Tumor cells are elusive targets for standard anticancer
chemotherapy due to their heterogeneity and genetic instability. On the other hand, proliferating host endothelial cells (ECs) are genetically stable and have a low mutational rate. Thus, antiangiogenic
therapy directed against
tumor's ECs should, in principle, improve the efficacy of antitumor
therapy by inducing little or no drug resistance. Here we present a gene-directed
enzyme prodrug therapy (GDEPT) strategy for targeting the
tumor vasculature, using the Escherichia coli
nitroreductase (ntr) gene delivery associated with the treatment with the
prodrug CB1954. In a first time we demonstrated the ability of the ntr/
CB1954 system to induce an apoptotic-mediated cell death on monolayer cultures of human umbilical vein ECs (HUV-EC-C). Then, when ntr-transfected HUV-EC-C cells (HUV-EC-C/ntr(+)) were associated in a three-dimensional (3-D) multicellular nodule model with untransfected B16-F10 murine
melanoma cell line, we observed a CB1954-mediated bystander cell killing effect from endothelial to neighboring
melanoma cells. To our knowledge, this is the first report indicating that GDEPT-based antiangiogenic targeting may be an effective approach for
cancer treatment relied on the spreading of the bystander effect from endothelial to
tumor cells.