Acquired drug resistance to chemotherapy is a major problem in the treatment of cancer. After primary surgical intervention, followed by chemotherapy treatments, the majority of patients develop disease recurrence. This is due to tumor cell heterogeneity and genetic instability. In contrast to tumor cells, proliferating host endothelial cells (ECs) are genetically stable and have a low mutational rate. Furthermore, tumor angiogenesis plays an important role in tumor development, vascular invasion and hematogenous metastasis. Thus, anti-angiogenic therapy directed against tumor ECs should, in principle, improve the efficacy of antitumor therapy by inducing little or no drug resistance. We review different therapeutic approaches directed against tumor angiogenesis, showing potent antitumor activity in vitro and in vivo. These strategies involve the inhibition of the expression of proangiogenic molecules, as well as the overexpression of anti-angiogenic molecules by either injection of recombinant proteins or transfer of genes encoding anti-angiogenic molecules. The gene therapy approach based on the gene-directed enzyme prodrug therapy (GDEPT) system, as well as the use of endothelial progenitor cells (EPCs) as angiogenesis-selective gene-targeting vectors, will be further discussed.

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