Abstract
BackgroundThe sustained growth of tumors necessitates neovascularization. As one of the potent endogenous vascular inhibitors, endostatin has been widely used in antiangiogenesis therapy for tumor. Cisplatin is normally administered in chemotherapy for lung cancer but accompanied with serious side effects. In the current study, we investigated a novel chemo-antiangiogenesis therapeutic strategy to both improve toxic effects on lung cancer cells and reduce damages to normal cells in the anti-tumor therapy.MethodsIn vitro, we transduced LLC cells with Ad-hEndo and collected supernatants. Western blotting analysis of the supernatants revealed expression of endostatin. In vivo, to fully investigate the suppression effect on murine lung cancer of the combination therapy, we injected recombinant human endostatin adenovirus intratumorally plus a low dose of cisplatin intraperitoneally routinely. The tumor volume and survival time were observed. Angiogenesis was apparently inhibited within the tumor tissues and on the alginate beads. Assessment of apoptotic cells by the TUNEL assay was conducted in the tumor tissues.ResultsThe combination treatment significantly suppressed the tumor growth and prolonged survival time of the murine LLC tumor model. This anti-tumor activity was associated with decreased microvessel density and increased apoptotic index of tumor cells.ConclusionAccording to the results in this study, recombinant human endostatin adenovirus in combination with a low dose of cisplatin demonstrated apparent synergistic anti-tumor activity without marked toxicity. Thus, these observations may provide a rational alternative for lung cancer treatment.
Highlights
The sustained growth of tumors necessitates neovascularization
Construction of recombinant adenovirus Construction of recombinant human endostatin adenovirus has been described in the previous study[8]
The endostatin cDNA encoding C-terminal 184 amino acids of human collagen XVIII was amplified by RT-PCR
Summary
As one of the potent endogenous vascular inhibitors, endostatin has been widely used in antiangiogenesis therapy for tumor. We investigated a novel chemo-antiangiogenesis therapeutic strategy to both improve toxic effects on lung cancer cells and reduce damages to normal cells in the anti-tumor therapy. Neovascularization includes multiple complex sequential steps: degradation of basement membranes, proliferation and migration of endothelial cells, and deposition of basement membranes. One of the potent endogenous angiogenesis inhibitors, endostatin, is a cleavage fragment containing COOH-terminal 184 amino acids of the basement membrane collagen XVIII. This product inhibits endothelial cell migration and proliferation, and induces regression of tumors[5]
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