Abstract | BACKGROUND: Gene therapy is a promising therapeutic approach for cancer. Targeted expression of desired therapeutic proteins within the tumor is the best approach to reduce toxicity and improve survival. This study is to establish a more effective and less toxic gene therapy of cancer. METHODS: Combined gene therapy strategy with recombinant adenovirus expressing horseradish peroxidase (HRP) mediated by human telomerase reverse transcriptase (hTERT) promoter (AdhTERTHRP) and murine interleukin-12 (mIL-12) under the control of Cytomegalovirus (CMV) promoter (AdCMVmIL-12) was developed and evaluated against Lewis lung carcinoma (LLC) both in vivo and in vitro. The mechanism of action and systemic toxicities were also investigated. RESULTS: The combination of AdhTERTHRP/ indole-3- acetic acid (IAA) treatment and AdCMVmIL-12 resulted in significant tumor growth inhibition and survival improvement compared with AdhTERTHRP/IAA alone ( tumor volume, 427.4 ± 48.7 mm3 vs 581.9 ± 46.9 mm3, p = 0.005 on day 15; median overall survival (OS), 51 d vs 33 d) or AdCMVmIL-12 alone ( tumor volume, 362.2 ± 33.8 mm3 vs 494.4 ± 70.2 mm3, p = 0.046 on day 12; median OS, 51 d vs 36 d). The combination treatment stimulated more CD4+ and CD8+ T lymphocyte infiltration in tumors, compared with either AdCMVmIL-12 alone (1.3-fold increase for CD4+ T cells and 1.2-fold increase for CD8+ T cells, P < 0.01) or AdhTERTHRP alone (2.1-fold increase for CD4+ T cells and 2.2-fold increase for CD8+ T cells, P < 0.01). The apoptotic cells in combination group were significantly increased in comparison with AdCMVmIL-12 alone group (2.8-fold increase, P < 0.01) or AdhTERTHRP alone group (1.6-fold increase, P < 0.01). No significant systematic toxicities were observed. CONCLUSIONS: Combination gene therapy with AdhTERTHRP/IAA and AdCMVmIL-12 could significantly inhibit tumor growth and improve host survival in LLC model, without significant systemic adverse effects.
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Authors | Yu Xu, Jinxuan Hou, Zhengchun Liu, Haijun Yu, Wenjie Sun, Jie Xiong, Zhengkai Liao, Fuxiang Zhou, Conghua Xie, Yunfeng Zhou |
Journal | Journal of translational medicine
(J Transl Med)
Vol. 9
Pg. 39
(Apr 11 2011)
ISSN: 1479-5876 [Electronic] England |
PMID | 21481255
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Biomarkers, Tumor
- Indoleacetic Acids
- Interleukin-12
- indoleacetic acid
- Horseradish Peroxidase
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Topics |
- Adenoviridae
(drug effects, genetics)
- Animals
- Apoptosis
(drug effects)
- Biomarkers, Tumor
(blood)
- Carcinoma, Lewis Lung
(blood, genetics, pathology, therapy)
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- Disease Models, Animal
- Genes, Transgenic, Suicide
(genetics)
- Genetic Therapy
(adverse effects)
- Horseradish Peroxidase
(metabolism)
- Humans
- Indoleacetic Acids
(pharmacology)
- Interleukin-12
(genetics, therapeutic use)
- Lymphocytes, Tumor-Infiltrating
(drug effects, pathology)
- Mice
- Mice, Inbred C57BL
- Organ Specificity
(drug effects)
- Promoter Regions, Genetic
(genetics)
- Survival Analysis
- Transduction, Genetic
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