Vascular Endothelial Growth Factor (
VEGF) functions as a key regulator in
tumor angiogenesis. In addition,
VEGF is an important survival factor for endothelial cells under chemical or physical stress. In our report, we show that treatment of endothelial cells with the chemotherapeutic agent
carboplatin significantly increased the expression of
VEGF. Furthermore, neutralization of secreted
VEGF with specific polyclonal anti-
VEGF antibodies or
monoclonal antibody sensitized endothelial cells to
carboplatin treatment and increased apoptosis several-fold. Interestingly,
carboplatin treatment did not alter
VEGF expression in
tumor cells. Similarly, antibody to
VEGF did not change the chemosensitivity of
tumor cells to this drug. Most importantly,
tumor-bearing animals treated with
carboplatin showed an increase in
VEGF immunoreactivity in the
tumor vasculature, confirming the in vitro studies. Based on these observations, we determined whether neutralization of
VEGF could enhance the anti-
tumor activity of
carboplatin in an in vivo
ovarian cancer model system. A combination
therapy consisting of a suboptimal dose of
carboplatin (32.5 mg/kg/inj., q3d x 5; i.p.) and polyclonal anti-
VEGF antibody (2 mg/inj., q3d x 10; i.p.) significantly enhanced solid
tumor growth inhibition over individual monotherapies and included multiple complete responses. These findings suggest that
VEGF is a critical endothelial cell specific survival factor that is induced by
carboplatin and contributes to the protection of
tumor vasculature during
chemotherapy treatment. In addition, these results provide evidence for a potential mechanism that underlies enhanced anti-
tumor activity achieved with
chemotherapy and anti-
VEGF antibody combination treatment regimens as recently reported in a number of clinical trials. We conclude that a similar type of combination
therapy may be applicable to many types of
malignancies since
VEGF expression was differentially induced in the
tumor host environment (i.e.,
tumor vasculature) and not in the
tumor cells themselves; hence, this phenomenon may be independent of the type and origin of the primary
cancer.