Iurlaro M, Benelli R, Masiello L, Rosso M, Santi L, Albini A
Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
Eur J Cancer. 1998 Mar;34(4):570-6. doi: 10.1016/s0959-8049(97)10082-x.
Kaposi's sarcoma (KS) is a highly angiogenic lesion which frequently presents as an aggressive form in HIV-infected male patients. We have previously shown that the HIV-1 Tat protein induces endothelial cell migration and invasion in vitro and a rapid angiogenic response in vivo, suggesting that it acts as a cofactor in epidemic KS. In this study we tested beta interferon (IFN beta) and retinoic acid (RA) for the inhibition of Tat-induced angiogenesis using in vivo and in vitro models. IFN beta, at a concentration above 2500 U/ml, was an effective inhibitor of Tat-stimulated growth, migration and morphogenesis of an endothelial cell line in vitro and of angiogenesis in vivo. A strong reduction of properties associated with neovascularisation was induced by 10,000 U/ml. In vivo, RA alone was on ineffective inhibitor of angiogenesis, and in vitro gave only a limited inhibition of endothelial cell growth. However, 13-cis RA used in combination with IFN beta impressively potentiated its effects. A combination of lower doses of IFN beta (2500 U/ml) and 13-cis RA induced a virtually complete inhibition of the Tat-related angiogenic phenotype both in vivo and in vitro. The potentiation of the anti-angiogenic activity of IFN beta by 13-cis RA suggests that this combination could be a useful approach for the therapy of epidemic KS.
卡波西肉瘤（KS）是一种高度血管生成性病变，在感染HIV的男性患者中常表现为侵袭性形式。我们之前已经表明，HIV-1反式激活蛋白（Tat蛋白）在体外可诱导内皮细胞迁移和侵袭，并在体内引发快速的血管生成反应，这表明它在流行性卡波西肉瘤中作为一种辅助因子发挥作用。在本研究中，我们使用体内和体外模型测试了β干扰素（IFN-β）和视黄酸（RA）对Tat诱导的血管生成的抑制作用。浓度高于2500 U/ml的IFN-β在体外是Tat刺激的内皮细胞系生长、迁移和形态发生以及体内血管生成的有效抑制剂。10000 U/ml可强烈降低与新血管形成相关的特性。在体内，单独使用RA对血管生成无效，在体外对内皮细胞生长仅有有限的抑制作用。然而，13-顺式视黄酸（13-cis RA）与IFN-β联合使用可显著增强其效果。较低剂量的IFN-β（2500 U/ml）与13-顺式视黄酸联合使用在体内和体外均可几乎完全抑制与Tat相关的血管生成表型。13-顺式视黄酸增强IFN-β的抗血管生成活性表明，这种联合用药可能是治疗流行性卡波西肉瘤的一种有效方法。
