【作者】 李勇；

【导师】 郭志；

【作者基本信息】 天津医科大学 ， 肿瘤学（专业学位）， 2011， 博士

【摘要】 背景：冷冻消融逐渐成为治疗局限性前列腺癌的一线治疗手段,对于残存肿瘤血管生成活性的研究可以解释临床常见的实际问题。目的：复制激素难治性前列腺癌肺转移模型,评价冷冻消融治疗前列腺癌移植瘤后残存前列腺癌组织的血管生成活性,探讨联合治疗的可行性与必要性。并建立数学模型计划系统,服务于临床实际。材料与方法：通过表达谱基因芯片研究及荧光定量PCR研究,获得冷冻消融后残存瘤体m-RNA表达的差异。并使用双向电泳蛋白质谱分析手段验证蛋白表达的变化。在此基础之上利用免疫组化方法动态检测冷冻治疗术后相关蛋白空间与时间的变化特点。设立新的实验分组,研究氩氦冷冻消融联合抗血管内皮药物YH-16的联合治疗策略所产生的影响,以所得结果构建数学模型及靶向计划程序,获得完整的治疗计划及预后评测系统,直接辅助临床工作。结果：1)基因表达谱芯片筛选结果提示肿瘤细胞凋亡、血管生成及肿瘤细胞侵袭增殖能力变化等过程具有显著性差异。2)荧光定量PCR证实筛选出的HIF-1α, VEGFA, MMP2, Caspase3及Caspase6均出现了显著性变化。3)二维双向电泳技术蛋白质谱分析进一步验证了基因表达谱芯片及荧光定量PCR的研究结果。4)对于VEGF、MMP2及MVD时间分布的研究结果证实了冷冻消融后,随着时间推移,与血管生成活性相关的蛋白指标呈现显著增长,其可以为YH-16联合治疗策略所有效阻断,提示在冷冻消融治疗的基础上,联合抗血管生成靶向药物治疗,可能获得较好的治疗收益。对于VEGF、MMP2、MVD及Caspase3空间分布的研究结果说明了,血管生成增强剂凋亡增加在冷冻消融治疗后的残存前列腺癌组织中同时存在,但空间分布呈现互补态势。5)本研究在合理假设的前提基础上,成功地建立了数学模型靶向计划实验系统,以此系统为蓝本的初步临床实验,在相关性回归分析的方法中,确立了重要的模型参数,其使得数学模型靶向计划实验系统与临床表现具有较高的一致性。结论：冷冻消融治疗后,残存前列腺癌组织以血管生成活性为代表的生物学行为特征发生了复杂的改变,血管生成活性分布具有空间特征,联合抗血管生成治疗可能成为可选择的治疗策略。建立的数学模型靶向计划实验系统,可以为临床工作提供辅助性技术理论平台。更多还原

【Abstract】 Background:Cryoablation has become primary treatment of localized prostate cancer treatment, the residual activity of tumor angiogenesis may explain common clinical practice problems. Objective:To copy the hormone refractory prostate cancer lung metastasis model to evaluate cryoablation of surviving prostate cancer tumor angiogenesis in prostate cancer activity, explore the feasibility and necessity of combination therapy. Planning system and the establishment of mathematical models, services in clinical practice. Materials and Methods:The expression profiles by cDNA microarray and quantitative PCR studies, access to residual tumor after cryoablation m-RNA expression differences. And use the means of two-dimensional electrophoresis proteomic analysis of protein expression changes verified. On this basis, the dynamic use of immunohistochemical detection of proteins after cryoablation, the changes of space and time. Establishment of a new group to study the argon-helium cryoablation combined vascular endothelial drugs YH-16combined impact of treatment strategies to build mathematical models and the results of targeted planning process, a complete treatment plan and prognosis evaluation system, direct support of clinical work. Results:1) gene chip screening results suggest that tumor cell apoptosis, angiogenesis and proliferation of tumor cell invasion process of change, significant differences.2) The fluorescence quantitative PCR screening confirmed the HIF-1α, VEGFA, MMP2, Caspase3and Caspase6there were significant changes.3) two-dimensional spectral analysis of two-dimensional electrophoresis technology to further validate the protein microarray and quantitative PCR results.4) For VEGF, MMP2and temporal distribution of MVD confirmed the findings after cryoablation, as time goes on, and angiogenesis activity of protein targets associated with significant growth, which can be as YH-16combined treatment strategies are effective in blocking, Tip cryoablation, based on the joint anti-angiogenic targeted drug therapy may be a better therapeutic gains. For VEGF, MMP2, MVD, and the spatial distribution of Caspase3results suggest that angiogenesis enhancer increased apoptosis after the frozen remnant ablation therapy in prostate cancer exist, but a complementary distribution trend.5) In this study, based on the premise of reasonable assumptions, the mathematical model successfully established experimental system targeted programs, this system is modeled on the initial clinical trials, the relevance of the method of regression analysis to establish an important model parameters The mathematical model makes the targeted programs and clinical manifestations of experimental system has a higher consistency. Conclusion:Cryoablation treatment, residual prostate cancer to angiogenic activity represented characteristics of the biological behavior of complex changes have taken place, angiogenesis activity of distribution of spatial characteristics, combined anti-angiogenesis therapy might be alternative treatment strategies. Targeted programs established mathematical model experimental system for providing assistive technology clinical theory of platform.更多还原