Combined effects of radiotherapy and angiostatin gene therapy in glioma tumor model

Abstract

The objective of the present study was to evaluate the antitumor effect of a defective adenovirus expressing a secretable angiostatin-like molecule (AdK3) in combination with radiotherapy in rat C6 gliomas s.c. preestablished into athymic mice. In vitro, the combination regimen was significantly (P < 0.001) more cytotoxic for human microcapillary endothelial cells than either treatment alone, whereas survival of C6 glioma cells was not affected in the conditions used. Radiotherapy and AdK3 gene delivery was then studied on well established C6 xenografts (165 ؎ 70 mm 3 ). In these tumors, AdK3 intratumoral injections had only a marginal effect. Interestingly, when experimental radiotherapy was added, significantly higher (P < 0.005), and possibly synergistic, antitumoral effects were observed that tightly correlated a marked decrease of intratumoral vascularization. The combination of radiotherapy and AdK3 intratumoral injections also revealed a significant (P < 0.05) inhibition of tumor growth as compared with either treatment alone for larger tumors (467 ؎ 120 mm 3 ). Altogether, these data emphasize the potential of combining a destructive strategy directed against the tumor cells with an anti-angiogenic approach to fight cancer.angiogenesis ͉ recombinant adenovirus ͉ cancer

Fatty acid synthase: a novel target for antiglioma therapy

“…Cell viability was determined using a modified MTT assay (Griscelli et al, 2000). Briefly, 1000 -5000 cells well À1 were plated in 24-well plates and incubated overnight.…”

Intratumoral gene therapy of malignant brain tumor in a rat model with angiostatin delivered by adeno-associated viral (AAV) vector

“…Gene transfer of angiostatin represents a highly viable alternative strategy to the direct protein delivery methods of angiogenic inhibitors. 43 Previous studies using purified angiostatin protein to treat malignant glioma 19,20,24,44,45 showed its effectiveness, but also suffered drawbacks. Direct protein delivery as a pharmaceutical reagent has formidable limitations to overcome in treating malignant brain tumor.…”

“…For example, in the third week after C6 glioma cell implantation, the tumor volumes in the AdRSVtktreated group and the AdRSVtk plus AAV-angiostatintreated group were respectively 12.7% and 7.6% of the control C6 glioma group, which did not undergo any therapeutic intervention (Figure 5a). Other combined therapeutic strategies, eg angiostatin plus radiation therapy 45 or the delivery of more than one angiostatic factor, 52,53 could also synergize the tumor-suppressive effects. We have recently explored systemic delivery of angiostatin by injection of the AAV-angiostatin vector into the skeletal muscle tissues.…”

A novel strategy for the generation of angiostatic kringle regions from a precursor derived from plasminogen

“…Although others and ourselves found that vector-mediated gene transfer of angiostatin could induce significant inhibition of tumor growth, this type of therapy was not sufficient to induce complete tumor regression, even in a prophylactic setting. [13][14][15][16]23 Recent reports have demonstrated that combination of anti-angiogenic therapy (angiostatin and vasostatin) and immunotherapy (interleukin-12) had synergistic effect on tumor regression in different mouse tumor models. 24,25 This synergism can be explained by the fact that the antiangiogenic therapy induces tumor cell death and releases tumor antigens which potentiate the immune response elicited by immunotherapy.…”