| The research presented in this dissertation focuses on the role of angiogenesis in development of ovarian surface epithelial cancer and novel antiangiogenic cancer therapies. This work first investigated 1,4-phenylenebis(methylene)selenocyanate (p-XSC), a novel organoselenium compound, as a possible antiangiogenic agent. Earlier studies showed that p-XSC effectively prevented chemically induced cancers. However, further studies were necessary to evaluate the mechanism of action and potential use of p-XSC as an antiangiogenic agent. Therefore, I investigated the effects of p-XSC on endothelial cell growth in vitro and angiogenesis in vivo. P-XSC inhibited endothelial cell proliferation and induced apoptosis in a concentration-dependent manner. In addition, p-XSC inhibited angiogenesis in multiple in vivo models. This research establishes p-XSC as a useful antiangiogenic agent.; In the second part of this dissertation, I describe studies of the functional role of vascular endothelial growth factor (VEGF) in the development of ovarian cancer. I discovered that over-expression of VEGF165 in a normal rat ovarian surface epithelial cell line (VR) induced both subcutaneous and intraperitoneal tumor formation as well as malignant ascites fluid without altering normal in vitro epithelial cell characteristics. Furthermore, use of antiangiogenic agents targeting VEGF (anti-VEGF antibody) or its receptor tyrosine kinase (SU5416) significantly inhibited tumor growth and prolonged the survival of athymic mice. I also evaluated the effect of combination antiangiogenic and cytotoxic therapies on an additional murine ovarian carcinoma, LM-3. Usage of SU5416 alone showed an increase in survival of immunocompetent mice; however, combination treatment with cytotoxicagents significantly inhibited tumor formation and increased survival time.; Finally, the effects of switching the balance pro-angiogenic and antiangiogenic growth factors expressed by VR cells was studied. Using a tetracycline inducible retroviral expression system, I expressed endostatin by addition of doxycycline. Transduction of endostatin in these cells did not alter their growth in vitro; however, it significantly inhibited VR cell induced angiogenesis in matrigels and tumor formation in athymic mice.; Results obtained from these studies have significant implications for the importance of inhibition of angiogenesis in early stages of tumor initiation as well as the use of antiangiogenic therapy in combination with cytotoxic agents for treatment of ovarian cancer. |
