Anti-angiogenic treatment (Bevacizumab) improves the responsiveness of photodynamic therapy in colorectal cancer
Anti-angiogenic treatment (Bevacizumab) improves the responsiveness of photodynamic therapy in colorectal cancer
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DOI：
10.1016/j.pdpdt.2018.06.008
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发表时间：
2018-09-01
影响因子：
3.3
通讯作者：
Shieh, Ming-Jium
中科院分区：
文献类型：
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作者：
Peng, Cheng-Liang;Lin, Hua-Ching;Shieh, Ming-Jium
光动力疗法（PDT）是利用光敏剂和光的组合作用来治疗各种癌症的治疗。PDT后肿瘤破坏的机制包括通过单线态氧（OS）直接杀死肿瘤细胞、通过血管损伤间接杀死细胞和引发免疫应答。然而，据报道，许多细胞活化剂，包括血管内皮生长因子（VEGF），产生的肿瘤细胞后PDT。在这项研究中，我们证明，间四（羟苯基）二氢卟酚（mTHPC）为基础的光动力疗法与贝伐单抗（阿瓦斯丁（TM）），一种抗VEGF中和单克隆抗体，阻断VEGF结合其受体，可以提高每种治疗方式的有效性。我们在人结肠癌小鼠模型中评价了基于贝伐珠单抗的抗血管生成联合PDT的疗效以及由此产生的VEGF水平和微血管密度（MVD）。进行酶联免疫吸附测定（ELISA）和免疫组织化学（IHC）以评估各个治疗组中的VEGF浓度和微血管密度，并使用共聚焦成像和高效液相色谱（HPLC）分析来测量肿瘤中mTHPC的分布和浓度。我们的研究结果表明，联合PDT后贝伐单抗显着elevened一个更大的肿瘤反应，而贝伐单抗治疗前PDT导致肿瘤反应降低。免疫染色和ELISA分析显示，在用PDT联合治疗后再用贝伐单抗治疗的肿瘤中，VEGF的表达较低。然而，贝伐珠单抗治疗在给药后24小时降低了肿瘤中mTHPC的蓄积，这补充了贝伐珠单抗随后PDT的抗肿瘤疗效降低的结果。
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 (TM)), 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.