Gefitinib (ZD1839)

Gefitinib (ZD1839), is a potent EGFR-TKI (EGFR tyrosine kinase inhibitor) with IC50 of 0.033 µM, selectively inhibits EGF-stimulated tumor cell growth with IC50 of 0.054 µM and that blocks EGF-stimulated EGFR (epidermal growth factor receptor) autophosphorylation in tumor cells[1].

In vitro, the NR6wtEGFR and NR6M cell lines had low levels of PLC-γ phosphorylations but the level in the NR6M cell line was more resistant to inhibition by gefitinib (IC50 of 43 and 369 nm, respectively)[2]. A gefitinib concentration above 0.1 µm decreases the colony-forming ability of NR6W and NR6wtEGFR cells and a concentration of 1.5 µm completely abolishes the ability of these cell lines to form colonies[2]. The IC50 values of four NSCLC cells for gefitinib were 18.90 µmol/L, 16.40 µmol/L, 1.794 µmol/L and 15.99 µmol/L for A549, H1975, PC9, and PC9/GR, respectively[3]. In addition, a small concentration of gefitinib (0.62 µmol/L) significantly inhibited IL-13-induced M2-like polarization of macrophages[4].

In vivo, C57BL/6 mice were treated with 20, 40 and 80 mg/kg, once-daily for 18 days, intragastrically significantly inhibited lung metastases compared with lung tumor metastatic model mice, further indicating that the lung tissue had a reduced number of metastatic lesions and cancer cells[5]. In vivo, the growth of D341 and Daoy (medulloblastoma cell lines) xenografts treated with gefitinib at 150 mg/kg per day was inhibited by approximately 50%. Ectopically overexpressed HER2 in Daoy cells significantly increased sensitivity to gefitinib's antitumor effects in vivo (tumor volume inhibition = 78%)[6].

References:

[1]. Wakeling AE, et al. ZD1839 (Iressa): an orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy. Cancer Res. 2002 Oct 15;62(20):5749-54.

[2]. Pedersen MW, et al. Differential response to gefitinib of cells expressing normal EGFR and the mutant EGFRvIII. Br J Cancer. 2005 Oct 17;93(8):915-23.

[3]. Sun C, et al. FGL1 regulates acquired resistance to Gefitinib by inhibiting apoptosis in non-small cell lung cancer. Respir Res. 2020 Aug 10;21(1):210.

[4]. Tariq M, et al. Gefitinib inhibits M2-like polarization of tumor-associated macrophages in Lewis lung cancer by targeting the STAT6 signaling pathway. Acta Pharmacol Sin. 2017 Nov;38(11):1501-1511.

[5]. Fan Q, et al. Pedunculoside inhibits epithelial-mesenchymal transition and overcomes Gefitinib-resistant non-small cell lung cancer through regulating MAPK and Nrf2 pathways. Phytomedicine. 2023 Jul 25;116:154884.

[6]. Meco D, et al. Antitumor effect in medulloblastoma cells by gefitinib: Ectopic HER2 overexpression enhances gefitinib effects in vivo. Neuro Oncol. 2009 Jun;11(3):250-9.

吉非替尼(Gefitinib, ZD1839)是一种强效的表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI),IC50为0.033 µM,能选择性抑制表皮生长因子刺激的肿瘤细胞生长,IC50为0.054 µM,并能阻断表皮生长因子刺激的表皮生长因子受体(EGFR)在肿瘤细胞中的自身磷酸化[1]。

在体外,NR6wtEGFR 和 NR6M 细胞系的 PLC-γ 磷酸化水平较低,但吉非替尼对NR6M 细胞系的 PLC-γ 磷酸化水平抑制作用更强(在NR6wtEGFR 和 NR6M 细胞系的IC50 分别为 43 nM和 369 nM)[2]。吉非替尼浓度超过 0.1 µm 会降低 NR6W 和 NR6wtEGFR 细胞的集落形成能力,而 1.5 µm 的浓度则会完全削弱这些细胞系形成集落的能力[2]。A549、H1975、PC9和PC9/GR四种NSCLC细胞对吉非替尼的IC50值分别为18.90 µmol/L、16.40 µmol/L、1.794 µmol/L和15.99 µmol/L[3]。此外,小浓度的吉非替尼(0.62 µmol/L)可显著抑制 IL-13 诱导的巨噬细胞 M2 样极化[4]。

在体内,与肺部肿瘤转移模型小鼠相比,C57BL/6小鼠胃内注射吉非替尼20、40和80 mg/kg,每日一次,连续18天,可明显抑制肺转移,进一步表明肺组织转移灶和癌细胞数量减少[5]。在体内,每天 150 mg/kg的吉非替尼可抑制 D341 和 Daoy(髓母细胞瘤细胞系)异种肿瘤移植模型的肿瘤生长约 50%。在 Daoy 细胞中异位过表达的 HER2 能显著提高吉非替尼体内抗肿瘤作用的敏感性(肿瘤体积抑制率 = 78%)[6]。