This study was designed to determine the effects of
vandetanib, a small-molecule
receptor tyrosine kinase inhibitor of
vascular endothelial growth factor and
epidermal growth factor receptor, on
paclitaxel (PTX)
tumor distribution and antitumor activity in xenograft models of human ovarian
carcinoma. Nude mice bearing A2780-1A9 xenografts received daily (5, 10, or 15 days) doses of
vandetanib (50 mg/kg per os), combined with PTX (20 mg/kg intravenously). Morphologic and functional modifications associated with the
tumor vasculature (CD31 and alpha-smooth muscle actin staining and
Hoechst 33342 perfusion) and PTX concentrations in plasma and
tumor tissues were analyzed. Activity was evaluated as inhibition of
tumor growth subcutaneously and spreading into the peritoneal cavity.
Vandetanib treatment produced no significant change in
tumor vessel density, although a reduced number of large vessels, an increased percentage of mature vessels, and diminished
tumor perfusion were evident. Pretreatment with
vandetanib led to decreased
tumor PTX levels within 1 hour of PTX injection, although 24 hours later,
tumor PTX levels were comparable with controls. In efficacy studies, the combination of
vandetanib plus PTX improved antitumor activity compared with
vandetanib or PTX alone, with greater effects being obtained when PTX was administered before
vandetanib. The combination of PTX plus
vandetanib reduced
tumor burden in the peritoneal cavity of mice and significantly increased their survival. Analysis of vascular changes and PTX
tumor uptake in
vandetanib-treated
tumors may help to guide the scheduling of
vandetanib plus PTX combinations and may have implications for the design of clinical trials with these drugs.