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The future success of cancer gene therapy is critically dependent upon the development of safe, practical and effective targeting strategies. In this study, we describe a novel and broadly applicable targeting approach in which the induction of apoptotic tumor cell death is linked to the differential expression within the tumor microenvironment of elevated levels of the pro-angiogenic cytokine vascular endothelial growth factor (VEGF). As VEGF is generally absent or produced at only low levels in most normal tissues, undesirable toxicity will not result even if the therapeutic gene in question is inadvertently expressed in non-targeted tissue sites. The basic approach makes use of a chimeric cell-surface protein in which the membrane-spanning and cytoplasmic ‘death domain’ of the pro-apoptotic protein Fas are fused in frame to the extracellular ligand-binding domain of the VEGF receptor Flk-1/KDR/VEGFR2 (Flk-1/Fas). The resultant chimeric Flk-1/Fas receptor was found to be stable and capable of inducing a rapid apoptotic response when expressed in tumor cells that produce endogenous VEGF. Importantly, in the absence of VEGF, transduced tumor cells remain viable although they can be triggered to die by the addition of recombinant VEGF. Given the key role played by VEGF in tumor development and progression, it is proposed that the Flk-1/Fas chimera may have great potential in the context of tumor cell-targeted cancer gene therapy.Cancer Gene Therapy (2009) 16, 279–290; doi:10.1038/cgt.2008.72; published online 26 September 2008 [ABSTRACT FROM AUTHOR]