Styrene Maleic Acid-Pirarubicin Disrupts Tumor Microcirculation and Enhances the Permeability of Colorectal Liver Metastases
Styrene Maleic Acid-Pirarubicin Disrupts Tumor Microcirculation and Enhances the Permeability of Colorectal Liver Metastases
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DOI：
10.1159/000165380
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发表时间：
2009-01-01
影响因子：
1.7
通讯作者：
Christophi, Chris
中科院分区：
文献类型：
--
作者：
Daruwalla, Jurstine;Greish, Khaled;Christophi, Chris
背景：阿霉素是一种心脏毒性受限的常用化疗药物。吡柔比星来源于阿霉素，当包裹在苯乙烯马来酸(SMA)中时，选择性地靶向肿瘤，形成大分子SMA吡柔比星。由于增强的渗透性和保留率(EPR)效应，实现了选择性靶向。SMA-吡柔比星可抑制结直肠癌肝转移的生长，但对肿瘤的破坏是不完全的。肿瘤微循环所起的作用尚不确定。本研究调查了SMA-吡柔比星治疗后微循环的变化模式。方法：用小鼠来源的结肠癌细胞系建立CBA小鼠肝转移模型。SMA-吡柔比星(总剂量100 mg/kg)分3次静脉给药。化疗后24小时，用CD34免疫组织化学和扫描电子显微镜观察肿瘤微血管。用体内共聚焦显微镜和伊文思蓝方法检测肿瘤的血流灌注和通透性。结果：SMA-吡柔比星可使微血管指数降低40%。治疗后血管广泛闭塞、坏死。活细胞排列在肿瘤血管周围。肿瘤通透性也增加。结论：SMA-吡柔比星可损伤肿瘤细胞和肿瘤微血管，增强肿瘤血管通透性。然而，肿瘤坏死是不完全的，残留细胞的生长是由微血管网络维持的。与血管靶向剂的联合治疗可能会影响残留细胞，从而使肿瘤得到更广泛的破坏。版权所有(C)2008 S.Karger AG，巴塞尔
Background: Doxorubicin is a commonly used chemotherapy limited by cardiotoxicity. Pirarubicin, derived from doxorubicin, selectively targets tumors when encapsulated in styrene maleic acid (SMA), forming the macromolecular SMA pirarubicin. Selective targeting is achieved because of the enhanced permeability and retention (EPR) effect. SMA-pirarubicin inhibits the growth of colorectal liver metastases, but tumor destruction is incomplete. The role played by the tumor microcirculation is uncertain. This study investigates the pattern of microcirculatory changes following SMA-pirarubicin treatment. Methods: Liver metastases were induced in CBA mice using a murine-derived colon cancer line. SMA-pirarubicin (100 mg/kg total dose) was administered intravenously in 3 separate doses. Twenty-four hours after chemotherapy, the tumor microvasculature was examined using CD34 immunohistochemistry and scanning electron microscopy. Tumor perfusion and permeability were assessed using confocal in vivo microscopy and the Evans blue method. Results: SMA-pirarubicin reduced the microvascular index by 40%. Vascular occlusion and necrosis were extensive following treatment. Viable cells were arranged around tumor vessels. Tumor permeability was also increased. Conclusion: SMA-pirarubicin damages tumor cells and the tumor microvasculature and enhances tumor vessel permeability. However, tumor necrosis is incomplete, and the growth of residual cells is sustained by a microvascular network. Combined therapy with a vascular targeting agent may affect residual cells, allowing more extensive destruction of tumors. Copyright (c) 2008 S. Karger AG, Basel