Direct evidence for rapid and selective induction of tumor neovascular permeability by tumor necrosis factor and a novel derivative, colloidal gold bound tumor necrosis factor
Direct evidence for rapid and selective induction of tumor neovascular permeability by tumor necrosis factor and a novel derivative, colloidal gold bound tumor necrosis factor
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DOI：
10.1002/ijc.22270
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发表时间：
2007-06-01
影响因子：
6.4
通讯作者：
Alexander, H. Richard
中科院分区：
文献类型：
--
作者：
Farma, Jeffrey M.;Puhlmann, Markus;Alexander, H. Richard
当与美法仑隔离灌注时，肿瘤坏死因子（TNF）可导致晚期癌症消退;证据表明，这些作用是通过对肿瘤新生血管的选择性但未表征的作用介导的。一种新的衍生物，胶体金结合的肿瘤坏死因子（cAu-TNF）已被证明具有类似的抗肿瘤作用，天然TNF在小鼠中具有较低的全身毒性。这些研究是为了确定它们对肿瘤新生血管的影响，使用体内视频显微镜。携带20 mm（2）MC 38或LLC肿瘤（分别为TNF敏感性和耐药性肿瘤）的雌性C57 BL/6小鼠植入背侧皮褶腔。静脉注射TNF、cAu-TNF或PBS后，测定肿瘤和正常血管中德克萨斯红荧光标记白蛋白的间质蓄积率。间质荧光强度随时间的变化被定量为血管通透性改变的反映。用TNF或cAu-TNF处理的MC 38荷瘤小鼠显示，与正常脉管系统相比，在新生脉管系统区域中示踪剂积聚快速、选择性和显著增加。在LLC荷瘤小鼠中的实验显示出类似的结果。抗组织因子单克隆抗体可部分阻断TNF对MC 38新生血管的作用。这些数据提供了TNF和cAu-TNF选择性地和快速地改变肿瘤新血管系统中的渗透性的直接证据;这种现象可用于增强化疗剂向肿瘤的选择性递送。(c)2007 Wiley-Liss，Inc.
Tumor necrosis factor (TNF) causes regression of advanced cancers when used in isolation perfusion with melphalan; evidence suggests these effects are mediated via selective yet uncharacterized actions on tumor neovasculature. A novel derivative, colloidal gold bound TNF (cAu-TNF) has been shown to have similar antitumor effects as native TNF with less systemic toxicity in mice. These studies were done to determine their effects on tumor neovasculature, using in vivo video microscopy. Female C57BL/6 mice bearing 20 mm(2) MC38 or LLC tumors that are TNF sensitive and resistant tumors, respectively, had dorsal skinfold chambers implanted. The rate of interstitial accumulation of Texas red fluorescently labeled albumin in tumor and normal vasculature was measured after intravenous TNF, cAu-TNF or PBS. Changes in interstitial fluorescent intensity over time were quantified as a reflection of alterations in vascular permeability. MC38 bearing mice treated with TNF or cAu-TNF demonstrated a rapid, selective and significant increase in tracer accumulation in areas of neovasculature compared to those of normal vasculature. Experiments in LLC tumor bearing mice showed similar results. Monoclonal antibody against tissue factor partially abrogated the effects of TNF on MC38 neovasculature. These data provide direct evidence that TNF and cAu-TNF selectively and rapidly alter permeability in tumor neovasculature; a phenomenon that may be exploited to enhance selective delivery of chemotherapeutics to tumor. (c) 2007 Wiley-Liss,Inc.