丹参联合化疗和VEGF靶向药物对结肠癌的协同作用及机制研究

Cancer-associated hypercoagulation is really common in malignancy and directly affects the sensitivity of anticancer drug and the prognosis of patients with cancer. Chemotherapies are prone to deteriorate cancer patients' hypercoagulation. It is hypothesized that anticoagulant herb extracts in combination with chemotherapy and anti-VEGF targeted therapy might alleviate hypercoagulation and result in synergistic effects for treatment of solid tumors. The aim of this study is to investigate and demonstrate the potential synergistic effects and mechanism of anticoagulant herb extracts such as Danshen injection in combination with chemotherapy such as capecitabine and anti-VEGF targeted therapy such as FP3 for treatment of metastatic colon carcinoma using previously established patient-derived tumor tissue (PDTT) xenograft models of primary colon carcinoma and related lymphatic and hepatic metastases and GFP-marked LoVo cell line xenograft model via the methods of fluorescent imaging, fluorescent immunohistochemistry, laser scanning confocal microscope, scanning electron microscope, and pharmacological experiments. The main purpose of this study is to find the optimal "therapy window" and optimal strategy for combination use of anticoagulant herb extracts, chemotherapy and anti-VEGF targeted therapy to provide scientific data of this antitumor strategy, to augment the antitumor effects of Chinese herbal medicine, and to expand the field of clinical applications of anticoagulant herb extracts.

血液高凝是恶性肿瘤微环境的一个普遍现象并且直接影响抗肿瘤药物疗效和患者预后。单纯化疗易恶化肿瘤患者的血液高凝。联合应用活血化瘀中药、化疗和抗VEGF靶向药物可能改善血液高凝并起到协同抗肿瘤作用。本项目选择丹参注射液，卡培他滨及FP3等作为工具药物，利用前期建立的转移性结肠癌患者新鲜肿瘤组织来源（Patient-derived tumor tissue，PDTT）裸鼠移植瘤模型和GFP标记的LoVo细胞株尾静脉注射转移模型，采用荧光显像、免疫荧光、激光共聚焦显微、扫描电镜等技术方法结合动物药效实验,来研究和证明活血化瘀疗法联合化疗及抗VEGF靶向治疗对转移性结肠癌潜在的协同抗肿瘤作用及机制。旨在寻找中药活血化瘀疗法、化疗和抗VEGF靶向治疗联合应用的最佳"治疗时间窗"，寻找三种疗法联合应用的最佳方案，为临床开展活血化瘀中药联合化疗和抗VEGF靶向药物治疗转移性结肠癌提供研究数据和理论依据。

血液高凝是恶性肿瘤微环境的一个普遍现象并且直接影响抗肿瘤药物疗效和患者预后。单纯化疗易恶化肿瘤患者的血液高凝。联合应用活血化瘀中药、化疗和抗VEGF靶向药物可能改善血液高凝并起到协同抗肿瘤作用。项目选择丹参注射液，卡培他滨及FP3等作为工具药物，利用前期建立的结肠癌患者新鲜肿瘤组织来源（Patient-derived tumor tissue，PDTT）裸鼠移植瘤模型开展动物药效实验，来研究和证明活血化瘀疗法联合化疗及抗VEGF靶向治疗对转移性结肠癌潜在的协同抗肿瘤作用及机制。研究成功建立了高度生物学稳定的结肠癌PDX移植瘤模型。研究结果发现FP3具有抑制结肠癌血管生成作用从而抑制肿瘤的生长，而且FP3还能实现对肿瘤血管的“正常化”作用。研究结果初步确定HIF-1α及相关通路可能为FP3的药效预测标志物。研究结果表明FP3、Bevacizumab联合化疗（奥沙利铂、卡培他滨）、丹参注射液对结肠癌PDX移植瘤模型的协同抗肿瘤作用。研究结果表明丹参可能通过改变肿瘤基质成分来实现与化疗和抗血管生成治疗的协同作用。本研究结果初步获得了活血化瘀疗法（丹参注射液）、化疗和抗血管生成靶向治疗联合应用的最佳“治疗时间窗”，获得三种疗法联合应用的最佳方案，为临床开展活血化瘀中药联合化疗和抗VEGF靶向药物治疗转移性结肠癌提供了初步研究数据和理论依据。