INHIBITION OF ANGIOGENESIS IN-VIVO BY INTERLEUKIN-12
INHIBITION OF ANGIOGENESIS IN-VIVO BY INTERLEUKIN-12
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DOI：
10.1093/jnci/87.8.581
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发表时间：
1995-04-19
期刊：
影响因子：
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通讯作者：
FOLKMAN, J
中科院分区：
文献类型：
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作者：
VOEST, EE;KENYON, BB;FOLKMAN, J
背景：以往的动物研究表明，白介素12(IL-12)在体内可抑制多种肿瘤的生长，但在体外对肿瘤细胞无直接作用。此外，与T细胞介导效应的预期相反，在T细胞缺陷小鼠的测试中，IL 12的抗肿瘤活性并未完全被取消。这些观察表明，IL-12可能具有抗血管生成的特性，这是其在体内具有肿瘤抑制作用的原因。目的：我们的目标是研究IL-12具有抗血管生成特性的假说。方法：采用碱性成纤维细胞生长因子诱导的小鼠角膜新生血管模型，观察IL-12和干扰素-γ对新生血管形成的影响。不同品系的雄性小鼠，如免疫功能正常的C57BL/6小鼠、严重联合免疫缺陷(SCID)小鼠、自然杀伤细胞缺陷的米色小鼠和T细胞缺陷的裸鼠，连续5天给予IL-12(1微克/天)。通过测量新生血管形成所涉及的最大血管长度和角膜周长来评估碱性成纤维细胞生长因子颗粒对新生血管的反应程度以及IL 12或干扰素γ对新生血管的抑制作用。用Letvis肺癌荷瘤小鼠评价IL-12和血管生成抑制剂AGM-1470的抗肿瘤活性。对牛血管内皮细胞、小鼠胰岛内皮细胞和小鼠血管内皮瘤细胞进行了体外增殖研究。结果：IL-12治疗几乎完全抑制了C57BL/6、SCID和褐鼠的角膜新生血管形成。这种对血管生成的有效抑制可以通过给予干扰素-伽马中和抗体来阻止，这表明这种抑制是通过干扰素-伽马介导的。IL-12和AGM-1470联合应用对Lewis肺癌小鼠的毒性没有增加，且有增强抗肿瘤作用的趋势。结论：IL-12对新生血管有明显的抑制作用。这种影响不是由免疫系统的特定细胞类型介导的。相反，IL-12可诱导干扰素-γ，而干扰素-γ则在IL-12的抗血管生成作用中起着重要的中介作用。提示：对IL-12抗血管生成特性的机制的认识可能是计划其临床应用的关键，包括与其他新生血管抑制剂联合应用的可能性。
Background: In previous animal studies, interleukin 12 (IL 12) was shown to inhibit the growth of a wide spectrum of tumors in vivo but to have no direct effect on tumor cells in vitro. Also, contrary to the expectation of a T-cell-mediated effect, the antitumor activity of IL 12 was not completely abrogated in tests of T-cell-deficient mice. These observations suggest that IL 12 may possess antiangiogenic properties that account for its tumor-inhibitory effects in vivo. Purpose: Our goal was to investigate the hypothesis that IL 12 has antiangiogenic properties. Methods: A model of basic fibroblast growth factor-induced corneal neovascularization in mice was used to evaluate the effects of IL 12 and interferon gamma (IFN gamma) on angiogenesis in vivo. Different strains of male mice, e.g., immunocompetent C57BL/6 mice, severe combined immune-deficient (SCID) mice, natural killer cell-deficient beige mice, and T-cell-deficient nude mice, were treated with IL 12 (1 mu g/day) intraperitoneally for 5 consecutive days. The extent of neovascularization in response to a basic fibroblast growth factor pellet and the inhibition of neovascularization by IL 12 or IFN gamma were assessed by measuring the maximal vessel length and the corneal circumference involved in new blood vessel formation. The antitumor activities of IL 12 and of the angiogenesis inhibitor AGM-1470 were evaluated in Letvis lung carcinoma-bearing mice. In vitro proliferation studies were performed on bovine capillary endothelial cells, mouse pancreatic islet endothelial cells, and mouse hemangioendothelioma cells. Results: IL 12 treatment almost completely inhibited corneal neovascularization in C57BL/6, SCID, and beige mice. This potent suppression of angiogenesis was prevented by the administration of IFN gamma-neutralizing antibodies, suggesting that the suppression was mediated through IFN gamma. In addition, the administration of IFN gamma reproduced the antiangiogenic effects observed during treatment with IL 12. Treatment with IL 12 and AGM-1470 combined did not increase toxicity and showed a trend toward enhanced antitumor efficacy in Lewis lung carcinoma-bearing mice. Conclusions: IL 12 strongly inhibits neovascularization. This effect is not mediated by a specific cell type of the immune system. Instead, IL 12 has been shown to induce IFN gamma, which, in turn, appears to play a critical role as a mediator of the antiangiogenic effects of IL 12. Implications: Recognition of the mechanisms of the antiangiogenic properties of IL 12 may be crucial in planning its clinical applications, including a possibility of coadministration with other inhibitors of neovascularization.