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Figure 6 Formation of vascular structures in VEGF-myoblast-implanted legs. Myoblasts expressing the murine VEGF164 gene were injected into mouse hindlimb. Histological analysis of injected muscles were conducted at day 44-47 postimplantation using hematoxylin/eosin staining of cryostat sections. Uninjected control legs were normal both in size and in morphology (left panel), whereas legs injected with VEGF myoblasts (right panel) were greater than twice the diameter of control legs, and consisted primarily of hemangioma and pools of blood. Both panels are shown at the same magnification. These results demonstrate the importance of regulating recombinant gene expression in gene therapy applications. (Adapted and reprinted from Ref. 110 with permission, copyright 1998 Cell Press.)

primary tumor (115,116). Moreover, removal of certain tumors can lead to rapid growth of metastases (117). Isolation of fractions taken from serum and urine that were capable of inhibiting endothelial cell proliferation in vitro and metastatic tumor growth in vivo led to the discovery of two antian-giogenic proteins, angiostatin (118) and endostatin (119), proteolytic products of plasminogen and collagen XVIII, respectively. A recent study demonstrated that viral vectors encoding angiostatin cDNA could inhibit endothelial cell proliferation in vitro and glioblastoma growth in vivo (120). An interesting therapy for cancer could be to engineer myoblasts to express these proteins, such that their secretion may inhibit growth of tumors at distant sites. Reconfirmation that desired blood vessel synthesis at sites of injury, for example, is not impaired would be critical. Because angiostatin and endostatin are difficult to produce in adequate amounts in bacteria, gene therapy protocols will be invaluable for discerning their biological function and possible application as anticancer agents in vivo.

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