Endostar联合放疗对肺肿瘤血管“正常化”及能量代谢影响的机制研究

Lung cancer is a malignant disease with high rate of fatality. The effect of radiation therapy alone is unsatisfactory, scholars of domestic and foreign try to research and develop the radiosensitization drugs to improve the efficacy of radiotherapy.Our pilot study confirmed that the recombinant human endostatin combined with radiotherapy has a synergistic effect ,and the mechanisms have been preliminary studied, Which still no complete theoretical system at home and abroad to elaborate it，So far. This confused us in the clinical application and promotion for endostar combined with radiotherapy. We hypothesized that: Endostar make tumor vascular structure and function "normalization" ,improving acidosis and hypoxia of micro-environment, achieving the goal of increasing radiation sensitivity.The project intends to apply technology of three-dimensional cell culture, confocal microscopy, vascular ultrasound contrast micro-PET/CT, phosphorescence quenching, quantum dots, RT-PCR, western blot and so on for further exploring the Endostar combined with radiotherapy on the impact in angiogenesis, vascular morphology, hemodynamics, oxygen content, the hydraulic pressure of the tissue space and energy metabolism for Lung adenocarcinoma cells and tissues from molecular, cellular and tissue level. analyzing the role from various factors in order to discover whether there is tumor vascular "normalization" and "normalization window" in the treatment of lung cancer. To provide a theoretical basis for clinical use.

肺癌是一个致死率极高的恶性疾病,单纯放射治疗的效果并不理想,国内外学者试图研发放疗增敏药物来提高肿瘤放疗的疗效。我们前期研究证实了重组人血管内皮抑素(Endostar)联合放疗具有协同作用,并对其机制进行了初步研究。但至今国内外仍无完整的理论体系来阐述其联合作用的机制,我们提出假说:Endostar使肿瘤血管结构及功能"正常化"，改善酸中毒及乏氧，达到放疗增敏。本项目拟应用三维细胞培养、共聚焦显微镜、血管超声造影、micro-PET/CT、磷光淬冷、量子点等技术,从分子、细胞及组织水平,进一步探讨Endostar与放疗联用对肺腺癌细胞和组织血管形成、血管形态、血流动力学、氧含量、组织间隙液压及细胞能量代谢的影响,从多方面分析各种因素在这种协同效应中所起的作用,以期发现在肺癌治疗中Endostar联合放疗是否存在肿瘤血管"正常化"及其"时间窗",并探讨其最佳联用方式,为临床使用提供理论依据。

本课题采用共聚焦显微镜、血管超声造影、量子点等技术,从分子、细胞及组织水平,进一步探讨Endostar与放疗联用对肺腺癌细胞和组织血管形成、血管形态、血流动力学、氧含量及细胞能量代谢的影响。细胞实验证明了Endostar联合放疗能够抑制肺腺癌A549细胞增殖，促进其凋亡，其协同作用机制可能是通过抑制HIF-1、VEGF、肿瘤细胞糖酵解来实现的。动物实验证明了Endostar联合放疗能够抑制肿瘤增长，其机制可能通过抑制的HIF-1、VEGF、肿瘤细胞糖酵解、血管生成实现的。另外随着移植瘤小鼠的生长，由于恩度的作用，肿瘤血管形态逐渐变得规则与完整，酸中毒和乏氧情况改善，出现血管相对正常的一段时间，恩度使肿瘤血管出现“正常化”的时间窗口时间点为d5-d9天之间。