Alterations in vascular architecture and permeability following OXi4503 treatment
Alterations in vascular architecture and permeability following OXi4503 treatment
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DOI：
10.1097/cad.0b013e3282f077a1
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发表时间：
2008-01-01
影响因子：
2.3
通讯作者：
Christophi, Christopher
中科院分区：
文献类型：
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作者：
Chan, Lie Sam;Malcontenti-Wilson, Cathy;Christophi, Christopher
OXi 4503以剂量依赖性方式延缓肿瘤生长，并改善结肠直肠肝转移小鼠模型的存活率。这种药物通过选择性改变肿瘤血管内皮细胞内的微管蛋白细胞骨架而引起广泛的血管关闭。然而，肿瘤血管的破坏是不完全的，并且在治疗后发生肿瘤血管重建。本研究评估了由OXi 4503治疗引起的微循环变化的模式和肿瘤脉管系统的超微结构特性的改变。通过脾内注射鼠源性结肠直肠细胞系诱导雄性CBA小鼠肝转移。在施用单次腹膜内剂量的OXi 4503后，在各个时间点评估肿瘤灌注、微血管结构和渗透性的变化。在给予100-mg/kg剂量的OXi 4503后1小时，观察到肿瘤灌注百分比的显著降低（对照组中为63.96 +/-1.98对比治疗小鼠中为43.77 +/-2.71，P < 0.001），这在治疗后5天仍然明显。观察到大量肿瘤微血管损伤和最小的正常肝损伤。在OXi 4503处理后45分钟，肿瘤血管渗透性显著升高（对照中为67.5 +/-3.60 μ g/g对80.5 +/-2.24 μ g/g，P < 0.05）。研究结果表明，OXi 4503选择性地靶向肿瘤血管并导致立即的微血管破坏。然而，即使在最大耐受剂量下，治疗后仍存在残留的通畅肿瘤血管，这意味着肿瘤破坏不完全。OXi 4503与其他化疗方式的组合可能实现完全的肿瘤根除并改善长期生存。
OXi4503 retards tumor growth in a dose-dependent manner and improves survival in a murine model of colorectal liver metastases. This agent causes extensive vascular shutdown by selectively altering the tubulin cytoskeleton within the endothelial cells of tumor vessels. The destruction of tumor vessels is incomplete, however, and tumor revascularization occurs after the treatment. This study evaluates the pattern of microcirculatory changes and alterations to the ultrastructural properties of the tumor vasculature that result from OXi4503 treatment. Male CBA mice were induced with liver metastases via an intrasplenic injection of a murine-derived colorectal cell line. After administering a single intraperitoneal dose of OXi4503, changes in tumor perfusion, microvascular architecture and permeability were assessed at various time points. One hour after a 100-mg/kg dose of OXi4503, a significant decrease in the percentage of tumor perfusion (63.96 +/- 1.98 in controls versus 43.77 +/- 2.71 in treated mice, P < 0.001) was observed, which was still evident 5 days after the treatment. Substantial tumor microvascular damage and minimal normal liver injury were observed. Tumor vascular permeability was significantly elevated 45 min after the OXi4503 treatment (67.5 +/- 3.60 in controls versus 80.5 +/- 2.24 mu g/g, P < 0.05). The findings suggest that OXi4503 selectively targets tumor vessels and causes immediate microvascular destruction. Even at the maximum tolerated dose, however, residual patent tumor vessels were still present after treatment, implying incomplete tumor destruction. A combination of OXi4503 with other chemotherapeutic modalities might achieve complete tumor eradication and improve long-term survival.