Targeting
tumor-associated vascular endothelium by replication-competent viral vectors is a promising strategy for cancer gene
therapy. Here we describe the development of a viral vector based on the Edmonston
vaccine strain of measles virus targeted to
integrin alpha(v)beta3, which is expressed abundantly on activated but not quiescent vascular endothelium. We displayed a
disintegrin, M28L
echistatin that binds with a high affinity to
integrin alpha(v)beta3 on the COOH terminus of the viral attachment (H)
protein and rescued the replication-competent recombinant virus by reverse genetics. The new targeted virus was named measles virus
echistatin vector (MV-ERV). Its native binding to CD46 was purposefully retained to allow
virus infection of
tumor cells expressing this receptor. MV-ERV correctly displayed
echistatin on the outer surface of its envelope and produced interesting ring formation phenomena due to cell detachment upon
infection of susceptible Vero cells in vitro. MV-ERV grew to 10(6) plaque-forming units/mL, slightly lower than the parental Edmonston strain of measles virus (MV-Edm), but it selectively infected Chinese hamster ovary cells expressing
integrin alpha(v)beta3. It also selectively infected both bovine and human endothelial cells on matrigels and unlike MV-Edm, MV-ERV infected newly formed blood vessels in chorioallantoic membrane assays. In animal models, MV-ERV but not the control MV-Edm caused the regression of s.c. xenografts of resistant
multiple myeloma tumors (MM1) in severe combined immunodeficient mice. The
tumors were either completely eradicated or their growth was significantly retarded. The specificity, potency, and feasibility of MV-ERV
infection clearly show the potential use of MV-ERV in gene therapy for targeting
tumor-associated vasculature for the treatment of solid
tumors.