Adenoviral herpes simplex virus thymidine kinase gene therapy in an orthotopic lung cancer model Mari Fukunaga, MD, Shinzo Takamori, MD, Akihiro Hayashi,

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Adenoviral herpes simplex virus thymidine kinase gene therapy in an orthotopic lung cancer model Mari Fukunaga, MD, Shinzo Takamori, MD, Akihiro Hayashi, MD, Kazuo Shirouzu, MD, Ken-ichiro Kosai, MD, PhD The Annals of Thoracic Surgery Volume 73, Issue 6, Pages 1740-1746 (June 2002) DOI: 10.1016/S0003-4975(02)03572-5

Fig 1 (A) Adenoviral gene transduction efficiencies in murine Lewis lung cancer (LLC) and human A549 lung cancer cell lines. A549 and LLC cells were infected with AdCMVlacZ at various multiplicities of infection and subsequently stained with X-gal. Adenoviral gene transduction efficiencies in both cell lines were increased in a dose-dependent manner. (B) Cytotoxic effects of AdRSVtk with and without ganciclovir in LLC cells in vitro, respectively. The cytotoxic effects of AdRSVtk/ganciclovir were significantly higher than those of AdRSVtk/PBS at each multiplicity of infection ([MOI] p < 0.0001). Nearly all cells were killed with AdRSVtk/ganciclovir at MOI of 3,000. Treatment with AdRSVtk/PBS at MOI of 3,000 also showed significant cytotoxicity compared with treatment with AdCMVlacZ/PBS at MOI of 3,000 (p < 0.0001). (GCV = ganciclovir; PBS = phosphate-buffered saline.) The Annals of Thoracic Surgery 2002 73, 1740-1746DOI: (10.1016/S0003-4975(02)03572-5)

Fig 2 Macroscopic pictures of intrapulmonary inoculated tumor and transgene expression at the initiation of ganciclovir treatment. (A) The low-power view. The arrow indicates the tumor nodule at 3 days after inoculation of Lewis lung cancer cells that had been infected with AdCMVlacZ beforehand. (B) The high-power view of the tumor lesion. The white tumor nodule was not completely circumscribed and some tumor cells were invading the surrounding lung parenchyma. X-gal staining revealed transgene (β-galactosidase) expression. The Annals of Thoracic Surgery 2002 73, 1740-1746DOI: (10.1016/S0003-4975(02)03572-5)

Fig 3 Macroscopic and microscopic pictures of the lung of a mouse that had received AdCMVlacZ- or AdCMVtk-infected tumor cells. (A–C) The lung at the time of death of a mouse that had received AdCMVlacZ-infected Lewis lung cancer (LLC) cells at multiplicity of infection (MOI) of 3,000 and subsequent ganciclovir administration. Large tumor nodules and mediastinal metastases are prominent. (D–F) The mouse lung at 40 days after intrapulmonary inoculation of AdRSVtk-infected LLC cells at MOI of 3,000 and subsequent ganciclovir administration. Tumor nodules were not microscopically detected in the lung although histologic examination revealed a very small tumor nodule. Magnification (hematoxylin and eosin staining) is ×6 (B and E) and ×40 (C and F). The Annals of Thoracic Surgery 2002 73, 1740-1746DOI: (10.1016/S0003-4975(02)03572-5)

Fig 4 Survival prolongation after intrapulmonary inoculation with adenovirally infected Lewis lung cancer (LLC) cells and subsequent administration of ganciclovir. LLC cells were infected with each adenoviral vector at each multiplicity of infection (MOI), as shown, or with a vehicle instead of an adenoviral vector. After 48 hours of incubation LLC cells were percutaneously and intrapulmonarily inoculated into the left lung in mice. Three days later all mice including control mice were given intraperitoneal injections of ganciclovir twice a day for 14 consecutive days. Survival advantages, which were seen in AdRSVtk and AdCMVtk groups, became more significant as higher adenoviral gene transduction efficiencies and higher transgene (HSVtk gene) expressions were used. The Annals of Thoracic Surgery 2002 73, 1740-1746DOI: (10.1016/S0003-4975(02)03572-5)