Summary And Prospective

The range of potent biological activities that have been attributed to growth factors presents a compelling argument for their use in a wide range of clinical settings. FGF-2 and VEGF-A have especially been the subject of considerable attention, and a number of small and large clinical trials have evaluated the effectiveness of administering these proteins and their cognate gene sequences (1,2,24,31,187,188). However, the majority of these trials have produced little evidence of clear clinical benefit. The lack of success might reflect the fact that the design of these trials did not effectively account for the complexity of the endogenous mechanisms in place to control the action of these growth factors. In particular, the interactions of both FGF-2 and VEGF-A with the ECM are likely a major factor controlling tissue response. Thus, in this chapter, we have focused on how the interaction of these growth factors with HSPGs within the ECM might begin to be appreciated in a quantitative manner. The initial models that we have developed reveal a range of ways in which HSPGs might influence growth factor access to target cells. The interactions of growth factors with ECM might represent a process that could be exploited in the design of the most effective and specific therapeutic modalities. For example, modifications in growth factor binding to HSPGs via alterations in growth factor sequence and structure, or codelivery of heparin-like compounds might be used to effectively alter the local pharmacokinetics and pharmacodynamics of ECM-binding growth factors. Alternatively, increased knowledge about the specific composition of the ECM in various tissues and in particular disease states might allow for the targeting of growth factors on the basis of their particular ECM-binding characteristics. However, it is important to note that the interactions of growth factors with HSPGs that we have described in detail above are likely only one of the many important interactions that will impact growth factor activity and distribution. Indeed, the binding of VEGF-A to fibronectin likely represents the major interaction within the ECM for this growth factor. Thus, considerably more research is needed to fully identify the various elements involved in controlling growth factor function normally to develop comprehensive models that will allow the design of rational treatment regimes. In this way, the full potential of specific growth factor-based therapies may be realized.

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