PD153035, a tyrosine kinase inhibitor, prevents epidermal growth factor receptor activation and inhibits growth of cancer cells in a receptor number-dependent manner.
PD153035, a tyrosine kinase inhibitor, prevents epidermal growth factor receptor activation and inhibits growth of cancer cells in a receptor number-dependent manner.
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发表时间：
1997-11
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通讯作者：
Monique Bos;John Mendelsohn;Young Mee Kim;Joan Albanell;David W. Fry;David W. Fry;José Baselga
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作者：
Monique Bos;John Mendelsohn;Young Mee Kim;Joan Albanell;David W. Fry;David W. Fry;José Baselga
据报道，PD 153035是表皮生长因子（EGF）受体酪氨酸激酶的特异性和强效抑制剂，并且在较小程度上是密切相关的HER 2/neu受体的抑制剂。我们发现，PD 153035抑制EGF依赖的EGF受体磷酸化，并抑制了广泛的EGF受体过表达的人癌细胞系的增殖和克隆形成。在过度表达EGF受体的细胞中，当PD 153035浓度>75 nM时，EGF受体自身磷酸化反应被完全抑制。相比之下，PD 153035仅在显著更高浓度（1400-2800 nM）下降低HER 2/neu过表达细胞系中的调蛋白依赖性酪氨酸磷酸化。PD 153035暴露不影响EGF受体或HER 2/neu的表达。PD 153035在低微摩尔浓度下引起EGF受体过表达细胞系的剂量依赖性生长抑制，在大多数测试的细胞系中，单层培养物中的IC 50小于1 μ M。在高达2.5 μ M的剂量下，未达到HER 2/neu过表达细胞的IC 50。在集落形成试验中，由内源性（自分泌）配体驱动的培养物中的PD 153035生长抑制活性与EGF受体数量相关，在表达较高数量EGF受体的细胞中具有较高活性，而在表达正常数量EGF受体但高HER 2/neu水平的细胞中仅具有最小活性。PD 153053还消除了由添加外源性EGF介导的所有生长效应;这种情况可以在去除化合物后逆转。与C225，抗EGF受体阻断单克隆抗体，共治疗，进一步增强PD 153035的抗肿瘤活性，提示C225的作用机制，而不是与配体结合的竞争。后一项发现还表明，联合抗EGF受体策略可能对EGF受体表达水平高的肿瘤具有增强的益处。
PD153035 is reported to be a specific and potent inhibitor of the epidermal growth factor (EGF) receptor tyrosine kinase and, to a lesser degree, of the closely related HER2/neu receptor. We show that PD153035 inhibits EGF-dependent EGF receptor phosphorylation and suppresses the proliferation and clonogenicity of a wide panel of EGF receptor-overexpressing human cancer cell lines. EGF receptor autophosphorylation in response to exogenous EGF was completely inhibited at PD153035 concentrations of >75 nM in cells overexpressing the EGF receptor. In contrast, PD153035 only reduced heregulin-dependent tyrosine phosphorylation in HER2/neu-overexpressing cell lines at significantly higher concentrations (1400-2800 nM). PD153035 exposure did not affect the expression of either EGF receptors or HER2/neu. PD153035 caused a dose-dependent growth inhibition of EGF receptor-overexpressing cell lines at low micromolar concentrations, and the IC50 in monolayer cultures was less than 1 microM in most cell lines tested. At doses of up to 2.5 microM, the IC50 for HER2/neu-overexpressing cells was not reached. In colony-forming assays, the PD153035 growth-inhibitory activity in cultures driven by endogenous (autocrine) ligand was correlated with EGF receptor number, with higher activity in cells expressing higher numbers of EGF receptors and only minimal activity in cells expressing normal numbers of EGF receptors but high HER2/neu levels. PD153053 also abolished all growth effects mediated by the addition of exogenous EGF; this condition could be reversed upon removal of the compound. Cotreatment with C225, an anti-EGF receptor-blocking monoclonal antibody, further enhanced the antitumor activity of PD153035, suggesting mechanisms of action for C225 other than competition with ligand binding. This latter finding also suggests that combined anti-EGF receptor strategies may be of enhanced benefit against tumors with high levels of EGF receptor expression.