Expression of thymidine kinase driven by an endothelial-specific promoter inhibits tumor growth of Lewis lung carcinoma cells in transgenic mice

The possibility of inhibiting tumor growth by limiting angiogenesis has raised considerable interest. In this study, we examined the feasibility of inhibiting tumor growth by targeting a suicide gene in the endothelium. Toxicity must be directed solely to angiogenic cells. Therefore, we used the herpes simplex virus-thymidine kinase (TK) gene, in combination with the prodrug ganciclovir (GCV), which affects replicative cells. To test this strategy, we produced transgenic mice carrying the TK gene driven by the vascular endothelial (VE)-cadherin promoter. Lewis lung carcinoma cells were injected subcutaneously to establish tumors and to test the effect of GCV on tumor growth. In two independent transgenic lines, GCV treatment (75 mg/kg/day) resulted in a 66-71% reduction of tumor volume at day 20 postimplantation compared to wild-type mice (650 and 550 versus 1930 mm(3), P<0.02 and 0.01, respectively), whereas no significant difference was observed when vehicle alone was injected. Tumor growth inhibition was accompanied by a marked reduction in tumor vascular density (151 versus 276 vessels/mm(2), P<0.05) and an increase in tumor cell death, suggesting that tumor growth inhibition was caused by a reduction in tumor angiogenesis. Our data support the potential utility of endothelial targeting of suicide genes in cancer therapy.