OVARIAN CANCER OR PRIMARY PERITONEAL CARCINOMA

点击翻译按钮获取中文摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. There is accumulating evidence that angiogenesis plays a central role in ovarian cancer (7,8,), but the impact of angiogenic activity on clinical outcomes for patients with ovarian cancer has yet to be convincingly determined. However, several historical cohort studies have suggested a negative prognostic relationship (4, 9-11). For example, Gasparini et al. recently reported on 60 women with advanced (FIGO stage III and IV) ovarian carcinoma treated with standard surgery and chemotherapy, in which MVD was determined by quantitative immunohistochemistry (IHC) for the expression of CD31, an endothelial antigen. They demonstrated that CD31 expression was a negative prognostic factor for survival.(4) The same association was demonstrated by Hollingsworth et al. in their study of CD31 expression by quantitative IHC in 43 similar patients. (9) Mean MVD was independently prognostic for poor survival by multivariate analysis. In addition tousing immunohistochemistry (IHC) to identifyspecific proteins known to participate in angiogenesis, intratumoral angiogenesis may be evaluated through analysis of tumor micro-vessel density (MVD) determined by IHC using antibodies to CD31 CD105, and VCAM-I. CD-MRI studies have also been used to examine the relationship between CD-MRI-derived characteristics and both tumor MVD and VEGF expression, from cancers of the uterine cervix.(12-16) Pharmacokinetic parameters (amplitude, A; exchange rate constant, k21), calculated from CD-MRI were directly associated with MVD in primary tumors treated by radical hysterectomy. However, no significant associations were found between the pharmacokinetic parameters (A, k21) and VEGF expression. Interestingly, k21 was shown to be a significant predictor of poor patient survival.(12,13,16) It should be noted that a small DTPA (0.5 kD) was used in these studies. Given that a direct relationship has been demonstrated between the expression of biomarkers of angiogenesis and the biologic behavior of EOC, it would seem implicit that pharmacological inhibitors of angiogenesis could arrest tumor progression.(17- 20) Indeed, active inhibitors of tumor angiogenesis have been identified based on in vitro and pre-clinical cytostatic activity.(21-31) Neutralizing anti-VEGF monoclonal antibodies have demonstrated therapeutic activity in a variety of preclinical solid tumor models.(32,33) Bevacizumab is a recombinant humanized version of a murine anti-human VEGF monoclonal antibody, named rhuMAb VEGF. Bevacizumab has been advanced into clinical development by Genentech, Inc. for use as a single agent to induce tumor growth inhibition in patients with solid tumors and for use in combination with cytotoxic chemotherapy to delay the time to disease progression in patients with metastatic solid tumors. Inhibition of VEGF using this anti-VEGF monoclonal antibody blocks the growth of a number of human cancer cell lines in nude mice by interfering with endothelial cell proliferation and neovascularization required for the continued growth of tumors.(34) This pathway seems to be important in ovarian cancer progression and metastasis. Both preclinical and clinical studies have been completed to evaluate the safety, maximally tolerated dose (MTD) and pharmacokinetics of Bevacizumab.