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Adeno-associated Virus-mediated Delivery of Antiangiogenic Factors as an Antitumor Strategy¹

Department of Radiological Sciences [J. T. N., M. E. C.] and Division of Experimental Medicine [P. W., E. F. T.], Beth Israel Deaconess Medical Center, Boston, MA 02115, and Dana-Farber Cancer Institute and Joint Center for Radiation Therapy [L. H.], Harvard Medical School, Boston, MA 02115

Antiangiogenic tumor therapies have recently attracted intense interest for their broad-spectrum action, low toxicity, and, in the case of direct endothelial targeting, an absence of drug resistance. To promote tumor regression and to maintain dormancy, antiangiogenic agents need to be chronically administered. Gene therapy offers a potential way to achieve sustained therapeutic release of potent antiangiogenic substances. As a step toward this goal, we have generated recombinant adeno-associated virus (rAAV) vectors that carry genes coding for angiostatin, endostatin, and an antisense mRNA species against vascular endothelial growth factor (VEGF). These rAAVs efficiently transduced three human tumor cell lines tested. Transduction with an rAAV-encoding antisense VEGF mRNA inhibited the production of endogenous tumor cell VEGF. Conditioned media from cells transduced with this rAAV or with rAAV-expressing endostatin or angiostatin inhibited capillary endothelial cell proliferation in vitro. Antiangiogenic rAAVs may offer a novel gene therapy approach to undermining tumor neovascularization and cancer progression.

¹ Supported by a National Cancer Institute Training Grant in Cancer Radiology (to M. E. C.), a grant from Concerned Parents for AIDS Research (to E. F. T.), and a grant from the Gerry and Nancy Pencer Brain Trust (to L. H.).

² To whom requests for reprints should be addressed, at Dana-Farber Cancer Institute, JFB, Room 523, 44 Binney Street, Boston, MA 02115. Phone: (617) 735-8785; Fax: (617) 735-8772; E-mail: Lynn_Hlatky@dfci.harvard.edu.

³ These authors have contributed equally to this work.

Received 5/15/98. Accepted 10/27/98.

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