Pharmacodynamic studies of the epidermal growth factor receptor inhibitor ZD1839 in skin from cancer patients: Histopathologic and molecular consequences of receptor inhibition
Pharmacodynamic studies of the epidermal growth factor receptor inhibitor ZD1839 in skin from cancer patients: Histopathologic and molecular consequences of receptor inhibition
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DOI：
10.1200/jco.2002.20.1.110
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发表时间：
2002-01-01
影响因子：
45.3
通讯作者：
Baselga, J
中科院分区：
文献类型：
--
作者：
Albanell, J;Rojo, F;Baselga, J
目的：表皮生长因子受体（EGFR）酪氨酸激酶抑制剂ZD1839 （Iressa; Astra-Zeneca Pharmaceuticals, Alderley Park, uk）正在开发作为抗癌药物。我们在参加ZD1839一期临床试验的癌症患者中研究了ZD1839对皮肤中EGFR （EGFR依赖组织）的药效学影响。患者和方法：我们研究了104例ZD1839治疗前和/或ZD1839治疗后的皮肤活检（大约在治疗的第28天），这些患者来自65例接受每日递增剂量口服ZD1839的患者。我们通过免疫组织化学方法测量了ZD1839对EGFR激活的影响，使用了一种针对活化（磷酸化）EGFR的抗体。对受体信号（活化丝裂原活化蛋白激酶[MAPK]）、增殖、p27（KIP1）和成熟的影响也进行了评估。结果：治疗期间表皮角质层变薄（P < 0.001）。在毛囊中，发现了明显的角蛋白塞和扩大的漏斗微生物。ZD1839在所有EGFR表达细胞中抑制EGFR磷酸化（P < 0.001）。此外，ZD1839抑制MAPK活化（P < 0.001），降低角质细胞增殖指数（P < 0.001）。同时，ZD1839增加了p27（KIP1）和成熟标志物的表达（P < 0.001），增加了细胞凋亡（P < 0.001）。在达到剂量限制毒性之前，在所有剂量水平下都观察到这些效应。结论：ZD1839在体内抑制EGFR激活并影响下游受体依赖过程。当剂量远低于产生不可接受毒性的剂量时，这些影响是深远的，这一发现有力地支持了药效学评估，以选择最佳剂量，而不是最大耐受剂量，进行最终疗效和安全性试验。(C) 2001年美国临床肿瘤学会。
Purpose: The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor ZD1839 (Iressa; Astra-Zeneca Pharmaceuticals, Alderley Park, United Kingdom) is under development as an anticancer agent. We studied the pharmacodynamic effects of ZD1839 on EGFR in the skin, an EGFR-dependent tissue, in cancer patients participating in ZD1839 phase I clinical trials.Patients and Methods: We studied 104 pre- and/or on-ZD1839 therapy (approximate to at day 28 of therapy) skin biopsies from 65 patients receiving escalating doses of daily oral ZD1839. We measured ZD1839 effects on EGFR activation by immunohistochemistry using an antibody specific for the activated (phosphorylated) EGFR. Effects on receptor signaling (activated mitogen-activated protein kinase [MAPK]), proliferation, p27(KIP1), and maturation were also assessed.Results: Histopathologically, the stratum corneum of the epidermis was thinner during therapy (P < .001). In hair follicles, prominent keratin plugs and microorganisms were found in dilated infundibula. ZD1839 suppressed EGFR phosphorylation in all EGFR-expressing cells (P < .001). In addition, ZD1839 inhibited MAPK activation (P < .001) and reduced keratinocyte proliferation index (P < .001). Concomitantly, ZD1839 increased the expression of p27(KIP1) (P < .001) and maturation markers (P < .001) and increased apoptosis (P < .001). These effects were observed at all dose levels, before reaching dose-limiting toxicities.Conclusion: ZD1839 inhibits EGFR activation and affects downstream receptor-dependent processes in vivo. These effects were profound at doses well below the one producing unacceptable toxicity, a finding that strongly supports pharmacodynamic assessments to select optimal doses instead of a maximum-tolerated dose for definitive efficacy and safety trials. (C) 2001 by American Society of Clinical Oncology.