Intra-arterial delivery of endostatin gene to brain tumors prolongs survival and alters tumor vessel ultrastructure

Abstract

Glioblastoma multiforme (GBM) is an incurable malignant brain tumor, usually fatal within 1 year of diagnosis. Using a syngeneic rat 9L gliosarcoma model, we have developed a novel drug delivery method in which naked plasmid DNA is selectively targeted to brain tumors via intra-arterial injection. Using a plasmid encoding the antiangiogenic endostatin, transgene expression can be detected in tumor cells in vivo, and therapeutic efficacy is observed. Administration of this plasmid resulted in an 80% tumor volume reduction 1 week after treatment and enhanced survival time by up to 47%.Treated tumors exhibited a 40% decrease in the number of tumor vessels; ultrastructural analysis of remaining tumor vessels demonstrated a number of changes including markedly narrowed or collapsed lumens. We conclude that intra-arterial injection of plasmids selectively targets therapeutic genes to CNS neoplasms. This method of gene therapy holds promise for the treatment of these highly malignant brain tumors.

Biology of Angiogenesis and Invasion in Glioma

“…98 Multiple animal studies confirm a functional role of endostatin in decreasing tumor angiogenesis and growth in vivo. 99,100 Analogous to endostatin, proteolytic cleavage of collagen-4 by MMPs produces tumstatin, which early evidence suggests may play a role in inhibiting angiogenesis by interaction with ␣v␤ 3 integrin and PI3K pathways. 101,102 Brain angiogenesis inhibitor-1 (BAI1), also known as vasculostatin, is expressed in glia and neurons of normal brain but not in blood vessels.…”

Genetic strategies for brain tumor therapy

“…22 Finally, there are occasional examples of the use of naked plasmid DNA in brain tumor gene therapy. 23 Cellular gene delivery methods are gaining importance because of the emerging utility of neural stem cells (NSCs). 24 NSCs are tolerated by the immune system, have and endothelial progenitor cells.…”

“…73 When endostatin was delivered in the form of naked plasmid DNA injected intra-arterially, transgene expression was seen in brain tumors, enhancing survival time by up to 47% in a rat syngeneic brain tumor model. 23 Extensive tumor invasion is highly characteristic of brain tumors, and represents a major therapeutic challenge. Invasion involves extracellular matrix modification by proteases and protease inhibitors, cytoskeletal reorganization, growth factors, cytokines, and intracellular signaling molecules.…”

E10A, an adenovirus-carrying endostatin gene, dramatically increased the tumor drug concentration of metronomic chemotherapy with low-dose cisplatin in a xenograft mouse model for head and neck squamous-cell carcinoma

“…Furthermore, we found significantly more apoptotic cells in the combined treatment tumors than in those exposed to the other treatments ( Figure 5). Clearly, the inhibition of tumor vascularization should decrease the supply of oxygen and nutrients to tumor cells, as well as decreasing the perfusion and vascular permeability, 35 leading to apoptosis of the tumor cells. Further, each of these putative mechanisms would tend to reinforce the efficacy of cisplatin.…”