Objective: To investigate the synergistic effects of antisense HIF-1alpha gene therapy combined with B7-1-mediated immunotherapy on cancer treatment.
Methods: Antisense HIF-1alpha and B7-1 expression vector were constructed. Lymphoma cells EL-4 were injected subcutaneously into C57BL/6 mice and transplanted lymphomas were established. The mice received either antisense HIF-1alpha, B7-1, or a combinational agent, complexed with DOTAP cationic liposomes. The tumor growth in the mice was monitored. Expression of HIF-1alpha, B7-1 and VEGF were detected by immunohistochemistry and Western blotting. The tumor blood vessels were immunostained with CD31- antibodies and the tumor vascular density was assessed by light microscopy.
Results: Gene transfer of plasmid expressing the encoded antisense HIF-1alpha inhibited VEGF expression and reduced vascular density in the tumors, eradicated tumors in diameter smaller than 0.1 cm and only retarded the growth of larger tumors. Whereas combination of antisense HIF-1alpha gene therapy and B7-1 immunotherapy eradicated all tumors in diameter of 0.4 cm.
Conclusion: Antisense HIF-1alpha blocks tumor hypoxia pathway by downregulating VEGF expression, reduction of vascular density and enhances B7-1-mediated immunotherapy. Strategies that target HIF-1 may have therapeutic potential in cancer treatment and are worthy of further studying.
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