Limitations of Retrovirus-Mediated HSV-tk Gene Transfer to Pulmonary Adenocarcinoma Cells In Vitro and In Vivo

Abstract

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.

Overview summary

The efficacy of retrovirus-mediated gene transfer of herpes simplex virus thymidine kinase (HSV-tk) genes in treating lung adenocarcinomas has been evaluated in vitro and in vivo. Successful HSV-tk gene transfer to pulmonary adenocarcinomas cells and cooperative tumoricidal activity by GCV were achieved in vitro. However, escape of residual tumors from GCV cytotoxicity, insignificant gene transfer by retroviral producer cells, and ineffectiveness of the bystander effect were observed in vivo.