The epidermal growth factor receptor tyrosine kinase inhibitor gefitinib sensitizes colon cancer cells to irinotecan

吉非替尼 表皮生长因子受体 序号38 癌症研究 酪氨酸激酶抑制剂 伊立替康 药理学 酪氨酸激酶 下调和上调 蛋白激酶A 结直肠癌 信号转导 激酶 化学 生物 癌症 医学 内科学 生物化学 基因
作者
Ada Braun,Katrin Stark,Olaf Dirsch,Ralf A. Hilger,S. Seeber,U. Vanhoefer
出处
期刊:Anti-Cancer Drugs [Ovid Technologies (Wolters Kluwer)]
卷期号:16 (10): 1099-1108 被引量:27
标识
DOI:10.1097/00001813-200511000-00009
摘要

Epidermal growth factor receptor (EGFR) overactivity plays a significant role in colon cancer biology and has been associated with poor clinical prognosis. Early clinical trials reported efficacy of receptor-targeted compounds, including modulation of clinical irinotecan resistance. We investigated the effects of the EGFR tyrosine kinase inhibitor gefitinib on cellular determinants of irinotecan resistance in human colon cancer cells. At non-cytotoxic concentrations, gefitinib sensitized colon cancer cells to SN-38, the active metabolite of irinotecan. Gefitinib increased the SN-38-mediated induction of protein-linked DNA single-strand breaks in a dose-dependent manner, with no alteration of topoisomerase (Topo) I protein expression or enzymatic activity. Whereas Topo IIβ protein expression was not affected by gefitinib, significant time- and concentration-dependent downregulation of Topo IIα protein and inhibition of its enzymatic function were observed, corresponding to a G1 phase cell cycle arrest. Gefitinib significantly inhibited EGFR-associated signaling molecules, including phospho-mitogen-activated protein kinase or protein kinase C, which may account for decreases in proliferation or topoisomerase activity, respectively. Although a dose-dependent decrease of the BCRP/MXR/ABCP half-transporter was observed under gefitinib, cellular pharmacokinetics revealed no significant differences in accumulation or retention of the active SN-38 lactone using reverse-phase HPLC analysis. This study delineates mechanisms that may contribute to the synergism observed between irinotecan and EGFR inhibitors.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
刚刚
不懈奋进应助科研通管家采纳,获得30
1秒前
威武乐瑶发布了新的文献求助10
2秒前
2秒前
大然完成签到,获得积分10
4秒前
开心的又夏完成签到,获得积分20
4秒前
不懈奋进应助科研通管家采纳,获得30
4秒前
4秒前
5秒前
西大喜完成签到,获得积分10
5秒前
qiqiqi发布了新的文献求助10
6秒前
279发布了新的文献求助10
6秒前
依萱应助初闻采纳,获得20
6秒前
不懈奋进应助科研通管家采纳,获得30
8秒前
完美问枫完成签到,获得积分10
8秒前
allin完成签到,获得积分10
8秒前
怪诞完成签到,获得积分10
8秒前
勤劳的凝海完成签到,获得积分10
8秒前
123465发布了新的文献求助10
8秒前
9秒前
古的古的应助邢从丹采纳,获得10
9秒前
小八儿完成签到,获得积分10
9秒前
aldehyde应助科研通管家采纳,获得10
11秒前
SunHY发布了新的文献求助10
11秒前
yezi完成签到,获得积分10
11秒前
金22完成签到,获得积分10
11秒前
sunwei完成签到,获得积分10
11秒前
好久不见发布了新的文献求助10
12秒前
快乐小子发布了新的文献求助10
12秒前
Alice发布了新的文献求助20
12秒前
12秒前
albertxin应助科研通管家采纳,获得10
14秒前
qiqiqi完成签到,获得积分10
14秒前
16秒前
wen应助科研通管家采纳,获得20
17秒前
17秒前
18秒前
18秒前
19秒前
19秒前
高分求助中
Evolution 2024
Impact of Mitophagy-Related Genes on the Diagnosis and Development of Esophageal Squamous Cell Carcinoma via Single-Cell RNA-seq Analysis and Machine Learning Algorithms 2000
How to Create Beauty: De Lairesse on the Theory and Practice of Making Art 1000
Gerard de Lairesse : an artist between stage and studio 670
大平正芳: 「戦後保守」とは何か 550
Contributo alla conoscenza del bifenile e dei suoi derivati. Nota XV. Passaggio dal sistema bifenilico a quello fluorenico 500
Multiscale Thermo-Hydro-Mechanics of Frozen Soil: Numerical Frameworks and Constitutive Models 500
热门求助领域 (近24小时)
化学 医学 生物 材料科学 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 2996249
求助须知:如何正确求助?哪些是违规求助? 2656625
关于积分的说明 7190066
捐赠科研通 2292204
什么是DOI,文献DOI怎么找? 1215049
科研通“疑难数据库(出版商)”最低求助积分说明 593031
版权声明 592795