Targeted delivery of IFNγ to tumor vessels uncouples antitumor from counterregulatory mechanisms
Targeted delivery of IFNγ to tumor vessels uncouples antitumor from counterregulatory mechanisms
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DOI：
10.1158/0008-5472.can-04-4282
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发表时间：
2005-04-01
期刊：
影响因子：
11.2
通讯作者：
Corti, A
中科院分区：
文献类型：
--
作者：
Curnis, F;Gasparri, A;Corti, A
由于其免疫调节和抗癌活性，IFN γ已在几项临床研究中用作抗癌药物，不幸的是，结果不多。通过增加剂量或重复连续注射来增加反应的尝试通常会导致疗效降低，可能是由于反调节效应。我们在这里表明，有针对性地交付低剂量的IFN γ的CD 13，血管生成血管的标志物，可以克服主要的反调节机制和延迟肿瘤生长的两个小鼠模型，响应差IFN γ。通过基因工程技术将IFN γ偶联到CD 13配体GCNGRC上，实现肿瘤血管靶向。剂量-反应曲线呈钟形。0.005 μ g/kg剂量诱导最大效应，约为患者使用剂量的500倍。在0.003至250 μ g/kg的范围内，非靶向IFN γ诱导的作用很小或没有作用。对作用机制的研究表明，低剂量的靶向IFN γ可激活肿瘤坏死因子（TNF）依赖性抗肿瘤机制，而高剂量的靶向或非靶向IFN γ可诱导循环中可溶性TNF受体脱落，这是一种已知的TNF活性反调节机制。这些结果表明，肿瘤血管的抗肿瘤活性和反调节机制可能是解偶联的。用极低剂量的IFN γ靶向。
Because of its immunomodulatory and anticancer activities, IFN gamma has been used as an anticancer drug in several clinical studies, unfortunately with modest results. Attempts to increase the response by increasing the dose or by repeated continuous injection often resulted in lower efficacy, likely due to counterregulatory effects. We show here that targeted delivery of low doses of IFN gamma to CD13, a marker of angiogenic vessels, can overcome major counterregulatory mechanisms and delay tumor growth in two murine models that respond poorly to IFN gamma. Tumor vascular targeting was achieved by coupling IFN gamma to GCNGRC, a CD13 ligand, by genetic engineering technology. The dose-response curve was bell-shaped. Maximal effects were induced with a dose of 0.005 mu g/kg, about 500-fold lower than the dose used in patients. Nontargeted IFN gamma induced little or no effects over a range of 0.003 to 250 mu g/kg. Studies on the mechanism of action showed that low doses of targeted IFN gamma could activate tumor necrosis factor (TNF)-dependent antitumor mechanisms, whereas high doses of either targeted or nontargeted IFN gamma induced soluble TNF-receptor shedding in circulation, a known counterregulatory mechanism of TNF activity. These findings suggest that antitumor activity and counterregulatory mechanisms could be uncoupled by tumor vascular. targeting with extremely low doses of IFNy.