Sequence-dependent antiproliferative effects of cytotoxic drugs and epidermal growth factor receptor inhibitors
Sequence-dependent antiproliferative effects of cytotoxic drugs and epidermal growth factor receptor inhibitors
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DOI：
10.1093/annonc/mdi910
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发表时间：
2005-05-01
影响因子：
50.5
通讯作者：
Ciardiello, Fortunato
中科院分区：
文献类型：
--
作者：
Morelli, M. P.;Cascone, T.;Ciardiello, Fortunato
背景：表皮生长因子受体（EGFR）抑制剂在癌症治疗中处于临床开发阶段。临床前研究表明，这些药物与化疗或放疗联合使用具有潜在的抗肿瘤疗效。然而，在不同的临床试验中得到了有争议的结果。材料和方法：三种抗EGFR药物对细胞增殖、细胞周期分布及诱导凋亡的影响（吉非替尼、ZD 6474、西妥昔单抗）以不同顺序与铂衍生物组合进行评估（顺铂、卡铂、奥沙利铂）或紫杉烷（多西他赛，紫杉醇）在KYSE 30细胞中的作用，KYSE 30细胞是具有功能性EGFR自分泌途径的人癌细胞系的模型。细胞毒性药物与EGFR抑制剂的组合根据治疗方案对KYSE 30癌细胞产生不同的抗增殖作用。当在化疗前用每种EGFR抑制剂治疗时，观察到拮抗作用。相反，当化疗后用EGFR拮抗剂治疗时，获得了协同抗增殖活性。这种效果是伴随着增强的细胞凋亡和逮捕的存活的癌细胞在G2/M期的cycle.Conclusions：这项研究提供了一个潜在的协同序列的细胞毒性药物和EGFR抑制剂在临床环境中的评价的理由。
Background: Epidermal growth factor receptor (EGFR) inhibitors are in clinical development in cancer treatment. Preclinical studies have shown potential antitumor efficacy of these agents in combination with chemotherapy or with radiotherapy. However, controversial results have been obtained in different clinical trials.Materials and methods: The effects on proliferation, cell cycle distribution and induction of apoptosis of three different anti-EGFR agents (gefitinib, ZD6474, cetuximab) were evaluated in different sequences of combination with either a platinum derivative ( cisplatin, carboplatin, oxaliplatin) or a taxane (docetaxel, paclitaxel) in KYSE30 cells, a model of a human cancer cell line with a functional EGFR autocrine pathway.Results: The combination of a cytotoxic drug with an EGFR inhibitor caused different antiproliferative effects on KYSE30 cancer cells depending on the treatment schedule. An antagonistic effect was observed when treatment with each EGFR inhibitor was done before chemotherapy. In contrast, a synergistic antiproliferative activity was obtained when chemotherapy was followed by treatment with EGFR antagonists. This effect was accompanied by potentiation of apoptosis and arrest of the surviving cancer cells in the G2/M phases of the cell cycle.Conclusions: This study provides a rationale for the evaluation of a potentially synergistic sequence of cytotoxic drugs and EGFR inhibitors in a clinical setting.