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 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.
Paclitaxel 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 was 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
paclitaxel in all the models. Although
tumor paclitaxel 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
paclitaxel 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
paclitaxel, may explain the significant antitumor potentiation by the combination.