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首页> 外文期刊>Antibodies >Dissecting the Entry Route of Saporin-based α-CD7 Immunotoxins in Human T-Cell Acute Lymphoblastic Leukaemia Cells
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Dissecting the Entry Route of Saporin-based α-CD7 Immunotoxins in Human T-Cell Acute Lymphoblastic Leukaemia Cells

机译：解剖人T细胞急性淋巴细胞白血病细胞中基于Saporin的α-CD7免疫毒素的进入途径

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摘要

Elucidating the intracellular fate(s) of targeted toxins is of fundamental importance for their optimal use as anticancer drugs, since the biochemical targets of their enzymatic activity reside in the cell cytoplasm, as in the case of the plant ribosome inactivating proteins (RIP) saporin, ricin and of bacterial toxins. In this paper, we compared the cell surface binding and cytotoxic properties of the model RIP ricin to an immunotoxin constructed with a monoclonal antibody directed against the human T-cell marker CD7 covalently linked to saporin (CD7-SAP). Our results indicate that, despite the fact that internalization takes place via an apparently common entry route leading to the Golgi complex, surprisingly, the addition of an endoplasmic reticulum retrieval C-terminal signal (KDEL) to CD7-SAP does not potentiate its cytotoxicity. In addition, while ricin toxicity is clearly reduced by Brefeldin A under conditions where this fungal metabolite causes Golgi stack disruption, we paradoxically observed a potentiating effect by Brefeldin A on CD7-SAP cytotoxicity suggesting that this inhibitor interferes with retrograde route(s) other than the well established Trans-Golgi Network-ER retrograde route.
机译：阐明靶向毒素的细胞内命运对于它们作为抗癌药物的最佳用途至关重要，因为其酶促活性的生化靶标位于细胞质中，就像植物核糖体失活蛋白（RIP）皂素一样，蓖麻毒蛋白和细菌毒素。在本文中，我们将RIP蓖麻毒蛋白模型的细胞表面结合和细胞毒性特性与一种免疫毒素进行了比较，该免疫毒素由针对与Tap标记共价连接的人T细胞标记CD7的单克隆抗体（CD7-SAP）构建。我们的结果表明，尽管事实上通过一条通向高尔基体的常见进入途径发生了内在化，但令人惊讶的是，向CD7-SAP添加内质网检索C端信号（KDEL）并未增强其细胞毒性。此外，尽管在这种真菌代谢物引起高尔基体堆栈破坏的条件下，布雷菲德菌素A明显降低了蓖麻毒蛋白的毒性，但我们自相矛盾地观察到布雷菲德菌素A对CD7-SAP细胞毒性的增强作用，表明该抑制剂干扰了逆行途径，而不是完善的Trans-Golgi Network-ER逆行路线。

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