Gleevec在胰腺癌中的应用及其作用机制

目的探讨Gleevee对胰腺癌细胞的生长抑制作用及其作用机制。方法应用噻唑氮蓝（MTT）比色分析法测定测Gleevee对胰腺癌细胞株的生长抑制作用及对生长因子的抑制作用。应用膜联蛋白（annexin）V标记与碘化丙啶（propidium iodide，PI）染色检测胰腺癌细胞经Gleevec作用后的死亡与凋亡情况。采用Western blot检测Gleevec对生长因子受体及MAPK磷酸化的影响。结果Gleevec抑制胰腺癌细胞的生长，半数有效量介于17-31．5μM。Annexin与PI染色观察到胰腺癌细胞的坏死及细胞膜完整性破坏。Gleevec部分抑制生长因子对胰腺癌细胞的促生长作用，但是对生长因子受体与MAPK磷酸化没有影响。结论Gleevee对胰腺癌细胞有生长抑制作用，其体内疗效尚待进一步研究。     

表皮生长因子受体/丝氨酸/苏氨酸蛋白激酶途径在三苯氧胺耐药人乳腺癌细胞株MCF-7形成中的作用

目的 观察表皮生长因子受体( EGFR)/丝氨酸/苏氨酸蛋白激酶(AKT)途径在三苯氧胺(TAM)耐药人乳腺癌细胞株MCF-7形成过程的变化,及抑制该途径对肿瘤细胞周期的影响.方法 用1×10-7 nmoL/L的三苯氧胺诱导、建立三苯氧胺耐药细胞(TAM-R)细胞株,以荧光定量逆转录聚合酶链反应( fqRT-PCR)、Western blot法、流式细胞术检测MCF-7与TAM-R细胞中EGFR mRNA、p-AKT蛋白的表达及TAM-R细胞给予EGFR及AKT抑制剂后对细胞周期的影响.结果 TAM-R细胞中EGFR mRNA和p-AKT蛋白的表达较MCF-7显著提高(P＜0.05);给予ZD1839和SH-6阻断EGFR/AKT信号通路后,p-AKT表达受到抑制(P＜0.05),TAM-R细胞的G0～G1期比例提高,其中20 μmol/L ZD1839组高达88％,细胞增殖指数下降(P＜0.05).结论 EGFR/AKT信号通路在MCF-7细胞对TAM耐药的形成中提供了非雌激素途径的生长信号.     

成纤维细胞生长因子受体1在胰腺癌细胞中的表达和调控

目的 研究成纤维细胞生长因子受体1(FGFR1)蛋白和mRNA在胰腺癌细胞系中的表达和调控机制.方法 采用Western免疫印迹实验、Northern印迹分析和RT-PCR检测FGFR1在胰腺癌细胞中的表达.使用外源性生长因子刺激细胞并使用激酶抑制剂阻断细胞内信号转导通路,观察FGFR1蛋白和mRNA在胰腺癌细胞中表达的变化情况.结果 FGFR1蛋白和mRNA在胰腺癌细胞系中均有不同程度的表达.生长因子刺激可上调FGFR1蛋白和mRNA的表达水平.其中IGF-1、EGF和FGF2显著增加Mia PaCa-2细胞FGFR1的表达,EGF和FGF2显著增加PANC-1细胞FGFR1的表达(P＜0.05).FGF2对FGFR1表达的调节具有时间依赖性.ERK1/2抑制剂UO126和p38 MAPK抑制剂SB203580降低了PANC-1细胞中FGFR1的蛋白和mRNA的表达水平. 结论生长因子可上调FGFR1在胰腺癌细胞中的表达水平,MAPK信号转导通路中的ERK1/2和p38 MAPK亚通路参与FGFR1表达的调节.     

表皮生长因子受体阻断对前列腺癌细胞增殖的影响

目的：探讨阻断表皮生长因子受体（EGFR）对前列腺癌（PCa）细胞增殖的影响。方法：人PCa细胞株DU－145，分别加或不加抗EGFR单抗C225（20nmol/L)阻断EGFR体外细胞培养7d，收集细胞、计数以观察对PCa雄激素非依赖增殖的影响，并采用免疫沉淀和Western blot方法，探讨阻断EGFR后不同时相点磷酸化有丝分裂原激活下蛋白激酶MAPK，及p27^kipl的表达变化。结果：阻断EGFR与对照相比较可使DU－145细胞增殖被抑制达35％，8h后磷酸化MAPK的表达水平开始降低，p27^kip1表达开始升高，至24h最明显。结论：阻断EGFR可抑制PCa细胞增殖，可能的机制是MAPK的活性降低，使p27^kip1的表达升高而细胞周期被阻。     

铜绿假单胞菌对胰腺癌细胞的抑癌效应及分子机制研究

目的 :主要探讨铜绿假单胞菌抗胰腺癌细胞的效果及其主要机制。方法:采用CCK8法检测胰腺癌细胞经铜绿假单胞菌作用后细胞增殖率变化,并应用透射电镜观察药物处理后细胞超微结构的改变。通过AnnexinⅤ/PI流式细胞术检测细胞经不同浓度铜绿假单胞菌处理后细胞凋亡的变化,分析胰腺癌细胞周期改变。Western印迹检测胰腺癌细胞表皮生长因子受体(EGFR)信号通路相关蛋白质的表达。结果:铜绿假单胞菌可明显抑制胰腺癌细胞增殖,并可观察到形态学的明显凋亡改变。铜绿假单胞菌处理后肿瘤细胞凋亡明显增加,并诱导肿瘤细胞的细胞周期阻滞,肿瘤细胞EGFR信号通路磷酸化蛋白表达量明显下降。结论:铜绿假单胞菌可诱导胰腺癌细胞凋亡,抑制肿瘤生长,阻滞细胞周期,EGFR通路抑制是铜绿假单胞菌诱导胰腺癌细胞凋亡的重要机制之一。     

乳腺癌中雌激素诱导的细胞增殖与有丝分裂素激活蛋白激酶活性的关系

目的探讨雌二醇与有丝分裂素激活蛋白激酶(MAPK)信号通路的关系以及MAPK在乳腺癌细胞系中的表达情况。方法分别用上皮生长因子(EGF)和不同浓度的雌二醇诱导人类乳腺癌细胞系MCF-7细胞,诱导不同时间后用Western blot方法检测磷酸化ERK1／2的表达;用抗雌激素物质ICI182780和MAPK抑制剂PD98059作用于雌二醇诱导的MCF-7细胞,检测磷酸化ERK1／2的表达;用流式细胞仪检测雌二醇对MCF-7细胞周期的影响。结果MAPK信号通路的诱导剂EGF可以明显诱导磷酸化MAPK的表达;雌二醇也可以诱导磷酸化MAPK的表达。PD98059可以完全抑制雌二醇诱导的磷酸化ERK1／2水平,而ICI182780只能减少雌二醇诱导的磷酸化ERK1／2的表达。随着作用时间的延长,雌二醇可以使MCF-7细胞G2／M期的细胞数增加。结论雌二醇、雌激素受体与MAPK信号途径关系较为密切,MAPK是乳腺癌中重要的调节信号。     

有丝分裂激活蛋白激酶在人前列腺癌细胞中的激活

目的 探讨前列腺癌（PCa)细胞中有丝分裂激活蛋白激酶（MAPK）的激活。方法 采用免疫沉淀和Western blot方法,检测人PCa细胞株LNCaP及DU－145中磷酸化MAPK的表达及雄激素或表皮生长因子（EGF）对其表达的影响。结果 在DU－145中,磷酸化MAPK表达本底水平比LNCaP高10倍。雄激素和EGF处理后8hLNCaP中MAPK激活水平升高,24h达最高,分别比本底高约10倍和5倍,在DU－145中仅EGF可促使MAPK激活水平升高,8h开始升高,24h达最高,比本底高约10倍。结论 在雄激素非依赖性人PCa细胞增生中,MAPK激活比在雄激素依赖性人PCa细胞中作用大,MAPK激活也参与了雄激素和EGF的增生刺激作用。     

Gefitinib对前列腺癌DU145细胞EGFR、MAPK、AKt及PKC蛋白表达的影响

目的探讨在Gefitinib 作用下前列腺癌DU145细胞表皮生长因子受体(EGFR)、促分裂原活化蛋白激酶(MAPK)、丝氨酸蛋白激酶(AKt)及蛋白激酶C(PKC)蛋白表达水平的变化.方法使用终浓度为10μmol/L Gefitinib体外作用于DU145细胞,Western blot检测DU145细胞EGFR、MAPK、AKt、PKC蛋白表达水平.结果 经Gefitinib作用后DU145细胞EGFR、Akt蛋白水平分别降低了69.57%和58.31%,而MAPK及PKC 蛋白分别仅降低35.93%和32.7%.结论 Gefitinib作用后DU145细胞发生生长抑制可能和EGFR、Akt蛋白表达抑制有关,而和MAPK及PKC蛋白抑制无关.     

表皮生长因子及其受体在睾丸中的分布与功能

睾丸Sertoli细胞和早期生精细胞不仅存在表皮生长因子 (EGF)而且存在EGF受体 (EGFR) ,睾丸Leydig细胞也含有EGFR。EGF通过和EGFR结合 ,发挥特定的生物学效应 ,能刺激睾丸雄激素的合成和生精细胞的成熟。但是高浓度的EGF反而会抑制生精细胞的成熟。     

吉非替尼和靶向表皮生长因子受体小干扰RNA治疗前列腺癌

目的 观察吉非替尼(Gefitinib)和靶向表皮生长因子受体(EGFR)小干扰RNA(siRNA)体内外抑制前列腺癌的效果并探讨其作用机制.方法 前列腺癌细胞PC-3转染慢病毒为载体的EGFR siRNA或Gefitinib(0～10 ms/L)处理后,噻唑蓝(iT)比色法检测细胞生长抑制率,荧光聚合酶链反应(PCR)检测EGFR mRNA表达,Western blot检测EGFR、丝氨酸蛋白激酶(Akt)、促分裂原活化蛋白激酶(MAPK)和蛋白激酶c(PKC)表达.体内观察EGFR siRNA和Gefitinib单独或联合抑瘤效果.结果 EGFR siRNA对PC-3细胞转染率达85%,细胞生长抑制率为40%～50%,而Gefitinib细胞生长抑制率呈浓度.时间依赖性.EGFR siRNA对PC-3细胞EGFR mRNA和蛋白表达抑制率＞90%,明显高于Gefitinib的＜80%(P＜0.01);EGFR siRNA显著抑制Akt和MAPK表达,而Gefifimb仅明显抑制Akt表达.Gefitnib单独和联合EGFR siRNA的抑瘤率分别为53.95%和59.28%,明显高于EGFR siRNA组的34.83%(P＜0.05).结论 EGFR通路抑制剂能有效抑制前列腺癌生长,其机制主要通过阻断EGFR及其胞内蛋白Akt的表达来实现.     

Targeting the EGF/VEGF-R system by tyrosine-kinase inhibitors—a novel antiproliferative/antiangiogenic strategy in thyroid cancer

Aim In thyroid cancer (TC), endothelial growth factor (EGF) has been associated with dedifferentiation, tumor cell proliferation, and angiogenesis. Vascular endothelial growth factor (VEGF) has been documented to be the main stimulator of angiogenesis in the thyroid gland. Patients with undifferentiated thyroid cancer are in desperate need of new therapeutic strategies because common protocols of therapy usually fail. The aim of this study, therefore, was to evaluate two tyrosine-kinase inhibitors (TKI, ZD 1839 gefitinib and ZD 6474 vandetanib), directed against the EGF/VEGF receptor for possible antitumor therapy in thyroid cancer.Methods EGF/VEGF-R was documented in anaplastic (Hth74, C643), follicular (FTC133), and papillary (TPC1) thyroid cancer cell lines by Western blot analysis. The antiproliferative effect of two TKI (0.1–10 μM) on thyroid cancer cell lines in vitro was quantified by MTT assay, the antiangiogenic effect by assessing secretion of VEGF by enzyme-linked immunosorbent assay (R&D Systems). ZD 1839 is mainly directed against EGF-R and ZD 6474 against VEGF-R (AstraZeneca, UK), single applications and combinations of compounds were evaluated.Results EGF-R and VEGF-R as well as the phosphorylated receptor were documented in all of the cell lines. Administration of ZD1839 led to an up to 90% reduction of cell number in Hth74, 80% in C643, 50% in FTC133, and 90% in TPC1 (p < 0.05). ZD1839 induced a decrease of VEGF secretion between 30% in C643 and 90% in Hth74. Administration of ZD6474 led to an up to 95% reduction of cell number in Hth74, 85% in C643, 90% in FTC133, and 90% in TPC1 (p < 0.05). The ZD6474 induced decrease of VEGF secretion ranged between 20% (FTC133) and 60% (TPC1). Combinations of IC50 concentrations of TKI showed synergistic effects, resulting in additional inhibition of proliferation between 50 and 90% compared to single drug administration.Conclusion The EGF/EGF-R system resembles a powerful VEGF-stimulating pathway in all histiotypes of TC and can be inhibited by TKI. TKI directed against EGF-R as well as VEGF-R inhibit tumor cell proliferation and VEGF secretion in vitro. Combinations of TKI are more effective than strategies using single agents. It is suggested that targeting EGF-R/VEGF-R-mediated pathways may have therapeutic potential in some undifferentiated thyroid cancers.Presented at the 2nd Biennal Congress of the ESES, May 2006, Krakow, Poland.     

Anti-EGF receptor therapy

The epidermal growth factor receptor (EGFR) signalling pathway contributes to a number of processes important to tumour progression, including cell proliferation, apoptosis, angiogenesis and metastatic spread. EGFR signalling is thought to be an important cell survival mechanism in hormone-resistant prostate cancer. ZD1839 ('Iressa') is an orally active, selective EGFR-tyrosine kinase inhibitor (EGFR-TKI) which blocks signal transduction pathways implicated in promoting cancer growth. In preclinical studies, ZD1839 alone, and in combination with cytotoxic agents, produced reversible growth inhibition and growth delay in a wide range of tumour cell lines and human tumour xenografts. Preliminary results from phase I trials in patients with advanced disease suggest that ZD1839 has an acceptable tolerability profile and promising clinical efficacy in patients with a variety of tumour types, including hormone-resistant prostate cancer, where new treatment strategies are needed. Prostate Cancer and Prostatic Diseases (2000) 3, 296-302     

Synergistic antiproliferative and apoptotic effects induced by mixed epidermal growth factor receptor inhibitor ZD1839 and nitric oxide donor in human prostatic cancer cell lines

BACKGROUND: The specific inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, ZD1839 induces potent antitumoral effects on several advanced cancer types. The present study was undertaken to determine whether the combination of ZD1839 with an agent donating nitric oxide (NO(*)), sodium nitroprusside (SNP) results in a synergy of anticarcinogenic responses on metastatic prostate cancer (PC) cells. METHODS: The antiproliferative and apoptotic/necrotic effects of ZD1839 and SNP alone or in combination were estimated on EGF- and serum-stimulated LNCaP, DU145, and PC3 cells by MTT growth tests, trypan blue dye exclusion method, and flow cytometric analyses. Moreover, the cellular ceramide levels were evaluated by the diacylglycerol kinase enzymatic method and the amounts of cytosolic cytochrome c by ELISA assays. RESULTS: ZD1839 and SNP alone or in combination at lower concentrations induced an inhibition of EGF- and serum-stimulated growth of LNCaP, DU145, and PC3 concomitant with an arrest in the G1 phase of cellular cycle. Interestingly, the mixed ZD1839 and SNP also caused a more substantial apoptotic/necrotic death of these PC cells as compared to drugs alone. Moreover, we have observed that an inhibition of acidic sphingomyelinase, hydrogen peroxide (H(2)O(2)) accumulation and caspase cascades results in a significant reduction of apoptotic/necrotic death induced by mixed ZD1839 and SNP in EGF-stimulated PC3 cells. In addition, the combined ZD1839 plus SNP also induced a higher cellular ceramide and reactive oxygen species (ROS) production, mitochondrial transmembrane potential decrease, and cytochrome c amount released into cytosol as compared to drugs alone. CONCLUSIONS: The simultaneous use of EGFR inhibitor and compound releasing NO(*) might lead to a synergy in the ceramide and ROS production which might cause cellular membrane damages resulting in a massive apoptotic/necrotic death of metastatic PC cells.     

Blockade of growth factor receptors in ductal carcinoma in situ inhibits epithelial proliferation

BACKGROUND: Ductal carcinoma in situ (DCIS) expresses c-erbB-2 receptor and epidermal growth factor receptor (EGFR). The aim of this study was to determine whether blocking of c-erbB-2 receptor with a humanized monoclonal antibody, 4D5 (HerceptinTM), or of EGFR with an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), ZD1839 (IressaTM), would decrease epithelial proliferation in DCIS. METHODS: DCIS tissue from 18 women undergoing surgery was implanted into 16 to 20 athymic nude mice per experiment (eight xenografts per mouse). Treatment commenced 2 weeks after implantation and consisted either of twice-weekly intraperitoneal injections of 4D5 10 mg/kg or of daily gavage with ZD1839 at 100-200 mg/kg for 14 days; appropriate controls were included. Xenografts were removed on days 14, 21 and 28. Proliferation was assessed by counting 1000 epithelial cells after Ki67 immuno- staining. RESULTS: ZD1839 inhibited proliferation compared with that in controls after 14 days (P < 0.01), whereas 4D5 did not. CONCLUSION: Proliferation in DCIS was decreased by EGFR tyrosine kinase inhibition but not by c-erbB-2 receptor blockade. ZD1839, an orally active and selective EGFR-TKI, has potential as adjuvant therapy in DCIS.     

Lysophosphatidic acid-induced effects in human colon carcinoma DLD1 cells are partially dependent on transactivation of epidermal growth factor receptor

BACKGROUND: Lysophosphatidic acid (LPA) is a lipid mediator of diverse effects on various cells. LPA is well known to induce phosphorylation of the epidermal growth factor receptor (EGFR), which is termed transactivation, in some cell types. In this study, we investigated the contribution of EGFR transactivation in LPA-induced responses in colon cancer DLD1 cells. MATERIALS AND METHODS: Immunoprecipitation was performed to investigate whether LPA induced EGFR phosphorylation. Then, we investigated LPA-induced migration and IL-8 secretion in DLD1 cells. Migration was measured in a modified Boyden chamber and IL-8 secretion was measured by ELISA. In these experiments we used an EGFR inhibitor, AG1478 or matrix metalloproteinase (MMP) inhibitor, GM6001. RESULTS: Immunoprecipitation analysis revealed that LPA induced a significant level of tyrosine phosphorylation of EGFR in DLD1 cells. The LPA-induced phosphorylation of EGFR was almost completely abrogated by either AG1478 or GM6001. LPA induced significant migration and IL-8 secretion in DLD1, both of which were significantly inhibited by AG1478 or GM6001. However, the inhibitory effects were only partial (migration; 29% +/- 2%, 32 +/- 13% inhibition, IL-8 secretion; 33% +/- 1%, 26% +/- 5% inhibition, respectively). CONCLUSION: These results clearly indicate that LPA acts upstream of EGFR and compensates the EGF signal and antagonism of the EGF signal cannot completely block tumor progression in colon cancer cells. Blockade of the LPA signal may have clinical significance in the treatment of colon cancer.     

A serum factor after intestinal resection stimulates epidermal growth factor receptor signaling and proliferation in intestinal epithelial cells

BACKGROUND: In vivo, intestinal adaptation after massive small bowel resection (SBR) requires a functional epidermal growth factor (EGF) receptor (EGFR). In vitro studies have shown that serum from mice after SBR induces rat intestinal epithelial cells to proliferate. This study tested the hypothesis that the proliferative response to SBR serum is mediated by EGFR signaling. METHODS: Serum was collected from male Sprague-Dawley rats 7 days after 75% SBR or sham operation. Rat intestinal epithelial cells were incubated in the presence of sham or SBR serum. Total EGFR expression and phosphorylation of several EGFR downstream pathways were determined by Western blotting. In other experiments, a specific EGFR inhibitor (ZD1839) was added and cell growth determined over 5 days. RESULTS: SBR serum significantly increased total EGFR expression (3-fold) over sham operation and consistently activated the phosphatidylinositol 3-kinase pathway. Furthermore, SBR serum markedly augmented rat intestinal epithelial cell growth, an effect that was abolished by EGFR inhibition. CONCLUSIONS: SBR serum contains a factor or factors that stimulates proliferation of intestinal epithelial cells by an EGFR and phosphatidylinositol 3-kinase signaling mechanism. These data recapitulate in vivo studies supporting the hypothesis that EGFR is a central mediator of postresection intestinal adaptation. This in vitro model may provide a novel means to gain insight into the pathophysiology of intestinal adaptation.     

Antiangiogenic effect of ZD1839 against murine renal cell carcinoma (RENCA) in an orthotopic mouse model

INTRODUCTION: ZD1839 (Iressa) is a selective epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). We evaluated the antitumor and antiangiogenesis activities of ZD1839 in a murine renal cell carcinoma (RENCA) model. MATERIALS AND METHODS: The effect of ZD1839 on the cellular proliferation of RENCA cells in vitro was measured by colorimetric assay. For the in vivo studies, RENCA cells were adsorbed in Gelfoam and implanted into BALB/cJ mouse parenchyma with an agarose bar. Mice were treated with ZD1839 (40 mg/kg/day s.c.), genistein or saline for 14 days. Western blot analysis was performed to observe EGFR expression in RENCA cells and tumor tissues. Microvessel density (MVD) was quantified by immunostaining for factor VIII-related antigens and VEGF level was assayed by ELISA. RESULTS: ZD1839 showed a dose-dependent inhibition of RENCA cellular proliferation. ZD1839 treatment resulted in a marked decrease in tumor growth compared with saline treatment. The MVD and VEGF in the RENCA tumors were decreased significantly by ZD1839 (p<0.01 and p>0.05, respectively). Genistein also suppressed tumor growth and decreased MVD and VEGF level, but the efficacies were less than with ZD1839. CONCLUSION: The suppressive activity of ZD1839 on RENCA tumor growth was accompanied by decreases in the MVD and VEGF production. These results suggest that the antitumor effect of ZD1839 in a RENCA model is mediated partially by the inhibition of tumor angiogenesis.     

Molecular target-based cancer therapy: epidermal growth factor receptor inhibitors

Based on recent progress in cancer biology, numerous molecules that contribute to proliferation, invasion, and metastasis of cancer cells have been identified. The epidermal growth factor receptor (EGFR), a member of cell membrane receptors, is overexpressed by many tumors, and EGFR overexpression correlates with poor prognosis and disease progression. The EGFR is an attractive target for novel anticancer therapy. ZD1839 and OSI-774, highly specific EGFR tyrosine kinase inhibitors, have shown promising antitumor activity against cisplatin-resistant non-small cell lung cancer in phase I and phase II trials. IMC-C225, a monoclonal antibody against EGFR, has achieved significant disease control in head and neck cancer and colorectal cancer in combination with anticancer agents. These agents are under evaluation in phase III trials. In conclusion, it is expected that EGFR-directed therapies will soon be established as an effective novel treatment for many cancer patients.     

Inhibition of the epidermal growth factor receptor enhances castration-induced prostate involution and reduces testosterone-stimulated prostate growth in adult rats

BACKGROUND: The epidermal growth factor receptor (EGFR) mediates regulatory signals in the normal prostate, but the functional importance of this is unclear. METHODS: Adult male rats were castrated, or castrated + treated with gefitinib (Iressa, ZD1839), an EGFR tyrosine kinase inhibitor, for 3 days. Seven-day castrated rats were treated with testosterone, or testosterone + gefitinib, for 3 days. RESULTS: Both castration alone and testosterone treatment in castrated animals increased the mRNA and protein levels of EGFR and phospho-EGFR in the ventral prostate. Inhibition of EGFR during castration and during testosterone-stimulated prostate growth resulted in a decrease in total epithelial weight, epithelial cell proliferation, endothelial cell proliferation, and increased epithelial cell apoptosis. CONCLUSIONS: This study suggests that increased EGFR signaling during castration mediates stimulatory effects balancing castration-induced prostate regression, and that EGFR signaling is a necessary component in testosterone-stimulated prostate growth.     

Immune-enhancing enteral diet selectively augments ileal blood flow in the rat

BACKGROUND: Prior indirect studies have suggested that a functional epidermal growth factor receptor (EGFR) appears to be indispensable for the adaptive response of the remnant intestine to massive small bowel resection (SBR). The recent availability of a specific pharmacologic EGFR inhibitor enabled us to more directly test the hypothesis that EGFR signaling is required for postresection intestinal adaptation. METHODS: Mice (C57B1/6, n = 26) underwent a 50% SBR or sham operation and were then given orogastric EGFR inhibitor (ZD1839, 50 mg/kg/day) or vehicle. After 3 days, indices of adaptation (wet weight, crypt depth, and villus height) and apoptotic index (number of apoptotic bodies per crypt) were calculated in the ileum. The expression of proliferating cell nuclear antigen (PCNA) and activated EGFR was measured by Western blotting. RESULTS: ZD1839 prevented EGFR activation and the normal postresection increases in ileal wet weight, villus height, and crypt depth. Enterocyte proliferation was reduced twofold in the SBR group by ZD1839. Although not statistically significant, rates of enterocyte apoptosis were the highest in the inhibitor-treated mice. CONCLUSION: Following massive SBR, pharmacologic inhibition of the EGFR attenuates proliferation and the normal adaptive response of the intestine. These results more directly confirm the requirement of a functional EGFR as a mediator of the postresection adaptation response. This study demonstrates an in vivo application of a novel selective EGFR inhibitor and offers a unique experimental model to gain mechanistic insight into understanding postresection intestinal adaptation.