Concurrent delivery of GM-CSF and endostatin genes by a single adenoviral vector provides a synergistic effect on the treatment of orthotopic liver tumors.

Background: The immune resistance of large tumors represents a major problem for cancer immunotherapy, whereas the need for repeated injections of high doses of recombinant anti-angiogenic proteins represents a similar problem for anti-angiogenic therapy. To test whether antitumor activity could be increased by combining the above two mechanisms, this study examined the therapeutic effect of combination gene therapy using a murine granulocyte-macrophage colony-stimulating factor (mGM-CSF) gene and a human endostatin (hED) gene on a rat orthotopic liver tumor model.
Methods: An adenoviral vector was constructed that simultaneously carried two transcriptional cassettes, for the expression of mGM-CSF and hED, respectively, or that carried a single cassette of either gene. The adenoviruses were intratumorally administered to 3-day-old or 7-day-old tumors. Moreover, the antitumor effects of the combination therapy and monotherapy were assessed and compared.
Results: The double-gene-containing adenoviral vector expressed transgenes as efficiently as the single-gene-containing vector. Moreover, the adenovirally expressed endostatin was biologically active, as demonstrated in vitro and in vivo. Results from animal experiments demonstrated a synergistic antitumor effect induced by the combined mGM-CSF and hED therapy. The combination of hED with mGM-CSF enhanced tumor-specific CTL activity, but did not interfere with the infiltration of cellular effectors in the tumor regions. The blood vessel density of the liver tumors markedly reduced as a result of hED expression in both monotherapy and combination therapy. Furthermore, combination therapy significantly increased the number of apoptotic cells in the tumor regions.
Conclusions: The experimental results suggest that the combined gene therapy against tumor cells and the tumor vascular system using antitumor immune mechanisms and anti-angiogenic mechanisms holds promise as a strategy for treating cancers.
(Copyright 2003 John Wiley & Sons, Ltd.)