Concurrent delivery of GM-CSF and endostatin genes by a single adenoviral vector provides a synergistic effect on the treatment of orthotopic liver tumors
Journal
Journal of Gene Medicine
Journal Volume
5
Journal Issue
5
Pages
386-398
Date Issued
2003
Author(s)
Abstract
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.
Subjects
Anti-angiogenic therapy; Combination therapy; Endostatin; GM-CSF; Immunotherapy
SDGs
Other Subjects
adenovirus vector; endostatin; granulocyte macrophage colony stimulating factor; angiogenesis inhibitor; CD31 antigen; collagen; endostatin; granulocyte macrophage colony stimulating factor; laminin; matrigel; proteoglycan; animal experiment; animal model; antiangiogenic activity; antineoplastic activity; apoptosis; article; controlled study; drug potentiation; gene cassette; gene construct; gene expression; human; human cell; immunity; in vitro study; in vivo study; liver tumor; male; monotherapy; nonhuman; priority journal; rat; tumor model; tumor vascularization; viral gene delivery system; viral gene therapy; Adenovirus; animal; Bagg albino mouse; biological model; biosynthesis; cell division; cell line; cytology; cytotoxic T lymphocyte; drug combination; endothelium cell; enzyme linked immunosorbent assay; Fischer 344 rat; gene therapy; gene transfer; gene vector; genetic transcription; genetics; immunohistochemistry; immunotherapy; liver; liver tumor; metabolism; methodology; mouse; multimodality cancer therapy; neovascularization (pathology); nick end labeling; plasmid; reverse transcription polymerase chain reaction; time; transgene; tumor cell line; Western blotting; Adenoviridae; Angiogenesis Inhibitors; Animals; Antigens, CD31; Apoptosis; Blotting, Western; Cell Division; Cell Line; Cell Line, Tumor; Collagen; Combined Modality Therapy; Drug Combinations; Endostatins; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Gene Therapy; Gene Transfer Techniques; Genetic Vectors; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immunohistochemistry; Immunotherapy; In Situ Nick-End Labeling; Laminin; Liver; Liver Neoplasms; Mice; Mice, Inbred BALB C; Models, Genetic; Neovascularization, Pathologic; Plasmids; Proteoglycans; Rats; Rats, Inbred F344; Reverse Transcriptase Polymerase Chain Reaction; T-Lymphocytes, Cytotoxic; Time Factors; Transcription, Genetic; Transgenes
Publisher
John Wiley and Sons Ltd
Type
journal article