Abstract | BACKGROUND: Therapeutic gene transfer affords a clinically feasible and safe approach to cancer treatment but a more effective modality is needed to improve clinical outcomes. Combined transfer of therapeutic genes with different modes of actions may be a means to this end. Interleukin-12 (IL-12), a heterodimeric immunoregulatory cytokine composed of covalently linked p35 and p40 subunits, has antitumor activity in animal models. The enzyme/ prodrug strategy using cytosine deaminase (CD) and 5-fluorocytosine (5-FC) has been used for cancer gene therapy. We have evaluated the antitumor effect of combining IL-12 with CD gene transfer in mice bearing renal cell carcinoma (Renca) tumors. METHODS: Adenoviral vectors were constructed encoding one or both subunits of murine IL-12 (Ad.p35, Ad.p40 and Ad. IL-12) or cytosine deaminase (Ad.CD). The functionality of the IL-12 or CD gene products expressed from these vectors was validated by splenic interferon (IFN)-gamma production or viability assays in cultured cells. Ad.p35 plus Ad.p40, or Ad.IL-12, with or without Ad.CD, were administered (single-dose) intratumorally to Renca tumor-bearing mice. The animals injected with Ad.CD also received 5-FC intraperitoneally. The antitumor effects were then evaluated by measuring tumor regression, mean animal survival time, splenic natural killer (NK) cell activity and IFN-gamma production. RESULTS: The inhibition of tumor growth in mice treated with Ad.p35 plus Ad.p40 and Ad.CD, followed by injection of 5-FC, was significantly greater than that in mice treated with Ad.CD/5-FC, a mixture of Ad.p35 plus Ad.p40, or Ad.GFP (control). The combined gene transfer increased splenic NK cell activity and IFN-gamma production by splenocytes. Ad.CD/5-FC treatment significantly increased the antitumor effect of Ad.IL-12 in terms of tumor growth inhibition and mean animal survival time. CONCLUSION: The results suggest that adenovirus-mediated IL-12 gene transfer combined with Ad.CD followed by 5-FC treatment may be useful for treating cancers.
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Authors | Kyung-Sun Hwang, Won-Kyung Cho, Jinsang Yoo, Hwan-Jung Yun, Samyong Kim, Dong-Soo Im |
Journal | BMC cancer
(BMC Cancer)
Vol. 5
Pg. 51
(May 24 2005)
ISSN: 1471-2407 [Electronic] England |
PMID | 15910693
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antineoplastic Agents
- DNA, Complementary
- Prodrugs
- Green Fluorescent Proteins
- Interleukin-12
- Interferon-gamma
- Cytosine Deaminase
- Fluorouracil
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Topics |
- Adenoviridae
(genetics)
- Animals
- Antineoplastic Agents
(pharmacology)
- Blotting, Western
- Carcinoma, Renal Cell
(metabolism)
- Cell Line
- Cell Line, Tumor
- Cell Survival
- Cytosine Deaminase
(pharmacology)
- DNA, Complementary
(metabolism)
- Enzyme-Linked Immunosorbent Assay
- Escherichia coli
(metabolism)
- Female
- Fluorouracil
(pharmacology)
- Gene Transfer Techniques
- Genetic Therapy
(methods)
- Genetic Vectors
- Green Fluorescent Proteins
(metabolism)
- HeLa Cells
- Humans
- Interferon-gamma
(metabolism)
- Interleukin-12
(genetics, metabolism)
- Kidney Neoplasms
(metabolism)
- Killer Cells, Natural
(metabolism)
- Male
- Mice
- Mice, Inbred BALB C
- Neoplasm Transplantation
- Neoplasms
(genetics, therapy)
- Neoplasms, Experimental
(genetics, therapy)
- Prodrugs
(pharmacology)
- Spleen
(metabolism)
- Time Factors
- Treatment Outcome
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