Adenoviral herpes simplex virus thymidine kinase gene therapy in an orthotopic lung cancer model.
BACKGROUND
Although adenovirus-mediated herpes simplex virus thymidine kinase (HSVtk) gene therapy is a potential candidate for a novel effective therapy for lung cancer, previous studies have been performed only in a subcutaneous tumor model employing nude mice. We studied therapeutic potentials in correlation with accurate adenoviral gene transduction efficiency in a more clinically relevant orthotopic lung cancer model employing immunocompetent mice.


METHODS
To analyze the cytotoxicity of adenoviral HSVtk gene transduction and ganciclovir, a cell proliferation assay was performed in vitro. A survival study was carried out in immunocompetent mice with orthotopic lung cancer, which was generated by intrapulmonary inoculation with syngeneic murine lung cancer cells that had been infected beforehand with each adenoviral vector at the predetermined gene transduction efficiencies.


RESULTS
Tumor cells were efficiently killed by infection with adenovirus carrying the HSVtk gene with the addition of ganciclovir in vitro. In the in vivo experiment all control mice died of rapid growth of the primary lung cancer and of metastases to mediastinal lymph nodes within 26 days after tumor inoculation. In contrast 50% and 100% of mice survived more than 40 days after inoculation with adenovirally HSVtk-transfected tumor cells that moderately and highly expressed HSVtk, respectively, when followed by ganciclovir administration. Gene transduction efficiencies were 67%.


CONCLUSIONS
Adenovirus-mediated HSVtk gene therapy may be therapeutic for lung cancer when gene transduction efficiencies and sufficient expression levels of HSVtk can be achieved. Moreover, the present findings underscore the importance of the mouse orthotopic lung cancer model for studies of gene therapy.
Fukunaga
Mari
M
Cellular and Developmental Biology Division, Kurume University Research Center for Innovative Cancer Therapy, Kurume University School of Medicine, Kurume City, Fukuoka, Japan.
Takamori
Shinzo
S
Hayashi
Akihiro
A
Shirouzu
Kazuo
K
Kosai
Ken-ichiro
K
D000230:Adenocarcinoma / Q000628:therapy*; D000256:Adenoviridae; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D008175:Lung Neoplasms / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D018139:Simplexvirus; D013937:Thymidine Kinase / Q000235:genetics*; D014407:Tumor Cells, Cultured
D013937:Thymidine Kinase