A novel approach in the treatment of neuroendocrine gastrointestinal tumours. Targeting the epidermal growth factor receptor by gefitinib (ZD1839).
A novel approach in the treatment of neuroendocrine gastrointestinal tumours. Targeting the epidermal growth factor receptor by gefitinib (ZD1839).
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DOI：
10.1038/sj.bjc.6601346
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发表时间：
2003-11-03
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
抑制神经内分泌（NE）胃肠道肿瘤生长和扩散的治疗选择仍然有限。由于吉非替尼（4-（3-氯-4-氟苯胺基）-7-甲氧基-6-（3-吗啉代丙氧基）喹唑啉），表皮生长因子受体敏感性酪氨酸激酶（EGFR-TK）的抑制剂，已被证明可以有效地抑制各种非NE肿瘤实体的生长，我们研究了吉非替尼在NE胃肠道肿瘤细胞中的抗肿瘤效力。在人胰岛素瘤（CM）细胞、人胰腺类癌（BON）细胞和肠道NE肿瘤细胞（STC-1）中，吉非替尼诱导了几乎100%的时间和剂量依赖性生长抑制。吉非替尼的抗增殖效力与肿瘤细胞的增殖率相关。因此吉非替尼在快速生长的CM细胞中的IC 50值为4.7±0.6 μM，在中等生长的BON细胞中仍为16.8±0.4 μM，在缓慢生长的STC-1细胞中高达31.5±2.5 μM。同样，吉非替尼诱导的细胞凋亡和细胞周期阻滞也因生长特征而异：快速生长的CM细胞对吉非替尼表现出强烈的G 0/G1阻滞，而在缓慢生长的STC-1中没有观察到显著的细胞周期改变。反之亦然，吉非替尼的促凋亡作用，如通过caspase-3活化和DNA片段化所确定的，在缓慢生长的STC-1细胞中最为明显。使用cDNA微阵列，我们发现了广泛的变化，参与细胞凋亡和细胞周期的调控基因的表达与吉非替尼孵育后。其中，观察到生长停滞和DNA损伤诱导基因GADD 153的上调。磷酸化的ERK 1/2，抑制GADD 153的表达，减少在一个时间依赖性的方式。然而，没有检测到吉非替尼诱导的GADD 153诱导的p38有丝分裂原活化蛋白激酶的激活。我们的数据表明，抑制EGFR-TK吉非替尼诱导NE胃肠道肿瘤细胞的生长抑制，凋亡和细胞周期阻滞。因此，EGFR-TK抑制似乎是治疗NE肿瘤疾病的一种有前途的新方法。
Therapeutic options to inhibit the growth and spread of neuroendocrine (NE) gastrointestinal tumours are still limited. Since gefitinib (4-(3-chloro-4-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline), an inhibitor of epidermal growth factor receptor-sensitive tyrosine kinase (EGFR-TK), had been shown to suppress potently the growth of various non-NE tumour entities, we studied the antineoplastic potency of gefitinib in NE gastrointestinal tumour cells. In human insulinoma (CM) cells, in human pancreatic carcinoid (BON) cells and in NE tumour cells of the gut (STC-1), gefitinib induced a time- and dose-dependent growth inhibition by almost 100%. The antiproliferative potency of gefitinib correlated with the proliferation rate of the tumour cells. So the IC50 value of gefitinib was 4.7±0.6 μM in the fast-growing CM cells, still 16.8±0.4 μM in the moderate-growing BON cells, and up to 31.5±2.5 μM in the slow-growing STC-1 cells. Similarly, the induction of apoptosis and cell-cycle arrest by gefitinib differed according to growth characteristics: fast-growing CM cells displayed a strong G0/G1 arrest in response to gefitinib, while no significant cell-cycle alterations were seen in the slow-growing STC-1. Vice versa, the proapoptotic effects of gefitinib, as determined by caspase-3 activation and DNA fragmentation, were most pronounced in the slow-growing STC-1 cells. Using cDNA microarrays, we found extensive changes in the expression of genes involved in the regulation of apoptosis and cell cycle after incubation with gefitinib. Among them, an upregulation of the growth arrest and DNA damage-inducible gene GADD153 was observed. Phosphorylation of ERK1/2, which inhibits GADD153 expression, was reduced in a time-dependent manner. However, no gefitinib-induced activation of the GADD153-inducing p38 mitogen-activated protein kinase was detected. Our data demonstrate that the inhibition of EGFR-TK by gefitinib induces growth inhibition, apoptosis and cell-cycle arrest in NE gastrointestinal tumour cells. Thus, EGFR-TK inhibition appears to be a promising novel approach for the treatment of NE tumour disease.
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影响因子：
45.3
作者：
Baselga, J;Rischin, D;Albanell, J
通讯作者：
Albanell, J
影响因子：
5.8
作者：
Mendelsohn, J
通讯作者：
Mendelsohn, J
外周苯二氮卓受体的特定配体诱导人结肠直肠癌细胞中的细胞凋亡和细胞周期停滞。
影响因子：
8.8
作者：
Maaser, K;Hopfner, M;Jansen, A;Weisinger, G;Gavish, M;Kozikowski, A P;Weizman, A;Carayon, P;Riecken, E O;Zeitz, M;Scherubl, H
通讯作者：
Scherubl, H
影响因子：
8.8
作者：
Maaser, K;Hopfner, M;Kap, H;Sutter, A P;Barthel, B;von Lampe, B;Zeitz, M;Scherubl, H
通讯作者：
Scherubl, H
影响因子：
29.4
作者：
AhnertHilger, G;Stadtbaumer, A;Wiedenmann, B
通讯作者：
Wiedenmann, B