Ovarian cancer is the leading cause of death from gynecologic
cancer. Often, the disease has spread beyond the ovary to involve the peritoneal cavity and causes
ascites. Whereas
mammalian target of rapamycin (mTOR) functions to regulate protein translation, cell cycle progression, and
metastasis,
vascular endothelial growth factor promotes
tumor angiogenesis,
ascites formation, and
metastasis in
ovarian cancer. In this study, an i.p. model of human
ovarian cancer was used to determine the antitumor activity of
rapamycin,
bevacizumab, and
rapamycin plus
bevacizumab (BEV/RAPA). We report that administration of
rapamycin,
bevacizumab, and BEV/RAPA in mice bearing peritoneal OV-90 ovarian
carcinoma resulted in 74.6%, 82.4%, and 93.3% reduction in i.p.
tumor burden, respectively. BEV/RAPA-induced reduction in microvessel density and inhibition of cell proliferation were associated with significant reduction in
hypoxia-inducible factor-1alpha and
cyclin D1 and inactivation of downstream targets of mTOR, p70S6
kinase, S6R, and 4E-binding
protein 1. BEV/RAPA treatment was not only able to prolong life of i.p. mice but also more effective than
rapamycin and
bevacizumab to prevent the development of
peritoneal carcinomatosis in adjuvant setting and reverse
ascites accumulation in heavy
peritoneal disease. Our data indicate that simultaneous inhibition of the
vascular endothelial growth factor receptor and mTOR pathways with BEV/RAPA or their analogues may represent a novel approach for prevention of
metastasis, recurrence, and treatment of
ovarian cancer.