Intramuscular delivery of antiangiogenic genes suppresses secondary metastases after removal of primary tumors

Abstract

The success of surgery to remove primary tumors can be compromised by the subsequent outgrowth of metastases. It is recognized that primary tumors secrete antiangiogenic factors that suppress the outgrowth of their daughter metastases. In accord we show here that surgical removal of primary EL-4 lymphomas led to a marked decrease in the levels of circulating angiostatin and endostatin, and promoted the growth of distant nodular tumors. Expression vectors encoding angiostatin and endostatin, formulated with poly-N-vinyl pyrrolidone (PVP), were injected into the tibialis and gastrocnemia muscles, leading to expression of angiostatin and endostatin in muscle fibers. High levels of biologically active exogenous proteins were secreted into the circulation. Intramuscular gene therapy with angiostatin and endostatin plasmids significantly inhibited tumor vascularity and induced tumor cell apoptosis, and thereby suppressed the growth of secondary subcutaneous and disseminated metastatic tumors in the lung and liver. Simultaneous intramuscular delivery of both angiostatin and endostatin plasmids significantly prolonged the survival of mice after removal of primary tumors. These results suggest that intramuscular gene transfer of angiostatin and endostatin might serve as a prophylactic cancer-prevention strategy to combat the recurrence of cancer after surgical resection of primary tumors.

Arsenic trioxide synergizes with B7H3‐mediated immunotherapy to eradicate hepatocellular carcinomas

“…Purified plasmids were formulated with 5% PVP to generate a plasmid/PVP formulation with a concentration of 1 mg DNA/ml, as described previously. 24,25 Tumor implantation and treatment…”

Liposome–DNA complexes infused intravenously inhibit tumor angiogenesis and elicit antitumor activity in dogs with soft tissue sarcoma

“…For example, use of systemic gene delivery to express endostatin or other angiogenesis inhibitors to control tumor growth has been reported previously in mouse models. [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] However, potential hurdles to applying systemic gene therapy in humans include achieving efficient in vivo transfection, attaining durable in vivo gene expression, and administering the gene delivery vectors repeatedly. 2,17,23 The use of nonviral gene delivery systems, based principally on liposome-plasmid DNA-based systems, may help address some of these problems, particularly the issue of repeated gene delivery.…”

Prostate-Restricted Replicative Adenovirus Expressing Human Endostatin-Angiostatin Fusion Gene Exhibiting Dramatic Antitumor Efficacy

“…Angiostatin, an NH 2 -terminal fragment comprising kringles 1 to 3 of plasminogen, also shows potent antiangiogenic (8) and/or antitumor effects (25,26). Recently, an endostatin and angiostatin fusion protein, EndoAngio, has been developed that exhibits prolonged half-life and greater antiangiogenic and antitumor effects (13,27).…”