Chemotherapy-induced surge in endothelial precursor cells: Implications for antiangiogenic drugs as chemosensitizing agents

Abstract

1120

The approval of the antiangiogenic VEGF targeting drug bevacizumab for the treatment of colorectal and lung cancers was based on its ability to enhance the efficacy of conventional maximum tolerated dose (MTD) chemotherapy regimens involving drugs such as 5-FU, irinotecan, carboplatin and paclitaxel, among others, commonly used to treat such cancers. Several hypotheses have been proposed to explain such a ‘chemosensitization’ effect including slowing tumor regrowth between successive cycles of chemotherapies. Here we present preclinical evidence implicating a way how this may occur, namely by blocking chemotherapy-induced mobilization of bone marrow derived circulating endothelial cells (CEPs) and their subsequent homing to the drug treated tumors. Certain drugs, e.g. paclitaxel, were found to be potent inducers of CEP mobilization whereas others, e.g. gemcitabine were not. Evidence of CEP mobilization, observed within 4 hours, was mediated, at least in part, by induction of SDF-1 and could be prevented by pretreatment with an anti-VEGFR2 blocking antibody (DC101). Further support for this concept comes from studies with chemotherapy treatment in CEP-deficient Id mutant mice. Both approaches revealed increased anti-tumor effects of paclitaxel, but not gemcitabine. Evidence for acute CEP mobilization was also observed in patients treated with taxanes but not with other forms of chemotherapy. The results provide evidence for a novel paradigm to explain why some chemotherapy drugs, but not others, may have greater anti-tumor activity when combined with a VEGF pathway targeting drug.