The purpose of this study was to examine the therapeutic efficacy and underlying mechanisms of action of a vascular-disrupting agent,
AVE8062, and to determine its effects on
tumor metabolic activity. The in vitro and in vivo effects of
AVE8062 alone and in combination with
docetaxel were tested in
chemotherapy-sensitive and
chemotherapy-resistant
ovarian cancer models.
Tumors were analyzed for
necrosis, microvessel density, endothelial cell apoptosis, and proliferation following treatment. The effect of
AVE8062 on
tumor regression and metabolic activity was examined by magnetic resonance (MR) or by [
18F]fluorodeoxyglucose ([18F]FDG) uptake by positron emission tomography (PET) with MR imaging, respectively.
AVE8062 monotherapy was effective in inhibiting
tumor growth in all models (range 43-51% versus control; P < 0.05). Combination
therapy was even more effective in inhibiting
tumor growth (range 76-90% compared with controls, P < 0.01).
AVE8062 in combination with
chemotherapy significantly prolonged survival in HeyA8-injected mice (P < 0.001) compared with other groups. AVE8062-based
therapy resulted in rapid development of central
tumor necrosis, decreased microvessel density, decreased proliferation, and induction of apoptosis of
tumor-associated endothelial cells. MR imaging showed regression of established HeyA8 ovarian
tumors and [18F]FDG PET with MR showed rapid decrease in metabolic activity after
AVE8062 therapy. Combination of
AVE8062 plus
docetaxel results in potent inhibition of
ovarian cancer growth. These results suggest that
AVE8062 may be useful as a clinical therapeutic approach for
ovarian cancer patients and that functional [18F]FDG PET imaging may predict clinical response before an anatomic reduction in
tumor size.