TREATMENT OF EXPERIMENTAL HUMAN MESOTHELIOMA USING ADENOVIRUS TRANSFER OF THE HERPES-SIMPLEX THYMIDINE KINASE GENE

Objective The authors demonstrate the ability of an adenovirus vector expressing the herpes simplex thymidine kinase (HSVtk) gene to treat h uman malignant mesothelioma growing within the peritoneal cavity of se vere combined immunodeficient (SCID) mice. Background Data Introductio n of the HSVtk gene into tumor cells renders them sensitive to the ant iviral drug ganciclovir (GCV). This approach has been used previously to treat experimental brain tumors. Although malignant mesothelioma is refractory to current therapies, its localized nature and the accessi bility of the pleural space make it a potential target for a similar t ype of in vivo gene therapy using adenovirus. Methods An adenovirus co ntaining the HSVtk gene (Ad.RSVtk) was used to transduce mesothelioma cells in vitro. These cells were then injected into the flanks of SCID mice. Ad.RSVtk was also injected directly into the peritoneal cavity of SCID mice with established human mesothelioma tumors. Mice were sub sequently treated for 7 days with GCV at a dose of 5 mg/kg. Results Me sothelioma cells transduced in vitro with Ad.RSVtk formed nodules when injected in the subcutaneous tissue. These tumors could be eliminated by the administration of GCV, even when as few as 10% of cells were t ransduced to express HSVtk (bystander effect). Administration of Ad.RS Vtk into the peritoneal space of animals with established multifocal h uman mesothelioma followed by GCV therapy resulted in the eradication of macroscopic tumor in 90% of animals and microscopic tumor in 80% of animals when evaluated after 30 days. The median survival of animals treated with Ad.RSVtk/GCV was significantly longer than that of contro l animals treated with similar protocols. Conclusion These results ind icate that an adenoviral vector containing the HSVtk gene is effective in treating established malignant mesothelioma in an in vivo setting and raise the possibility of using adenovirus transfer of HSVtk for cl inical trials in mesothelioma and other localized tumors.