Bevacizumab-induced inhibition of angiogenesis promotes a more homogeneous intratumoral distribution of paclitaxel, improving the antitumor response
Menée à l'aide de xénogreffes sur des modèles murins, cette étude met en évidence des mécanismes par lesquels, en modifiant l'architecture vasculaire du microenvironnement tumoral, le bévacizumab favorise une distribution intratumorale homogène du paclitaxel et, ainsi, renforce son efficacité
The antitumor activity of angiogenesis inhibitors is reinforced in combination with chemotherapy. It is debated whether this potentiation is related to a better drug delivery to the tumor due to the antiangiogenic effects on tumor vessel phenotype and functionality. We addressed this question by combining bevacizumab with paclitaxel (PTX) on A2780-1A9 ovarian carcinoma and HT-29 colon carcinoma transplanted ectopically in the subcutis of nude mice and on A2780-1A9 and IGROV1 ovarian carcinoma transplanted orthotopically in the bursa of the mouse ovary. PTX concentrations together with its distribution by MALDI mass spectrometry imaging (MALDI MSI), were measured to determine the drug in different areas of the tumor, which are immunostained to depict vessel morphology and tumor proliferation. Bevacizumab modified the vessel bed, assessed by CD31 staining and dynamic contrast enhanced MRI (DCE-MRI), and potentiated the antitumor activity of PTX in all the models. Although tumor PTX concentrations were lower after bevacizumab, the drug distributed more homogeneously, particularly in vascularized, non-necrotic areas, and was cleared more slowly than controls. This happened specifically in tumor tissue, as there was no change in PTX pharmacokinetics or drug distribution in normal tissues. In addition the drug concentration and distribution were not influenced by the site of tumor growth, as A2780-1A9 and IGROV1 growing in the ovary gave results similar to the tumor growing subcutaneously. We suggest that the changes in the tumor microenvironment architecture induced by bevacizumab, together with the better distribution of PTX may explain the significant antitumor potentiation by the combination.
http://mct.aacrjournals.org/content/early/2015/10/21/1535-7163.MCT-15-0063.abstract