吉非替尼

酪氨酸激酶抑制剂；抑制EGFR

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产品号 #73162_C

酪氨酸激酶抑制剂；抑制EGFR

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总览

吉非替尼是表皮生长因子受体（EGFR）酪氨酸激酶的选择性抑制剂，其在ATP结合口袋中竞争性结合，对A431外阴鳞状癌细胞和KB细胞的IC₅₀值分别为为23和80 nM （Barker等人）。

癌症研究
·在体外和小鼠异种移植模型中，阻断多种癌症细胞类型的增殖，包括结肠癌、卵巢癌和乳腺癌细胞系（Ciardiello等人）。
·通过激活c-Jun N-末端激酶（JNK），诱导HaCaT人角质细胞细胞系凋亡（Lu等人），这是一种EGFR非依赖性机制，。

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Product Name

Catalog #

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Document Type

Product Information Sheet

Product Name

Gefitinib

Catalog #

73162

Lot #

All

Language

English

Document Type

Safety Data Sheet

Product Name

Gefitinib

Catalog #

73162

Lot #

All

Language

English

技术资料 (2)

Gefitinib-induced epidermal growth factor receptor-independent keratinocyte apoptosis is mediated by the JNK activation pathway. Lu P-H et al. The British journal of dermatology 2011

Abstract

BACKGROUND: Gefitinib (ZD1839) is a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor with a significant antitumour effect on various cancers. Skin toxicity induced by gefitinib is common, and has been shown to be related to the inhibition of EGFR signalling pathways. However, other mechanisms may be involved in gefitinib-induced skin toxicity. OBJECTIVES: To study the possible EGFR-independent mechanisms of gefitinib-induced skin toxicity. METHODS: The human immortalized keratinocyte cell line HaCaT and human lung adenocarcinoma cell lines (A549 and PC9) were treated with different concentrations of gefitinib for 24, 48 and 72 h. Cell viability was measured by MTT assay [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] after EGFR gene silencing. The signalling pathways were investigated by immunoblot analysis. Keratinocyte apoptosis was evaluated by nuclear condensation and flow cytometric analysis. RESULTS: Gefitinib maintained its cytotoxicity to HaCaT cells after EGFR gene silencing, indicating that an EGFR-independent mechanism exists. Increased phosphorylation of p38 mitogen-activated protein kinase and JNK by gefitinib was observed in a dose-dependent manner in HaCaT cells. The JNK inhibitor, SP600125, attenuated the gefitinib-induced cytotoxicity and apoptosis of HaCaT cells. Immunohistochemical examination of patient specimens showed an increased expression of phosphorylated JNK in lesional epidermis compared with nonlesional epidermis. CONCLUSIONS: Gefitinib can induce keratinocyte apoptosis through an EGFR-independent JNK activation pathway.

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Novel cell culture technique for primary ductal carcinoma in situ: role of Notch and epidermal growth factor receptor signaling pathways. Farnie G et al. Journal of the National Cancer Institute 2007 APR

Abstract

BACKGROUND The epidermal growth factor receptor (EGFR) and Notch signaling pathways have been implicated in self-renewal of normal breast stem cells. We investigated the involvement of these signaling pathways in ductal carcinoma in situ (DCIS) of the breast. METHODS Samples of normal breast tissue (n = 15), pure DCIS tissue of varying grades (n = 35), and DCIS tissue surrounding an invasive cancer (n = 7) were used for nonadherent (i.e., mammosphere) culture. Mammosphere cultures were treated at day 0 with gefitinib (an EGFR inhibitor), DAPT (N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester) (a gamma-secretase inhibitor), or Notch 4-neutralizing antibody. Mammosphere-forming efficiency (MFE) was calculated by dividing the number of mammospheres of 60 microm or more formed by the number of single cells seeded and is expressed as a percentage. The Notch 1 intracellular domain (NICD) was detected immunohistochemically in paraffin-embedded DCIS tissue from 50 patients with at least 60 months of follow-up. All statistical tests were two-sided. RESULTS DCIS had a greater MFE than normal breast tissue (1.5% versus 0.5%, difference = 1%, 95% confidence interval [CI] = 0.62% to 1.25%, Ptextless.001). High-grade DCIS had a greater MFE than low-grade DCIS (1.6% versus 1.09%, difference = 0.51%, 95% CI = 0.07% to 0.94%, P = .01). The MFE of high-grade DCIS treated with gefitinib in the absence of exogenous EGF was lower than that of high-grade DCIS treated with mammosphere medium lacking gefitinib and exogenous EGF (0.56% versus 1.36%, difference 0.8%, 95% CI = 0.33% to 1.4%, P = .004). Increased Notch signaling as detected by NICD staining was associated with recurrence at 5 years (P = .012). DCIS MFE was reduced when Notch signaling was inhibited using either DAPT (0.89% versus 0.51%, difference = 0.38%, 95% CI = 0.2% to 0.6%, Ptextless.001) or a Notch 4-neutralizing antibody (0.97% versus 0.2%, difference = 0.77%, 95% CI = 0.52% to 1.0%, Ptextless.001). CONCLUSION We describe a novel primary culture technique for DCIS. Inhibition of the EGFR or Notch signaling pathways reduced DCIS MFE.

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Studies leading to the identification of ZD1839 (IRESSA): an orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor targeted to the treatment of cancer. Barker AJ et al. Bioorganic & medicinal chemistry letters 2001

Abstract

This paper describes the development of the epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 from a lead series of 4-anilinoquinazoline compounds. ZD1839 has suitable properties for use as a clinically effective drug and shows activity against human tumours. In particular, the use of pharmacokinetic data in the development of ZD1839 is discussed.

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种属	Human, Mouse, Non-Human Primate, Other, Rat
Cas Number	184475-35-2
Chemical Formula	C₂₂H₂₄ClFN₄O₃
纯度	≥ 98%
Target	EGFR
Pathway	Tyrosine Kinase