Solomon Benjamin, Hagekyriakou Jim, Trivett Melanie K, Stacker Steven A, McArthur Grant A, Cullinane Carleen
Research Division, Department of Haematology and Medical Oncology, Peter MacCallum Cancer Institute, Melbourne, Victoria, Australia.
Int J Radiat Oncol Biol Phys. 2003 Mar 1;55(3):713-23. doi: 10.1016/s0360-3016(02)04357-2.
Signaling pathways initiated by the epidermal growth factor receptor (EGFR) play important roles in the response to ionizing radiation. In this study the consequences of inhibiting the EGFR on the response of A431 cells (human vulvar squamous cell carcinoma cells that overexpress EGFR) to radiation, were investigated in vitro and in vivo, using the selective EGFR-tyrosine kinase inhibitor, ZD1839 ("Iressa").
The effect of ZD1839 on proliferation, apoptosis, and clonogenic survival after radiation was determined in vitro. For in vivo studies, athymic nude mice with established subcutaneous A431 xenografts (approximately 100 mm(3)) were treated with either a single 10 Gy fraction or 4 daily 2.5 Gy fractions of radiation with or without ZD1839 (75 mg/kg/day intraperitoneally for 10 days) to determine effects on tumor growth delay.
Treatment of A431 cells with ZD1839 in vitro reduced proliferation, increased apoptosis, and reduced clonogenic survival after radiation. Strikingly greater than additive effects of ZD1839 in combination with radiation on tumor growth delay were observed in vivo after either a single 10 Gy fraction (enhancement ratio: 1.5) or multiple 4 x 2.5 Gy fractions (enhancement ratio: 4). ZD1839 reduced tumor vascularity, as well as levels of vascular endothelial growth factor (VEGF) protein and mRNA induced by stimulation with epidermal growth factor (EGF), suggesting a possible role of inhibition of angiogenesis in the effect.
Inhibiting EGFR-mediated signal transduction cascades with ZD1839 potentiates the antitumor effect of single and multiple fractions of radiation. These data provide preclinical rationale for clinical trials of EGFR inhibitors including ZD1839 in combination with radiation.
表皮生长因子受体（EGFR）启动的信号通路在对电离辐射的反应中起重要作用。在本研究中，使用选择性EGFR酪氨酸激酶抑制剂ZD1839（“易瑞沙”），在体外和体内研究了抑制EGFR对A431细胞（过表达EGFR的人外阴鳞状细胞癌细胞）辐射反应的影响。
在体外测定ZD1839对辐射后增殖、凋亡和克隆形成存活的影响。对于体内研究，将已建立皮下A431异种移植瘤（约100 mm³）的无胸腺裸鼠用单次10 Gy剂量或每日4次2.5 Gy剂量的辐射进行治疗，同时或不同时给予ZD1839（75 mg/kg/天腹腔注射，共10天），以确定对肿瘤生长延迟的影响。
在体外，用ZD1839处理A431细胞可降低增殖、增加凋亡并降低辐射后的克隆形成存活。在体内，单次10 Gy剂量（增强比：1.5）或多次4×2.5 Gy剂量（增强比：4）辐射后，观察到ZD1839与辐射联合对肿瘤生长延迟的作用显著大于相加效应。ZD1839降低了肿瘤血管生成以及表皮生长因子（EGF）刺激诱导的血管内皮生长因子（VEGF）蛋白和mRNA水平，提示抑制血管生成可能在该效应中起作用。
用ZD1839抑制EGFR介导的信号转导级联可增强单次和多次辐射的抗肿瘤作用。这些数据为包括ZD1839在内的EGFR抑制剂与辐射联合进行临床试验提供了临床前依据。
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