Nonclinical studies addressing the mechanism of action of trastuzumab (Herceptin).
Nonclinical studies addressing the mechanism of action of trastuzumab (Herceptin).
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发表时间：
1999-08
影响因子：
4
通讯作者：
M. Sliwkowski;J. Lofgren;G. Lewis;T. Hotaling;B. Fendly;J. Fox
中科院分区：
文献类型：
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作者：
M. Sliwkowski;J. Lofgren;G. Lewis;T. Hotaling;B. Fendly;J. Fox
HER 2是人表皮生长因子受体或酪氨酸激酶ErbB家族的无配体成员。在正常的生物系统中，HER 2作为多种表皮生长因子样配体的共受体发挥作用，所述表皮生长因子样配体结合并激活其他HER家族成员。在许多人腺癌中观察到HER 2过表达，并导致组成性HER 2活化。这些肿瘤的特异性靶向可以用针对HER 2蛋白的细胞外结构域的抗体来实现。这些抗体之一4D 5已被完全人源化并被称为曲妥珠单抗（Herceptin; Genentech，San弗朗西斯科，CA）。用曲妥珠单抗治疗HER 2过表达的乳腺癌细胞系导致p27 KIP 1和Rb相关蛋白p130的诱导，这反过来显著减少了经历S期的细胞数量。由于曲妥珠单抗与HER 2过表达细胞结合，在体外观察到许多其他表型变化。这些表型变化包括下调HER 2受体、抑制肿瘤细胞生长、逆转细胞因子抗性、恢复E-钙粘蛋白表达水平和减少血管内皮生长因子产生。曲妥珠单抗通过其人免疫球蛋白G1 Fc结构域与人免疫系统的相互作用可能增强其抗肿瘤活性。体外研究表明，曲妥珠单抗在介导针对HER 2过表达肿瘤靶点的抗体依赖性细胞介导的细胞毒性方面非常有效。曲妥珠单抗治疗小鼠异种移植模型导致肿瘤生长的显著抑制。当与标准细胞毒性化疗药物联合给药时，曲妥珠单抗治疗通常导致与单独给药的任一种药物相比具有统计学上级抗肿瘤疗效。总而言之，这些研究表明曲妥珠单抗的作用机制包括拮抗HER 2系统的组成性生长信号传导特性、招募免疫细胞攻击和杀死肿瘤靶点以及增强化疗诱导的细胞毒性。
HER2 is a ligand-less member of the human epidermal growth factor receptor or ErbB family of tyrosine kinases. In normal biological systems, HER2 functions as a co-receptor for a multitude of epidermal growth factor-like ligands that bind and activate other HER family members. HER2 overexpression is observed in a number of human adenocarcinomas and results in constitutive HER2 activation. Specific targeting of these tumors can be accomplished with antibodies directed against the extracellular domain of the HER2 protein. One of these antibodies, 4D5, has been fully humanized and is termed trastuzumab (Herceptin; Genentech, San Francisco, CA). Treatment of HER2-overexpressing breast cancer cell lines with trastuzumab results in induction of p27KIP1 and the Rb-related protein, p130, which in turn significantly reduces the number of cells undergoing S-phase. A number of other phenotypic changes are observed in vitro as a consequence of trastuzumab binding to HER2-overexpressing cells. These phenotypic changes include downmodulation of the HER2 receptor, inhibition of tumor cell growth, reversed cytokine resistance, restored E-cadherin expression levels, and reduced vascular endothelial growth factor production. Interaction of trastuzumab with the human immune system via its human immunoglobulin G1 Fc domain may potentiate its antitumor activities. In vitro studies demonstrate that trastuzumab is very effective in mediating antibody-dependent cell-mediated cytotoxicity against HER2-overexpressing tumor targets. Trastuzumab treatment of mouse xenograft models results in marked suppression of tumor growth. When given in combination with standard cytotoxic chemotherapeutic agents, trastuzumab treatment generally results in statistically superior antitumor efficacy compared with either agent given alone. Taken together, these studies suggest that the mechanism of action of trastuzumab includes antagonizing the constitutive growth-signaling properties of the HER2 system, enlisting immune cells to attack and kill the tumor target, and augmenting chemotherapy-induced cytotoxicity.