Combined anti-fetal liver kinase 1 monoclonal antibody and continuous low-dose doxorubicin inhibits angiogenesis and growth of human soft tissue sarcoma xenografts by induction of endothelial cell apoptosis.
Combined anti-fetal liver kinase 1 monoclonal antibody and continuous low-dose doxorubicin inhibits angiogenesis and growth of human soft tissue sarcoma xenografts by induction of endothelial cell apoptosis.
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发表时间：
2002-04
期刊：
影响因子：
11.2
通讯作者：
Lianglin Zhang;Dihua Yu;D. Hicklin;J. Hannay;L. Ellis;R. Pollock
中科院分区：
文献类型：
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作者：
Lianglin Zhang;Dihua Yu;D. Hicklin;J. Hannay;L. Ellis;R. Pollock
血管内皮生长因子 (VEGF) 和 VEGF 受体 2 [胎肝激酶 1 (Flk-1)/含有激酶插入结构域的受体] 已被证明在肿瘤血管生成中发挥重要作用。在本研究中，我们研究了抗Flk-1单克隆抗体DC101是否可以治疗性抑制人软组织肉瘤的生长和血管生成，并探讨其增强阿霉素杀肿瘤作用的能力。用 DC101 治疗严重联合免疫缺陷小鼠中成熟的平滑肌肉瘤 SKLMS-1 和横纹肌肉瘤 RD 异种移植物，产生了显着的抗肿瘤活性。在一项平行研究中，我们比较了连续低剂量“抗血管生成”方案与每两周一次的高剂量阿霉素标准方案对肿瘤的抑制作用。我们发现，连续低剂量治疗对RD异种移植物肿瘤生长的抑制约为标准治疗方案的46.5%，但连续低剂量治疗并不能抑制SKLMS-1异种移植物的肿瘤生长。值得注意的是，与单独使用任何药物进行长期皮下观察相比，DC101 和连续低剂量阿霉素联合使用对 SKLMS-1 和 RD 异种移植物的生长抑制更有效。肿瘤异种移植模型。与单独使用低剂量阿霉素相比，联合疗法对宿主动物没有额外的毒性。异种移植物的组织学检查显示，与单独给予任一药物的肿瘤相比，给予联合治疗的肿瘤中的微血管计数显着减少。这些结果与使用Matrigel栓塞测定联合DC101和阿霉素增强的体内血管生成抑制作用一致。此外，DC101联合阿霉素在体外直接对内皮细胞迁移、增殖和管状形成产生增强的抑制作用。此外，该组合诱导内皮细胞凋亡增强，这与 capase-3 活性的增加有关。因此，抑制血管生成和诱导内皮细胞凋亡可能是 DC101 和阿霉素联合抗肿瘤活性的重要机制。总的来说，我们的数据表明，抗 VEGF 受体 2 联合持续小剂量阿霉素可能为临床上人类软组织肉瘤提供新的治疗方法。
Vascular endothelial growth factor (VEGF) and VEGF receptor 2 [fetal liver kinase 1 (Flk-1)/kinase insert domain-containing receptor] have been shown to play a major role in tumor angiogenesis. In this study, we investigated whether anti-Flk-1 monoclonal antibody DC101 could therapeutically inhibit growth and angiogenesis of human soft tissue sarcoma, and we explored its capacity to enhance the tumoricidal effects of doxorubicin. Treatment of well-established leiomyosarcoma SKLMS-1 and rhabdomyosarcoma RD xenografts in severe combined immunodeficient mice with DC101 resulted in significant antitumor activity. In a parallel study, we compared tumor inhibition with continuous low-dose "antiangiogenic" schedule versus once-every-2-weeks high-dose standard schedule of doxorubicin. We found that continuous low-dose treatment inhibited the tumor growth of RD xenografts about 46.5% of that with standard-schedule treatment, but that continuous low-dose treatment did not inhibit the tumor growth of SKLMS-1 xenografts. Notably, combined DC101 and continuous low-dose doxorubicin resulted in more effective growth inhibition of SKLMS-1 and RD xenografts than has been observed with any agent alone in a long-term s.c. tumor xenograft model. The combination therapy was associated with no additional toxicity to the host animal compared with low-dose doxorubicin alone. Histological examination of xenografts showed significantly reduced microvessel counts in the tumors given combined therapy compared with the tumors given either agent alone. These results are consistent with an enhanced inhibition of angiogenesis in vivo by combined DC101 and doxorubicin using Matrigel plug assay. Additionally, DC101 plus doxorubicin directly exerted enhanced inhibitory effects on endothelial cell migration, proliferation, and tube-like formation in vitro. Furthermore, the combination induced an enhanced apoptosis of endothelial cells that was associated with an increase of capase-3 activity. Thus, the inhibition of angiogenesis and induction of endothelial cell apoptosis are likely important mechanisms for the antitumor activity of combined DC101 and doxorubicin. Collectively, our data suggested that anti-VEGF receptor 2 in combination with continuous low-dose doxorubicin may provide a new therapeutic approach for human soft tissue sarcoma in the clinic.