Infarction of solid Hodgkin's tumors in mice by antibody-directed targeting of tissue factor to tumor vasculature.
Infarction of solid Hodgkin's tumors in mice by antibody-directed targeting of tissue factor to tumor vasculature.
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发表时间：
1998-10
期刊：
影响因子：
11.2
通讯作者：
Sophia Ran;Sophia Ran;Boning Gao;S. Duffy;L. Watkins;Neal S. Rote;Philip E. Thorpe
中科院分区：
文献类型：
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作者：
Sophia Ran;Sophia Ran;Boning Gao;S. Duffy;L. Watkins;Neal S. Rote;Philip E. Thorpe
我们以前证明，小鼠实体瘤血管的选择性血栓形成可以通过靶向组织因子的细胞外结构域，通过实验诱导的肿瘤血管内皮标记物的抗体来实现。在本研究中，我们将这一发现扩展到肿瘤血管内皮细胞的天然标记物，血管细胞粘附分子-1（VCAM-1）。VCAM-1由何杰金氏病和小鼠和人的各种实体瘤中的血管内皮细胞表达。小鼠正常组织中的血管内皮细胞中不存在，但心脏和肺除外，其存在于小静脉上。将鼠VCAM-1的单克隆抗体与人组织因子的细胞外结构域共价连接以产生“凝血配体”。“对携带人类霍奇金肿瘤的严重联合免疫缺陷小鼠静脉注射后，凝血配体选择性地定位于表达VCAM-1的血管，引起这些血管的血栓形成，并延缓肿瘤生长。凝血配体也定位于小鼠心脏和肺中表达VCAM-1的血管，但在这些部位不诱导血栓形成。单克隆抗磷脂酰丝氨酸（PS）抗体在小鼠体内分布的免疫组织化学评价显示，肿瘤中表达VCAM-1的血管表达PS，而心脏和肺中表达VCAM-1的血管缺乏PS。凝血配体对心血管和肺血管缺乏血栓形成作用可能是因为需要PS来提供凝血复合物可以在其上组装的促凝血表面。肿瘤内皮细胞上靶向标记物和PS同时表达的要求可能有助于血栓形成作用的选择性和凝血配体的安全性。
We demonstrated previously that selective thrombosis of the blood vessels of solid tumors in mice can be achieved by targeting the extracellular domain of tissue factor by means of an antibody to an experimentally induced marker on tumor vascular endothelium. In the present study, we extend this finding to a naturally occurring marker of tumor vascular endothelium, vascular cell adhesion molecule-1 (VCAM-1). VCAM-1 is expressed by vascular endothelial cells in Hodgkin's disease and various solid tumors in mice and humans. It is absent from vascular endothelial cells in normal tissues in mice, with the exception of the heart and lungs, where it is present on venules. A monoclonal antibody to murine VCAM-1 was covalently linked to the extracellular domain of human tissue factor to create a "coaguligand." After i.v. administration to severe combined immunodeficient mice bearing human Hodgkin's tumors, the coaguligand localized selectively to VCAM-1-expressing vessels, caused thrombosis of those vessels, and retarded tumor growth. The coaguligand also localized to VCAM-1-expressing vessels in the heart and lungs of the mice but did not induce thrombosis in these sites. An immunohistochemical evaluation of the distribution of a monoclonal anti-phosphatidylserine (PS) antibody in the mice showed that the VCAM-1-expressing vessels in the tumor expressed PS, whereas the VCAM-1-expressing vessels in the heart and lungs lacked PS. The lack of thrombotic effect of the coaguligand on heart and lung vessels may be because PS is needed to provide the procoagulant surface upon which coagulation complexes can assemble. The requirement for coincident expression of the targeted marker and PS on tumor endothelium probably contributes to the selectivity of thrombotic action and the safety of coaguligands.