Replication -defective adenovirus vectors were generated in which the gene of interest B lacZ, luciferase or herpes simplex virus thymidine kinase (HSV-tk) B is driven by the adenovirus major late promoter (MLP) or the human cytomegalovirus immediate-early gene promoter/enhancer (CMV). In vitro experiments with rat and human mesothelioma cell lines revealed that the CMV promoter was stronger than the MLP promoter regarding levels of expression of the luciferase reporter gene and ganciclovir (GCV) killing efficiency after tk gene transfer.
Following administration of lacZ recombinant adenovirus into the pleural cavity of rats with established mesothelioma, a widespread distribution of infectious virus particles through the thorax contents was demonstrated. However, a relatively small proportion of tumor cells were transduced. Nevertheless, a strong growth inhibition was observed following treatment with recombinant tk adenovirus and GCV. In a survival study, animals were treated with recombinant tk adenovirus and a 14 days course of GCV. This treatment prolonged symptom-free survival time from 19 days in the controls to 33 days in the treated group. These responses can be best explained by assuming continued tk expression in or around the tumor tissue during GCV treatment. These results confirm and extend earlier findings with the same model and demonstrate the potential of the herpes simplex virus thymidine kinase suicide gene therapy as a local treatment for malignant mesothelioma. "Gene therapy of experimental malignant mesothelioma using adenovirus vectors encoding the HSV-tk gene", Esandi, et al.,Gene Therapy, 5(4):280-7, April, 1997.
Powered by Blogger.