How avastin potentiates chemotherapeutic drugs: Action and reaction in antiangiogenic therapy

At first glance, the antiangiogenic drug Avastin (bevacizumab) must paradoxically normalize angiogenesis, in order to potentiate chemotherapy. However, this may be only a part of the story. Here I discuss that the synergy between Avastin and chemotherapy is also consistent with the classic notion that antiangiogenic therapy actually inhibits angiogenesis. It has been previously predicted that inhibition of angiogenesis (action) will induce a reactive resistance (reaction), which is mediated by the HIF-1/VEGF pathway in cancer cells, thus allowing both endothelial and cancer cells to resist therapy. Therefore, inhibitors of the reactive resistance are needed to potentiate anti-angiogenic therapy. In the combination of chemotherapy plus Avastin, it is chemotherapy that is the principal antiangiogenic agent. This role of chemotherapy requires that something should be added to block the reaction. And this is exactly what Avastin does (by blocking VEGF). While chemotherapy inhibits angiogenesis, Avastin abrogates the reactive resistance, sensitizing both endothelial and cancer cells to therapy.