Hamner John B, Dickson Paxton V, Sims Thomas L, Zhou Junfang, Spence Yunyu, Ng Cathy Y, Davidoff Andrew M
Department of Surgery, St. Jude Children's Research Hospital, Memphis, Tenn, USA.
Surgery. 2007 Aug;142(2):185-91. doi: 10.1016/j.surg.2007.04.012.
Bortezomib is a proteasome inhibitor with pleiotropic antitumor activity. Here we investigate the antiangiogenic and antitumor efficacy of bortezomib against neuroblastoma both in vitro and in a murine model of localized and disseminated disease.
In vitro activity of bortezomib was assessed by evaluating its effect on cell proliferation and cell cycle status. Localized tumor burden was followed with caliper measurements and total-body bioluminescence in mice with disseminated disease. The antiangiogenic activity was evaluated with immunohistochemistry and human vascular endothelial growth factor (VEGF) enzyme-linked immunosorbent assay on tumor protein extracts.
Bortezomib treatment resulted in dose and time-dependent decreases in cell proliferation and resulted in cell cycle arrest. In vivo, bortezomib restricted tumor growth in a model of localized disease and decreased bioluminescence in mice with disseminated disease. That decreased bioluminescence reflected decreased tumor burden was confirmed at necropsy by assessing disease in specific organs. In addition, treatment resulted in a decrease in intratumoral vessel counts and reduced tumor VEGF expression.
Bortezomib shows significant activity against neuroblastoma in vitro, and it inhibits tumor growth and angiogenesis in vivo. These results suggest that clinical studies of bortezomib are warranted for the treatment of this difficult disease.
硼替佐米是一种具有多效抗肿瘤活性的蛋白酶体抑制剂。在此，我们研究硼替佐米在体外以及局部和播散性疾病小鼠模型中对神经母细胞瘤的抗血管生成和抗肿瘤疗效。
通过评估硼替佐米对细胞增殖和细胞周期状态的影响来测定其体外活性。在患有播散性疾病的小鼠中，用卡尺测量和全身生物发光法跟踪局部肿瘤负荷。通过免疫组织化学和对肿瘤蛋白提取物进行人血管内皮生长因子（VEGF）酶联免疫吸附测定来评估抗血管生成活性。
硼替佐米治疗导致细胞增殖呈剂量和时间依赖性下降，并导致细胞周期停滞。在体内，硼替佐米在局部疾病模型中限制肿瘤生长，并降低患有播散性疾病小鼠的生物发光。尸检时通过评估特定器官中的疾病证实，生物发光降低反映了肿瘤负荷减轻。此外，治疗导致肿瘤内血管计数减少和肿瘤VEGF表达降低。
硼替佐米在体外对神经母细胞瘤显示出显著活性，并且在体内抑制肿瘤生长和血管生成。这些结果表明，有必要对硼替佐米进行治疗这种难治性疾病的临床研究。
