tissue retention. In a clinical evaluation of the pharmacokinetics of a single dose of FGF-2 in 66 subjects after intravenous or intracoronary administration, biphasic elimination kinetics were observed with mean half-times of 21 minutes and 7.6 hours, and no differences were noted between the two routes of administration (32). Greater systemic exposure and slower elimination were noted when heparin was administered close to FGF-2 infusion. Heparin and HS can also modify cell receptor binding, uptake, and metabolism of FGF-2 in vitro and in vivo (7,29,33). As such, the modulation of endogenous HS interactions needs to be considered when interpreting the effects of heparin on FGF-2 pharmacokinetics and pharmacodynamics. The consequences of FGF-2 interactions with HS defy simple categorization and will need to be appreciated in greater detail if FGF-2 is to be effectively delivered to produce a predictable and controlled response. HS binding is an important aspect of FGF-2-ECM interactions, yet the influence of HS on FGF-2 is not restricted to the ECM, as described later in this chapter.

0 0

Post a comment