Isotope Application Division, Institute of Nuclear Energy Research, 1000 Wenhua Rd. Jiaan Village, Longtan District, Taoyuan City 32546, Taiwan.
Division of Colorectal Surgery, Chen-Hsin General Hospital, Taipei, Taiwan; Department of Healthcare Information and Management, Ming Chuan University, Taoyuan, Taiwan.
Photodiagnosis Photodyn Ther. 2018 Sep;23:111-118. doi: 10.1016/j.pdpdt.2018.06.008. Epub 2018 Jun 9.
Photodynamic therapy (PDT) is a treatment utilizing the combined action of photosensitizers and light for the treatment of various cancers. The mechanisms for tumor destruction after PDT include direct tumor cell kill by singlet oxygen species (OS), indirect cell kill via vascular damage, and an elicited immune response. However, it has been reported that many cellular activators, including vascular endothelial growth factor (VEGF), are produced by tumor cells after PDT. In this study, we demonstrate that meta-tetra(hydroxyphenyl) chlorin (mTHPC)-based photodynamic therapy combined with bevacizumab (Avastin™), an anti-VEGF neutralizing monoclonal antibody that blocks the binding of VEGF to its receptor, can enhance the effectiveness of each treatment modality. We evaluated the efficacy of bevacizumab-based anti-angiogenesis in combination with PDT as well as the resulting VEGF levels and microvessel density (MVD) in a mouse model of human colon cancer. Enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) were performed to assess VEGF concentrations and microvessel density in the various treatment groups, and confocal imaging and high performance liquid chromatography (HPLC) analyses were used to measure the distribution and concentration of mTHPC in tumors. Our results demonstrate that combination of PDT followed by bevacizumab significantly elicits a greater tumor response whereas bevacizumab treatment prior to PDT led to a reduced tumor response. Immunostaining and ELISA analyses revealed a lower expression of VEGF in tumors treated with combination therapy of PDT followed by bevacizumab. However, bevacizumab treatment decreased the accumulation of mTHPC in tumors 24 h after administration, which complemented the results of decreased anti-tumor efficacy of bevacizumab followed by PDT.
光动力疗法（PDT）是一种利用光敏剂和光联合作用治疗各种癌症的治疗方法。PDT 后肿瘤破坏的机制包括单线态氧（OS）直接杀死肿瘤细胞、通过血管损伤间接杀死细胞以及引发免疫反应。然而，据报道，许多细胞激活剂，包括血管内皮生长因子（VEGF），在 PDT 后由肿瘤细胞产生。在本研究中，我们证明了基于间四（羟基苯基）氯（mTHPC）的光动力疗法与贝伐单抗（Avastin™）联合使用，贝伐单抗是一种抗 VEGF 的中和单克隆抗体，可阻断 VEGF 与其受体的结合，可增强每种治疗方式的效果。我们评估了贝伐单抗为基础的抗血管生成联合 PDT 治疗以及由此产生的 VEGF 水平和微血管密度（MVD）在人结肠癌小鼠模型中的疗效。通过酶联免疫吸附试验（ELISA）和免疫组织化学（IHC）评估各种治疗组中的 VEGF 浓度和微血管密度，并通过共聚焦成像和高效液相色谱（HPLC）分析评估 mTHPC 在肿瘤中的分布和浓度。我们的结果表明，PDT 联合贝伐单抗治疗可显著引发更大的肿瘤反应，而 PDT 前的贝伐单抗治疗则导致肿瘤反应降低。免疫染色和 ELISA 分析显示，与 PDT 联合贝伐单抗治疗的肿瘤中 VEGF 的表达较低。然而，贝伐单抗治疗降低了给药后 24 小时肿瘤中 mTHPC 的积累，这补充了贝伐单抗治疗后 PDT 抗肿瘤疗效降低的结果。
