Successful inhibition of intracranial human glioblastoma multiforme xenograft growth via systemic adenoviral delivery of soluble endostatin and soluble vascular endothelial growth factor receptor-2

Abstract

Object-Glioblastoma multiforme (GBM) is characterized by neovascularization, raising the question of whether angiogenic blockade may be a useful therapeutic strategy for this disease. It has been suggested, however, that, to be useful, angiogenic blockade must be persistent and at levels sufficient to overcome proangiogenic signals from tumor cells. In this report, the authors tested the hypothesis that sustained high concentrations of 2 different antiangiogenic proteins, delivered using a systemic gene therapy strategy, could inhibit the growth of established intracranial U87 human GBM xenografts in nude mice.Methods-Mice harboring established U87 intracranial tumors received intravenous injections of adenoviral vectors encoding either the extracellular domain of vascular endothelial growth factor receptor-2-Fc fusion protein (Ad-VEGFR2-Fc) alone, soluble endostatin (Ad-ES) alone, a combination of Ad-VEGFR2-Fc and Ad-ES, or immunoglobulin 1-Fc (Ad-Fc) as a control.Results-Three weeks after treatment, magnetic resonance imaging-based determination of tumor volume showed that treatment with Ad-VEGFR2-Fc, Ad-ES, or Ad-VEGFR2-Fc in combination with Ad-ES, produced 69, 59, and 74% growth inhibition, respectively. Bioluminescent monitoring of tumor growth revealed growth inhibition in the same treatment groups to be 62, 74, and 72%, respectively. Staining with proliferating cell nuclear antigen and with terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling showed reduced tumor cell proliferation and increased apoptosis in all antiangiogenic treatment groups. HHS Public AccessConclusions-These results suggest that systemic delivery and sustained production of endostatin and soluble VEGFR2 can slow intracranial glial tumor growth by both reducing cell proliferation and increasing tumor apoptosis. This work adds further support to the concept of using antiangiogenesis therapy for intracranial GBM. Keywordsantiangiogenesis; endostatin; gene therapy; glioblastoma multiforme; vascular endothelial growth factor High-grade astrocytic tumors are the most common primary tumors of the central nervous system. Despite combined multimodal treatments (surgery, radiotherapy, and chemotherapy with oral alkylating agents such as temozolomide), the median survival time for patients with GBM is approximately 12-18 months. 7,27,45,78 The identification and development of novel therapeutic strategies therefore remains an important priority in this disease. Because GBM is characterized by endothelial cell proliferation and a high degree of vascularity, it has been suggested that antiangiogenic approaches may be an especially useful adjunct to other therapies.Use of antiangiogenic therapy for brain tumors is based on the premise that the progressively higher grade of glial tumors requires an extensive network of blood vessels. 20,25,34,60,61,91 Strategies to abrogate new blood vessel formation have been explored in preclinical models of GBM and have shown some success. 23,[31][32][33]37,41,62,69...

The corpora lutea proangiogenic state of VEGF system components is turned to antiangiogenic at the later phase of the oestrous cycle in cows

“…The soluble forms of the VEGF receptors bind to the ligand and block their angiogenic action (Kaczmarek et al, 2005). Cancer therapy studies have shown that an increase in the expression of sVEGFR1 (Owen et al, 2012) or sVEGFR2 (Wang et al, 2006;Szentirmai et al, 2008) reduce tumour cell proliferation and increase apoptosis (Szentirmai et al, 2008), which is associated with a reduction in blood flow to the tumour tissues. In the present study, mRNA expression of VEGFR2 on days 4 and 6 (CL formation) of the cycle was at least eightfold higher than that Figure 2 Changes in the ratio of mRNA expression for angiogenic (VEGF120a, VEGFR1 and VEGFR2) and antiangiogenic (VEGF120b, sVEGFR1 and sVEGFR2) VEGF system components in the corpus luteum during the oestrous cycle.…”

Regulation of soluble VEGFR-2 secreted by microvascular endothelial cells derived from human BPH

“…Recent studies suggest that endothelium has an important role in the regulation of normal and malignant tumor growth. [1][2][3] However, under physiological as well as pathological conditions, the function of microvascular endothelial cells is adapted to the respective organ and tissue. [4][5][6][7] Therefore, it is important to investigate the organ-specific function of the respective endothelium.…”

“…The inhibiting effect of sVEGFR-2 on the VEGF-stimulated proliferation of HPECs suggest that sVEGFR-2 functions as an antiangiogenic factor. 3,15,16 Materials and methods…”

AAV-P125A-endostatin and paclitaxel treatment increases endoreduplication in endothelial cells and inhibits metastasis of breast cancer

“…Synergy between antiangiogenic therapy and chemotherapy has been reported by others. Szentirmai et al 33 showed improved inhibition of intracranial growth of glioblastoma by adenovirus-mediated gene therapy with endostatin in combination with soluble VEGF receptor 1. Another study showed synergy between chemotherapy and intratumoral delivery of a nonviral construct of endostatin.…”