Limitations of retrovirus-mediated HSV-tk gene transfer to pulmonary adenocarcinoma cells in vitro and in vivo

The utility of conferring chemosensitivity to pulmonary adenocarcinoma tumor cells by retrovirus-mediated transfer of herpes simplex virus thymidine kinase (HSV-tk) gene was assessed in vitro and in vivo. Retrovirus-mediated HSV-tk gene transfer to human adenocarcinoma cells (A549 cells) or mouse lung epithelial carcinoma cells (MLE cells) resulted in expression of HSV-tk mRNA and sensitivity to ganciclovir (GCV) in vitro. In nude mice, tumors produced from HSV-tk transduced MLE-7 cells regressed after 14 days of GCV treatment. However, in residual tumors, the size of the HSV-tk mRNA was altered and the sensitivity to further GCV treatment decreased. Tumor regression following GCV treatment was not observed in nude mice bearing HSV-tk-infected adenocarcinoma cells, MLE-15 and A549. Intratumor injection of HSV-tk producer cells failed to transfer HSV-tk gene to the A549 tumor cells in vivo. The lack of a 'bystander' effect, failure to achieve tumor regression, and loss of GCV sensitivity in some tumors in vivo may limit the utility of HSV-tk for therapy of pulmonary adenocarcinoma.