Antiangiogenic
therapies are frequently used with concomitantly administered
cancer chemotherapy to improve outcomes, but the mechanism for the benefit of the combination is uncertain. We describe a mechanism by which a specific, cytotoxic antivascular agent causes
vascular remodeling and improved
chemotherapy results. By selectively killing
tumor neovasculature using short-ranged α-particles targeted to vascular endothelial (
VE)-cadherin on vascular endothelial cells (by use of 225Ac-labeled
E4G10 antibody) we were able both to reduce
tumor growth and to increase the efficacy of
chemotherapy, an effect seen only when the
chemotherapy was administered several days after the vascular targeting agent, but not if the order of administration was reversed. Immunohistochemical and immunofluorescence studies showed that the vasculature of 225Ac-E4G10-treated
tumors was substantially depleted; the remaining vessels appeared more mature morphologically and displayed increased pericyte density and coverage.
Tumor uptake and microdistribution studies with radioactive and fluorescent small molecule drugs showed better accumulation and more homogenous distribution of the drugs within 225Ac-E4G10-treated
tumors. These results show that 225Ac-E4G10 treatment leads to ablation and improvement of the
tumor vascular architecture, and also show that the resulting
vascular remodeling can increase
tumor delivery of small molecules, thus providing a process for the improved outcomes observed after combining antivascular
therapy and
chemotherapy. This study directly shows evidence for what has long been a speculated mechanism for antiangiogenic
therapies. Moreover, targeting the vessel for killing provides an alternative mode of improving
chemotherapy delivery and efficacy, potentially avoiding some of the drawbacks of targeting a highly redundant angiogenic pathway.