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

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Concurrent delivery of GM-CSF and endostatin genes by a single adenoviral vector provides a synergistic effect on the treatment of orthotopic liver tumors.
Authors:	Tai, KF Chen, PJ Chen, DS Hwang, LH
Citation:	Tai KF, etal., J Gene Med. 2003 May;5(5):386-98.
RGD ID:	10450243
Pubmed:	PMID:12731087 (View Abstract at PubMed)
DOI:	DOI:10.1002/jgm.376 (Journal Full-text)
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.

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Term	Qualifier	Evidence	With	Reference	Notes	Source	Original Reference(s)
hepatocellular carcinoma	treatment	ISO	Csf2 (Mus musculus)	10450243; 10450243		RGD
hepatocellular carcinoma	treatment	IMP		10450243		RGD

Objects Annotated

Genes (Rattus norvegicus)

Csf2 (colony stimulating factor 2)

Genes (Mus musculus)

Csf2 (colony stimulating factor 2 (granulocyte-macrophage))

Genes (Homo sapiens)

CSF2 (colony stimulating factor 2)

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