Suicidal gene therapy for pleural metastasis of lung cancer by liposome-mediated transfer of herpes simplex virus thymidine kinase gene

Abstract

Pleural metastasis is one of the most common complications in lung cancers. However, no effective therapy for pleural metastasis has been established thus far. We have constructed a metastatic model of non-small cell lung cancer (NSCLC) by injecting human NSCLC cell lines directly into the left pleural cavity of BALB/c nude mice. Because this model is easy to construct and the results are reproducible, we used this model for a preclinical evaluation of gene therapy for pleural metastasis of NSCLC. We took the novel approach of in vivo lipofection of a suicidal gene to lung cancer cells metastasized to the pleural cavity. A human lung cancer cell line, PC14, was inoculated into the pleural cavity of nude mice. After 1 day, a herpes simplex virus thymidine kinase gene expression plasmid was injected intrapleurally as a DNA-liposome complex, and ganciclovir was subsequently administered for 8 days. The survival rates of the ganciclovir-treated group were significantly better than those of the control groups. Flow cytometric analysis using a green fluorescent protein expression plasmid suggested that the transfection efficiency in the pleural cavity was 13.6%. Moreover, due to a bystander effect with PC14 cells, 10% of the gene transfer efficiency was sufficient to eradicate or suppress pleural metastasis. This preclinical study suggests the therapeutic feasibility of an in vivo lipofection-based suicidal gene/prodrug strategy for pleural metastasis of NSCLC.