title: Gene therapy with tumor-specific promoter mediated suicide gene plus IL-12 gene enhanced tumor inhibition and prolonged host survival in a murine model of Lewis lung carcinoma.
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.
authors.affiliation: Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan 430071, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Xu
authors.forename: Jinxuan
authors.initials: J
authors.lastname: Hou
authors.forename: Zhengchun
authors.initials: Z
authors.lastname: Liu
authors.forename: Haijun
authors.initials: H
authors.lastname: Yu
authors.forename: Wenjie
authors.initials: W
authors.lastname: Sun
authors.forename: Jie
authors.initials: J
authors.lastname: Xiong
authors.forename: Zhengkai
authors.initials: Z
authors.lastname: Liao
authors.forename: Fuxiang
authors.initials: F
authors.lastname: Zhou
authors.forename: Conghua
authors.initials: C
authors.lastname: Xie
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Zhou
mesh_terms: D000256:Adenoviridae / Q000187:drug effects / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000097:blood; D018827:Carcinoma, Lewis Lung / Q000097:blood / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D041722:Genes, Transgenic, Suicide / Q000235:genetics*; D015316:Genetic Therapy / Q000009:adverse effects; D006735:Horseradish Peroxidase / Q000378:metabolism; D006801:Humans; D007210:Indoleacetic Acids / Q000494:pharmacology; D018664:Interleukin-12 / Q000235:genetics* / Q000627:therapeutic use*; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009928:Organ Specificity / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics*; D016019:Survival Analysis; D014161:Transduction, Genetic
chemical_list: D014408:Biomarkers, Tumor; D007210:Indoleacetic Acids; D018664:Interleukin-12; C030737:indoleacetic acid; D006735:Horseradish Peroxidase