Tumor necrosis factor mutants with selective cytotoxic activity.

Cancer detection and prevention Pub Date : 1999-01-01 DOI:10.1046/j.1525-1500.1999.00067.x

N Berkova, A Lemay, V Korobko, L Shingarova, L Sagaidak, S Goupil

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引用次数: 7

Abstract

Tumor necrosis factor (TNF-alpha) has a cytotoxic or cytostatic effect when tested with various malignant cell lines. Clinical trials in cancer patients, however, revealed high systemic toxicity of TNF-alpha. The existence of two types of receptor may partially explain the pleiotropic activity of TNF-alpha. The purpose of this study was to characterize the relative cytotoxic activity of TNF-alpha and TNF mutants on the mouse fibrosarcoma L929 cells in a standard cytotoxicity test, on human larynx carcinoma HEp-2 cells, and on human monoblastoid leukemic cells U937. TNF mutants were obtained by site-directed mutagenesis. The purity of TNF-alpha was established by capillary electrophoresis. TNF-alpha and TNF mutants were analysed by Western blot analysis using monoclonal antibodies against TNF-alpha. The results show that TNF mutants can recognize the different TNF-receptors (TNF-R) selectivity. It is generally believed that activation of TNF-R75 is responsible for the systemic toxicity of TNF-alpha. Hence, the development of TNF mutants, binding selectively to TNF-R55, could lead to new option for an anticancer treatment that would be devoid of the deleterious effect of TNF-alpha.

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具有选择性细胞毒活性的肿瘤坏死因子突变体。

肿瘤坏死因子(tnf - α)对多种恶性细胞系具有细胞毒性或细胞抑制作用。然而，对癌症患者的临床试验显示，tnf - α具有很高的全身毒性。两种受体的存在可能部分解释了tnf - α的多效性。本研究的目的是在标准细胞毒性试验中表征TNF- α和TNF突变体对小鼠纤维肉瘤L929细胞、人喉癌HEp-2细胞和人单母细胞样白血病细胞U937的相对细胞毒活性。通过定点诱变获得TNF突变体。用毛细管电泳法确定tnf - α的纯度。使用抗TNF- α的单克隆抗体对TNF- α和TNF突变体进行Western blot分析。结果表明，TNF突变体可以识别不同的TNF-受体(TNF- r)选择性。一般认为，TNF-R75的激活是导致tnf - α全身毒性的原因。因此，TNF突变体的发展，选择性地结合TNF- r55，可能为抗癌治疗提供新的选择，而这种治疗将没有TNF- α的有害作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Cancer detection and prevention

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