Induction of therapeutic antitumor antiangiogenesis by intratumoral injection of genetically engineered endostatin-producing Semliki Forest virus

Abstract

Antiangiogenic therapy using Semliki Forest virus ( SFV ) carrying Endostatin gene for malignant brain tumor was investigated to improve the therapeutic efficacy. The efficiency of SFV -mediated gene delivery was first evaluated for B 16 cells and compared with the efficiency in cells of endothelial origin ( HMVECs ). HMVECs are more susceptible to SFV infection than B 16 cells. For the in vivo treatment model, phosphate -buffered saline, SFV -LacZ, retrovirus vector GCsap -Endostatin, and SFV -Endostatin were injected to mice bearing B 16 brain tumors. A very significant inhibition of tumor growth was observed in the group that had been treated with SFV -Endostatin. A marked reduction of intratumoral vascularization was seen in the tumor sections from the SFV -Endostatin group compared with tumor sections from the SFV -LacZ or GCsap -Endostatin groups. Moreover, at day 7 after intravenous administration of SFV -Endostatin, the serum level of endostatin was augmented more than 3 -fold compared to that after intravenous administration of GCsap -Endostatin. The results indicated that treatment with SFV -Endostatin inhibited the angiogenesis with established tumors. Gene therapy with Endostatin delivered via SFV may be a candidate for the development of new therapy for brain tumors. Cancer Gene Therapy ( 2001 ) 8, 796 -802

Endostatin inhibits lymph node metastasis by a down-regulation of the vascular endothelial growth factor C expression in tumor cells

“…It exhibits a specific inhibitory action on the proliferating endothelial cells of newly formed blood vessels, and it thereby represents one of the better defined and most potent negative regulators of angiogenesis [7]. Endostatin efficiently suppresses primary tumor growth and metastasis through the vascular system in experimental animal models [5,6,[8][9][10][11][12][13].…”

Novel Gene Therapeutic Approaches to Brain Cancer

“…These peptides are difficult to generate in sufficient quantities in vitro and are ideal candidates as transgenes for gene therapy. Recombinant viral vectors that express endostatin (58,59) or angiostatin (60,61) have been developed and tested in preclinical models of glioma. Improved survival of animals with intracranial neoplasms was observed in all cases and tumor growth rates were reduced by as much as 90%.…”

Treatment of rapidly growing K-BALB and CT26 mouse tumours using Semliki Forest virus and its derived vector

“…The antitumoural effect could possibly be further enhanced by the introduction of cytotoxic or antiangiogenic factors (including cytokines) into the vector, which would be secreted by cells and diffuse through the tumour. [14][15][16][17][18][19]36 In this study, we have administered VLPs expressing a viral antigen. This could induce a neutralizing immune response that may affect subsequent administrations.…”

“…Wells were sampled at 6,12,24,36,48, and 72 h postinfection. Cells were incubated with caspase inhibitors conjugated to fluorescein (Oncogene) for 1 h according to the manufacturer's instructions before being trypsinized, washed, fixed, and spun onto slides using a Cytospin III (Shandon).…”