ercept Exerts Antivascular Effects and Enhances Levels nthracycline Chemotherapy In vivo in Human

ownload examined whether potent vascular endothelial growth factor (VEGF) blockade mediated by aflibercept, y VEGF receptor (VEGFR) 1/2 moiety with stronger affinity for VEGF than bevacizumab, resulted in kemia effects and enhanced the efficacy of systemic chemotherapy. The efficacy of aflibercept alone combination with doxorubicin was evaluated in human VEGF-expressing acute myeloid leukemia ) cell lines and primary cells xenotransplanted into immunodeficient mice. Aflibercept reduced primary /VEGFR-positive AML colony formation growth in vitro and inhibited AML xenograft growth up to association with antiangiogenic and antiproliferative effects, hypoxia, and VEGF sequestration in mulodels. High VEGF-A expression by AML cells promoted in vivo xenograft growth and aflibercept sen. Aflibercept therapy slowed disease progression in two systemic human AML xenograft models and d peripheral leukemia disease in a primary relapsed AML model in NOD/SCID/IL2Rγnull mice. ination aflibercept and doxorubicin enhanced antitumor effects in local xenograft models. Sequential cept followed by doxorubicin resulted in progressive anthracycline accumulation in marrow and exdullary AML sites and resulted in 2-fold higher drug levels 24 hours after administration. In contrast, (tumor, plasma, marrow) treated with chemotherapy only showed progressive drug clearance over ombination aflibercept and doxorubicin also resulted in vascular narrowing, decreased vessel number, erivascular apoptosis. These data suggest that inefficient drug delivery by leukemia-associated vascuand p lature may mediate chemoresistance and support further clinical evaluation of combination aflibercept and anthracycline therapy in refractory/relapsed AML patients. Mol Cancer Ther; 9(10); 2737–51. ©2010 AACR.