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通过靶向碱性成纤维细胞生长因子的反义寡核苷酸阻断艾滋病相关卡波西肉瘤（KS）细胞生长、血管生成及裸鼠体内病损形成。一种治疗KS的新策略。

Block of AIDS-Kaposi's sarcoma (KS) cell growth, angiogenesis, and lesion formation in nude mice by antisense oligonucleotide targeting basic fibroblast growth factor. A novel strategy for the therapy of KS.

作者信息

Ensoli B, Markham P, Kao V, Barillari G, Fiorelli V, Gendelman R, Raffeld M, Zon G, Gallo R C

机构信息

Laboratory of Tumor Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.

出版信息

J Clin Invest. 1994 Nov;94(5):1736-46. doi: 10.1172/JCI117521.

DOI:10.1172/JCI117521
PMID:7525646
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC294564/
Abstract

Kaposi's sarcoma (KS) is the most frequent tumor of HIV-1-infected individuals (AIDS-KS). Typical features of KS are proliferating spindle-shaped cells, considered to be the tumor cells of KS, and endothelial cells forming blood vessels. Basic fibroblast growth factor (bFGF), a potent angiogenic factor, is highly expressed by KS spindle cells in vivo and after injection in nude mice it induces vascular lesions closely resembling early KS in humans. Similar lesions are induced by inoculating nude mice with cultured spindle cells from AIDS-KS lesions (AIDS-KS cells) which produce and release bFGF. Here we show that phosphorothioate antisense (AS) oligonucleotides directed against bFGF mRNA (ASbFGF) inhibit both the growth of AIDS-KS cells derived from different patients and the angiogenic activity associated with these cells, including the induction of KS-like lesions in nude mice. These effects are due to the block of the production of bFGF which is required by AIDS-KS cells to enter the cell cycle and which, after release, mediates angiogenesis. The effects of ASbFGF are specific, dose dependent, achieved at low (0.1-1 microM), nontoxic, oligomer concentrations, and are reversed by the addition of bFGF to the cells, suggesting that ASbFGF oligomers are promising drug candidates for KS therapy.

摘要

卡波西肉瘤（KS）是HIV-1感染个体中最常见的肿瘤（艾滋病相关卡波西肉瘤）。KS的典型特征是增殖的梭形细胞（被认为是KS的肿瘤细胞）和形成血管的内皮细胞。碱性成纤维细胞生长因子（bFGF）是一种有效的血管生成因子，在体内由KS梭形细胞高度表达，注射到裸鼠体内后可诱导出与人类早期KS极为相似的血管病变。用来自艾滋病相关卡波西肉瘤病变的培养梭形细胞（艾滋病相关卡波西肉瘤细胞）接种裸鼠也可诱导出类似病变，这些细胞能产生并释放bFGF。在此我们表明，针对bFGF mRNA的硫代磷酸反义（AS）寡核苷酸（ASbFGF）可抑制来自不同患者的艾滋病相关卡波西肉瘤细胞的生长以及与这些细胞相关的血管生成活性，包括在裸鼠中诱导出类似KS的病变。这些效应是由于阻断了bFGF的产生，而艾滋病相关卡波西肉瘤细胞进入细胞周期需要bFGF，并且bFGF释放后可介导血管生成。ASbFGF的效应具有特异性、剂量依赖性，在低浓度（0.1 - 1 microM）、无毒的寡聚物浓度下即可实现，并且通过向细胞中添加bFGF可逆转这些效应，这表明ASbFGF寡聚物有望成为治疗KS的候选药物。

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