OVARIAN CANCER OR PRIMARY PERITONEAL CARCINOMA

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 有越来越多的证据表明，血管生成在卵巢癌中起着核心作用(7，8，)，但血管生成活动对卵巢癌患者临床结果的影响尚未令人信服地确定。然而，几项历史队列研究表明，预后与预后呈负相关(4，9-11)。例如，Gasparini等人。最近报道了60例晚期(FIGO分期III、IV期)卵巢癌患者接受标准手术和化疗，其中微血管密度(MVD)采用定量免疫组织化学方法(IHC)检测内皮细胞抗原CD31的表达。他们证明CD31的表达是生存的负面预后因素。(4)Hollingsworth等人证实了同样的相关性。在他们对43例相似患者的CD31表达的定量免疫组化研究中。(9)多因素分析显示，平均MVD是预后不良的独立危险因素。 此外，还利用免疫组织化学(IHC)来鉴定已知的特定蛋白 在参与血管生成方面，可通过免疫组织化学检测肿瘤微血管密度(MVD)来评估肿瘤内血管生成。CD-MRI还研究了宫颈癌的CD-MRI特征与肿瘤微血管密度和血管内皮生长因子表达的关系。(12-16)CD-MRI计算的药代动力学参数(振幅，A；汇率常数，K21)与根治性子宫切除治疗的原发肿瘤的微血管密度直接相关。然而，未发现药代动力学参数(A、K21)与血管内皮生长因子表达之间的显著关联。有趣的是，K21被证明是患者生存不良的重要预测因子。(12，13，16)应该注意，在这些研究中使用了小的DTPA(0.5kD)。 鉴于血管生成生物标记物的表达与卵巢上皮性癌的生物学行为之间的直接关系，似乎隐含着血管生成的药物抑制物可以阻止肿瘤的进展。(17-20)事实上，基于体外和临床前的细胞抑制活性，已经确定了肿瘤血管生成的活性抑制物。(21-31)中和抗血管内皮生长因子的单抗已经显示出治疗活性 在各种临床前实体瘤模型中。(32，33)贝伐单抗是一种重组人源化版本的鼠抗人血管内皮生长因子单抗，命名为rhuMAb血管内皮生长因子。Genentech公司已将贝伐单抗推向临床开发，用于作为单一药物在实体肿瘤患者中诱导肿瘤生长抑制，并与细胞毒性化疗联合使用，以延缓转移性实体肿瘤患者的病情进展。 使用这种抗血管内皮生长因子的单抗抑制血管内皮生长因子，通过干扰肿瘤持续生长所需的内皮细胞增殖和新生血管，在裸鼠体内阻断一些人类癌细胞株的生长。(34)这一途径似乎在卵巢癌的进展和转移中很重要。临床前和临床研究已经完成，以评估贝伐单抗的安全性、最大耐受量(MTD)和药代动力学。

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.