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Use of Recombinant Adenovirus to Transfer the Herpes Simplex Virus Thymidine Kinase (HSVtk) Gene to Thoracic Neoplasms: An Effective in Vitro Drug Sensitization System¹

Thoracic Surgery Section, Department of Surgery [W. R. S., K. M. A., L. R. K.], and Pulmonary/Critical Care Section, Department of Medicine [H. C. H., S. M. A.], University of Pennsylvania Thoracic Oncology Research Laboratory; Hematology Oncology Section, Department of Medicine [S. L. E.], Department of Molecular and Cellular Engineering [J. M. W.], and Institute for Human Gene Therapy [S. L. E., J. M. W., L. R. K., S. M. A.], University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104; and Rheumatology Section, Department of Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109 [B. L. D.]

Transfer of the herpes simplex virus thymidine kinase (HSVtk) gene into tumor cells using retroviral vectors followed by administration of ganciclovir provides a potential strategy for the treatment of malignancy. Because of the limitations of using retroviral vectors for clinical application, the feasibility of using a recombinant adenovirus containing HSVtk was examined. Cell lines derived from human malignant mesotheliomas and non-small cell lung cancers infected with a recombinant adenovirus containing HSVtk showed strong expression of HSVtk protein as determined by immunohistochemical staining. Infection with a recombinant adenovirus containing HSVtk rendered cells sensitive to doses of ganciclovir that were 2–3 logs lower than uninfected cells or those infected with a control virus. A strong "bystander effect" was noted in mesothelioma lines; there was no diminution in the efficacy of ganciclovir treatment until the ratio of infected:uninfected cells fell below 1:10. This study thus demonstrates in vitro efficacy of an adenovirus-transduced HSVtk drug sensitization gene therapy system in thoracic malignancies. Recombinant adenovirus transfer of the HSVtk gene followed by ganciclovir may have promise as an in situ treatment for tumors.

¹ This study was partially supported by a development grant from the University of Pennsylvania Cancer Center.

² To whom requests for reprints should be addressed, at Thoracic Oncology Research Laboratory, Hospital of the University of Pennsylvania, Maloney Building, Room 809, 36th and Spruce Streets, Philadelphia, PA 19104.

Received 1/14/94. Accepted 3/ 4/94.

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