Abstract
The growth and development of solid tumors is critically dependent on angiogenesis in the absence of which tumors remain dormant and unable to metastasize. It is established that administration of angiogenesis inhibitor (e.g. endostatin or angiostatin) results in the inhibition of angiogenesis and tumor development in animal models. The primary objective of this study is to explore the feasibility of inhibiting tumor growth via the delivery of endostatin-angiostatin (Endo::Angio) fusion gene by baculovirus, which is an insect virus and emerges as a new gene therapy vector in recent years. We first constructed two recombinant baculoviruses: Bac-hEA harboring the Endo::Angio fusion gene under the transcriptional control of cytomegalovirus immediate-early promoter, and Bac-ITR-hEA harboring the same transgene cassette flanked by the adeno-associate virus (AAV) inverted terminal repeats (ITRs). Transduction of HEK293 cells with these two baculoviruses reveals enhanced expression of the Endo::Angio fusion protein by the flanking ITRs. The biological functions of the fusion protein in inhibiting blood vessel formation were confirmed in vitro by cell proliferation assay, HUVEC migration assay and tubular network formation assay. To test the efficacy the recombinant baculoviruses for cancer therapy, the tumor models were created by injecting 107 SKOV3 cells into the back of nude mice, and the baculoviruses (109 pfu) were injected into the muscle of the mouse models after the tumor developed. Strikingly, injection with Bac-ITR-hEA led to a higher degree of tumor growth inhibition compared with the injection with either Bac-hEA or phosphate buffered-saline (PBS), as evidenced by the reduced tumor volume and higher survival rate. Taken together, this study demonstrates that baculovirus can be a new gene delivery vector for cancer therapy.