The present review aimed to provide up-to-date information concerning tumor angiogenesis and gene delivery systems in anti-angiogenic gene therapy, with a focus on recent developments in the study and application of the most commonly studied and newly identified anti-angiogenic candidates for anti-angiogenesis gene therapy, including interleukin-12, angiostatin, endostatin, tumstatin, anti-angiogenic metargidin peptide and endoglin silencing.
Immunohistochemical studies demonstrated that, when tumor-bearing mice were infected with S636/pES, Salmonella colonization and endostatin expression were accompanied by the increase of apoptosis level and suppression of tumor angiogenesis within tumor tissues.
These results indicated that endostatin efficiently inhibited tumor angiogenesis and reversed the immunosuppressive microenvironment associated with the presence of tumors.
In the current study, F-labeled recombinant human endostatin (rh-endostatin) was developed and evaluated as a probe for PET imaging of tumor angiogenesis.
On the other hand, K96A, K96R, and E176A, endostatin mutants with lower ATPase activities than that of WT, showed reduced or comparable effects on targeting both in vitro endothelial cell activities and in vivo tumor angiogenesis and tumor growth.
The involvement of HS in signaling of pro-angiogenic factors (e.g. vascular endothelial growth factor and fibroblast growth factor 2), as well as interaction with anti-angiogenic factors (e.g. endostatin), warrants its role as an important modifier of (tumor) angiogenesis.
In the nude mouse xenograft model, the combined treatment with dl1520 and Ad-Endo significantly inhibited tumor angiogenesis and the growth of GC xenografts through the increased endostatin expression and oncolytic effects.
Retroviral bicistronic gene transfer led to the secretion of functional ES and IL-2 that was sufficiently active to: (i) inhibit tumor angiogenesis and tumor cell proliferation and (ii) increase the infiltration of immune cells.
Despite the finding that endostatin was superior to paclitaxel at inhibiting tumor angiogenesis, paclitaxel was nevertheless more effective at inducing tumor apoptosis.
In conclusion, retroviral endostatin gene transfer led to secretion of functional endostatin that was sufficiently active to inhibit tumor angiogenesis and tumor growth.
Combination therapy with endostatin gene therapy and doxorubicin showed a stronger effect in suppressing tumor growth, and tumor angiogenesis, than the respective monotherapies.
The results indicate that the antiangiogenic functions of ES critically depend on the mode of delivery and the site of expression: although its systemic application represses tumor angiogenesis and tumor growth efficiently, locally expressed ES appears to be less effective, and hence, additional mechanisms of solubilization or activation of latent ES seem to be required.
These results indicate HK is proangiogenic probably by releasing bradykinin and that a monoclonal antibody directed to HK could serve as an antiangiogenic agent with a potential for inhibiting tumor angiogenesis and other angiogenesis-mediated disorders.
Collectively, such distinct properties of human tumstatin and human endostatin provide the first insight into their diverse antiangiogenic actions and argue for combining them for targeting tumor angiogenesis.
In vivo, mice bearing Lewis lung carcinoma cells treated with a combination of endostatin and either DI-TSPa or TNP-470, at doses that were ineffective when used alone, resulted in a marked inhibition of tumor growth and decreased tumor angiogenesis.
Endostatin is a 20-kDa carboxy-terminal fragment of collagen XVIII that has been shown to inhibit endothelial cell proliferation and tumor angiogenesis.