Abstract
In solid tumors, angiogenesis occurs in the setting of a defective vasculature and impaired lymphatic drainage that is associated with increased vascular permeability and enhanced tumor permeability. These universal aspects of the tumor microenvironment can have a marked influence on intratumoral drug delivery that may often be underappreciated. In this study, we investigated the effect of blood vessel normalization in tumors by the antiangiogenic drug bevacizumab on antibody uptake by tumors. In mouse xenograft models of human ovarian and esophageal cancer (SKOV-3 and OE19), we evaluated antibody uptake in tumors by positron emission tomographic imaging 24 and 144 hours after injection of (89)Zr-trastuzumab (SKOV-3 and OE19), (89)Zr-bevacizumab (SKOV-3), or (89)Zr-IgG (SKOV-3) before or after treatment with bevacizumab. Intratumor distribution was assessed by fluorescence microscopy along with mean vessel density (MVD) and vessel normalization. Notably, bevacizumab treatment decreased tumor uptake and intratumoral accumulation compared with baseline in the tumor models relative to controls. Bevacizumab treatment also reduced MVD in tumors and increased vessel pericyte coverage. These findings are clinically important, suggesting caution in designing combinatorial trials with therapeutic antibodies due to a possible reduction in tumoral accumulation that may be caused by bevacizumab cotreatment.
Highlights
Angiogenesis, the formation of new blood vessels, is one of the hallmarks of cancer and is an anticancer drug target [1, 2]
We evaluated the effect of bevacizumab treatment on the tumor uptake of 89Zr-trastuzumab, 89Zr-bevacizumab, and 89Zr-immunoglobulin G (IgG)
This study shows that bevacizumab treatment substantially reduces the tumor uptake of the antibodies trastuzumab, bevacizumab, and IgG
Summary
Angiogenesis, the formation of new blood vessels, is one of the hallmarks of cancer and is an anticancer drug target [1, 2]. Extensive angiogenesis is accompanied by defective vascular architecture, leading to increased vascular permeability, hypoxia, low pH, and high interstitial fluid pressure. Several preclinical and clinical studies indicate that antiangiogenic drugs, including the anti-VEGF-A antibody bevacizumab, lead to vessel normalization in addition to their antivascular effect. Major characteristics of vessel normalization include reduced number and size of immature vessels, increased vessel pericyte coverage, and reduced interstitial fluid pressure [3, 4]. Normal (or normalized) blood vessels are lined with pericytes. This lining is absent in the abnormal, immature vessels created during tumor angiogenesis, which can cause increased leakiness [5]
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