| Anti-angiogenic therapies are frequently used with concomitantly administered cancer chemotherapy to improve outcomes, but the mechanism for the benefit of the combination is uncertain. There has been little direct evidence for pharmacokinetic changes in chemotherapy drugs resulting from anti-angiogenic agents. We describe a novel mechanism by which a specific, cytotoxic anti-vascular agent causes vascular remodeling and improved chemotherapy results. By selectively killing tumor neovasculature using short-ranged alpha particles targeted to VE-cadherin on vascular endothelial cells (by use of 225Ac-labeled E4G10 antibody) we were able to both reduce tumor growth and to increase the efficacy of chemotherapy, an effect that was 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, and that the remaining vessels appeared more mature as evidenced by morphological changes and increased pericyte density and coverage. Tumor uptake and micro-distribution 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 not only that 225Ac-E4G10 treatment leads to ablation and improvement of the tumor vascular architecture, but also demonstrate that the resulting vascular remodeling can increase tumor delivery of small molecules, thus providing a mechanism for the improved outcomes observed after combining anti-vascular therapy and chemotherapy. The data further underline the importance of anti-vascular and anti-angiogenic drug scheduling when designing clinical trials. |
