共查询到20条相似文献,搜索用时 15 毫秒
1.
Meric JB Faivre S Monnerat C Adi Vago N Le Chevalier T Armand JP Raymond E 《Bulletin du cancer》2000,87(12):873-876
ZD 1839 is a highly specific EGF receptor tyrosine kinase inhibitor. Inhibition of EGF receptor transphosphorylation by ZD 1839 blocks the signal transduction at the first step, thus providing antiproliferative effects. Preclinical studies demonstrated efficacy and good bioavailability. The terminal half-life of the compound in patients is ranging from 27 to 41 hours, allowing single oral dosing. Tolerance in healthy volunteers was excellent. In phase I studies, toxicity was manageable. Most common side effects were skin rash, nausea, vomiting, and diarrhea. During those studies, clinical responses were observed in patients with various malignant tumors, in particular non small cell lung cancer. Phase II and III studies are ongoing. 相似文献
2.
Herbst RS Khuri FR Fossella FV Glisson BS Kies MS Pisters KM Riddle JR Terry KA Lee JS 《Clinical lung cancer》2001,3(1):27-32
The epidermal growth factor receptor (EGFR) signaling pathway plays an important role in a number of processes that are key to tumor progression, including cell proliferation, angiogenesis, metastatic spread, and inhibition of apoptosis. EGFR is expressed or overexpressed in non-small-cell lung cancer (NSCLC), and EGFR-mediated growth has been associated with advanced disease and poor prognosis in NSCLC patients. ZD1839 (Iressa) is an orally active, selective EGFR-tyrosine kinase inhibitor that blocks EGFR signal transduction. In preclinical studies using NSCLC cell lines, ZD1839 has been shown to inhibit tumor cell growth. In addition, ZD1839, as monotherapy and in combination with commonly used cytotoxic agents, has produced growth delay in NSCLC human xenografts. Preliminary results from phase I trials in patients with advanced disease have shown that ZD1839 has excellent bioavailability, an acceptable tolerability profile, and promising clinical activity in patients with a variety of tumor types, particularly in NSCLC. ZD1839 is currently in phase III clinical development for the treatment of advanced NSCLC. 相似文献
3.
Cataldo Bianco Giampaolo Tortora Roberto Bianco Roberta Caputo Bianca Maria Veneziani Rosa Caputo Vincenzo Damiano Teresa Troiani Gabriella Fontanini David Raben Stefano Pepe A Raffaele Bianco Fortunato Ciardiello 《Clinical cancer research》2002,8(10):3250-3258
PURPOSE: The epidermal growth factor receptor (EGFR) is expressed in the majority of human epithelial cancers and has been implicated in the development of cancer cell resistance to cyotoxic drugs and to ionizing radiation. Experimental Design: We used ZD1839, a selective small molecule EGFR tyrosine kinase inhibitor currently in clinical development. We tested the antiproliferative and the proapoptotic activity of ZD1839 in combination with ionizing radiation in human colon (GEO), ovarian (OVCAR-3), non-small cell lung (A549 and Calu-6), and breast (MCF-7 ADR) cancer cell lines. The antitumor activity of this combination was also tested in nude mice bearing established GEO colon cancer xenografts. RESULTS: With ionizing radiation or ZD1839, a dose-dependent growth inhibition was observed in all of the cancer cell lines growing in soft agar. A cooperative antiproliferative and proapoptotic effect was obtained when cancer cells were treated with ionizing radiation followed by ZD1839. This effect was accompanied by inhibition in the expression of the antiapoptotic proteins bcl-xL and bcl-2, and by a suppression of the activated (phosphorylated) form of akt protein. Treatment of mice bearing established human GEO colon cancer xenografts with radiotherapy (RT) resulted in a dose-dependent tumor growth inhibition that was reversible upon treatment cessation. Long term GEO tumor growth regressions were obtained after RT in combination with ZD1839. This resulted in a significant improvement in survival of these mice as compared with the control group (P < 0.001), the RT-treated group (P < 0.001), or the ZD1839-treated group (P < 0.001). The only mice alive 10 weeks after tumor cell injection were in the RT-plus-ZD1839 group. Furthermore, 10% of mice in this group were alive and tumor-free after 26 weeks. Similar results were obtained in mice bearing established human A549 lung adenocarcinoma xenografts. Finally, the combined treatment with RT plus ZD1839 was accompanied by a significant potentiation in the inhibition of transforming growth factor alpha, vascular epidermal growth factor, and basic fibroblast growth factor expression in cancer cells, which resulted in significant antiangiogenic effects as determined by immunohistochemical count of neovessels within the GEO tumors. CONCLUSION: This study provides a rationale for evaluating in cancer patients the combination of ionizing radiation and selective EGFR tyrosine kinase inhibitors such as ZD1839. 相似文献
4.
Despite the advent of cisplatin-based combination chemotherapy for advanced non-small cell lung cancer (NSCLC), the prognosis for this patient population remains poor. Novel biologically targeted agents currently in development have the potential for greater efficacy against NSCLC, and possibly less toxicity than is associated with conventional cytotoxic chemotherapy. The epidermal growth factor receptor (EGFR) is recognized as a potentially useful target, and the small molecule, orally active EGFR-tyrosine kinase inhibitor ZD1839 (Iressa) is currently the furthest along in clinical development of the anti-EGFR agents. This review summarizes the currently available clinical data on the use of ZD1839 in the treatment of NSCLC. 相似文献
5.
ZD1839 (Iressa) induces antiangiogenic effects through inhibition of epidermal growth factor receptor tyrosine kinase 总被引:22,自引:0,他引:22
Epidermal growth factor receptor (EGFR) tyrosine kinase is a potential target for anticancer therapy. ZD1839 (Iressa) is a selective inhibitor of EGFR tyrosine kinase. In this study, we investigated the question as to whether the antitumor effect of ZD1839 is partly attributable to antiangiogenic activity and the potential mechanisms involved. Both ZD1839 and SU5416 [a vascular endothelial growth factor (VEGF)-receptor tyrosine kinase inhibitor] inhibited the migration of human umbilical vein endothelial cell cocultivated with EGF-stimulated cancer cells. ZD1839 also inhibited EGF-induced migration and the formation of tube-like structures by human microvascular endothelial cells. Moreover, ZD1839 almost completely blocked EGF-induced neovascularization of mice cornea, and SU5416 partially blocked neovascularization. In contrast, ZD1839 did not inhibit VEGF-induced angiogenesis. However, EGF-induced up-regulation of the angiogenic factors, VEGF and IL-8, was almost completely blocked by ZD1839. The antitumor effects of ZD1839 could, therefore, be mediated in part by the inhibition of tumor angiogenesis through direct effects on microvascular endothelial cells that express EGFR and also through reduced production of proangiogenic factors by tumor cells. 相似文献
6.
Targeting the EGF receptor in ovarian cancer with the tyrosine kinase inhibitor ZD 1839 ("Iressa") 总被引:7,自引:0,他引:7
The modulating effects of the orally active epidermal growth factor receptor-specific tyrosine kinase inhibitor ZD 1839 ("Iressa") on cell growth and signalling were evaluated in four ovarian cancer cell lines (PE01, PE04, SKOV-3, OVCAR-5) that express the epidermal growth factor receptor, and in A2780, which is epidermal growth factor receptor-negative. Transforming growth factor-alpha stimulated growth was completely inhibited by concentrations of ZD 1839 > or =0.3 microM in the epidermal growth factor receptor-expressing cell lines, as were transforming growth factor-alpha stimulated phosphorylation of the epidermal growth factor receptor and downstream components of the MAP kinase and PI-3 kinase signalling cascades. Growth inhibition in the absence of added transforming growth factor-alpha was also observed which could be consistent with suppression of action of autocrine epidermal growth factor receptor-activating ligands by ZD 1839. In support of this, transforming growth factor-alpha, EGF and amphiregulin mRNAs were detected by RT-PCR in the epidermal growth factor receptor-expressing cell lines. ZD 1839 inhibited growth of the PE04 ovarian cancer xenograft at 200 mg kg(-1)day(-1). These data lend further support to the view that targeting the epidermal growth factor receptor in ovarian cancer could have therapeutic benefit. 相似文献
7.
On May 5, 2003, gefitinib (Iressa), ZD1839) 250-mg tablets received accelerated approval by the U.S. Food and Drug Administration as monotherapy treatment for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of both platinum-based and docetaxel chemotherapies. Information provided in this summary includes efficacy and safety results of relevant clinical trials. Effectiveness was demonstrated in a randomized, double-blind, phase II, multicenter trial comparing two oral doses of gefitinib (250 mg/day versus 500 mg/day). Two hundred sixteen patients were enrolled. The 142 patients who were refractory to or intolerant of a platinum and docetaxel comprised the evaluable population for the efficacy analysis. A partial tumor response occurred in 14% (9 of 66) of patients receiving gefitinib 250 mg/day and in 8% (6 of 76) of patients receiving gefitinib 500 mg/day. The overall objective response rate for both doses combined was 10.6% (15 of 142 patients) (95% confidence interval 6.0%-16.8%). Responses were more frequent in females and in nonsmokers. The median duration of response was 7.0 months (range 4.6-18.6+ months). Other submitted data included the results of two large trials conducted in chemotherapy-naive, stage III and IV NSCLC patients. Patients were randomized to receive gefitinib (250 mg or 500 mg daily) or placebo, in combination with either gemcitabine plus cisplatin (n = 1,093) or carboplatin plus paclitaxel (n = 1,037). Results from those studies showed no benefit (response rate, time to progression, or survival) from adding gefitinib to chemotherapy. Consequently, gefinitib is only recommended for use as monotherapy. Common adverse events associated with gefitinib treatment included diarrhea, rash, acne, dry skin, nausea, and vomiting. Most toxicities were Common Toxicity Criteria grade 1 or 2. Interstitial lung disease (ILD) has been observed in patients receiving gefitinib. Worldwide, the incidence of ILD is about 1% (2% in the Japanese postmarketing experience and about 0.3% in a U.S. expanded access program). Approximately one-third of the cases were fatal. Physicians should promptly evaluate new or worsening pulmonary symptoms. If ILD is confirmed, appropriate management includes discontinuation of gefitinib. Gefitinib was approved under accelerated approval regulations on the basis of a surrogate end point response rate. No controlled gefitinib trials, to date, demonstrate a clinical benefit, such as improvement in disease-related symptoms or greater survival. Accelerated approval regulations require the sponsor to conduct further studies to verify that gefitinib therapy produces such a benefit. 相似文献
8.
9.
ZD1839(Iressa)在晚期非小细胞肺癌治疗中的应用 总被引:4,自引:0,他引:4
目的 探讨表皮生长因子受体酪氨酸激酶抑制剂———ZD183 9(Iressa)治疗晚期非小细胞肺癌的疗效和毒副反应。方法 分析 2 0 0 2年 12月至 2 0 0 3年 8月期间我院 3 9例晚期非小细胞肺癌患者经ZD183 92 5 0mg/d口服治疗的情况。应用 χ2 检验、t检验、Kaplan Meier进行统计分析。并采用欧洲癌症研究和治疗组织 (EuropeanOrganizationforResearchandTreatmentofCancer ,EORTC)简体中文版的生活质量调查核心问卷QLQ C3 0和肺癌专用问卷QLQ LC13对患者的生活质量进行评价。结果 全组患者有效率 (完全缓解 +部分缓解 )为 2 8.2 %,疾病控制率 (有效 +稳定 )为 5 9.0 %。疗效与患者性别和病理类型有密切关系。综合生活质量改善率为 3 4.8%,功能状态改善率为 65 .2 %,临床症状缓解率为 73 .9%。全组无疾病进展时间为 6.6月± 1.6月 ( 95 %CI为 3 .4~ 9.7) ,到截尾时间 5 6.4%( 2 2 /3 9)的患者仍存活 ,1年生存率为 5 4.3 %( 19/3 5 )。毒副反应主要为Ⅰ、Ⅱ度皮疹和腹泻 ,经对症处理可缓解。结论 ZD183 9治疗晚期非小细胞肺癌疗效确切 ,同时可改善生活质量 相似文献
10.
Ranson M 《The oncologist》2002,7(Z4):16-24
ZD1839 (Iressa) is an orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor that blocks signal transduction pathways involved in cell proliferation. Preclinical studies demonstrated that ZD1839 is a promising agent for the treatment of a wide range of tumors and has additive-to-synergistic effects when combined with radiation or chemotherapy in various cell lines and xenografts. Phase I clinical trials have reported that ZD1839 has acceptable tolerability and antitumor activity. In addition to non-small cell lung cancer, phase II/III studies are currently investigating ZD1839 as monotherapy or in combination therapy against prostate, breast, head and neck, gastric, and colorectal tumors. 相似文献
11.
Rosetti M Tesei A Ulivi P Fabbri F Vannini I Brigliadori G Granato AM Amadori D Zoli W 《Cancer biology & therapy》2005,4(10):1089-1095
High expression of the epidermal growth factor receptor (EGFR) family confers a growth advantage on malignant cells in various tumor types. Most pancreatic cancers express EGFR, which seems to play an important role in the acquisition of aggressive clinical behaviour and in tumor invasion. Iressa (ZD1839), a quinazoline tyrosine kinase inhibitor selective for the EGF receptor, has shown good anti-tumor activity in both preclinical and clinical studies. Using two pancreatic cancer cell lines that express different EGFR and ErbB-2 levels, we analyzed the activity of Iressa and evaluated its modulation effect on four conventional cytotoxic drugs: gemcitabine, oxaliplatin, docetaxel and SN38. Iressa was tested at scalar doses up to the plasma peak level concentration and showed a similar weak cytostatic effect in both cell lines. Conversely, an additive or weak synergistic effect was observed when the drug was administered simultaneously with or following cytotoxic drugs. Our data show that Iressa has only a weak activity at doses within the plasmatic peak concentration and that its effect is independent of EGFR and p42/p44 expression and phosphorylation levels. This is in agreement with recent literature data that attribute an essential role to a specific EGFR mutation in mediating response to Iressa. This mutation was absent in both pancreatic cell lines tested. 相似文献
12.
Ieki R Saitoh E Hashimoto E Ohta T Yuasa K Iguchi M Okamura T Shibuya M Moriyama S Goto H 《Gan to kagaku ryoho. Cancer & chemotherapy》2003,30(7):977-980
We experienced a case in which severe alveolar hemorrhage occurred in the course of gefitinib therapy. A 56-year-old man with non-small cell lung cancer had been treated with CDDP + CPT-11, CDDP + GEM + VNR, CDDP + TXT. After the chemotherapy with these regimens was found to be ineffective, daily oral gefitinib was started. Four weeks later, the patient complained of cough, bloody sputum and dyspnea. Chest X-ray and CT showed bilateral infiltrations with air bronchogram. Fiberoptic bronchoscopy revealed alveolar hemorrhage with an increase of lymphocytes in the BALF. After the cessation of gefitinib therapy and the administration of steroid, he gradually recovered. 相似文献
13.
14.
Maddineni SB Sangar VK Hendry JH Margison GP Clarke NW 《British journal of cancer》2005,92(1):125-130
The epidermal growth factor receptor (EGFR) is expressed in a wide variety of epithelial tumours including carcinoma of the bladder. Stimulation of the EGFR pathway is blocked by ZD1839 (Iressa), a highly selective EGFR tyrosine kinase inhibitor. Radical radiotherapy is an established organ sparing treatment option for muscle invasive bladder cancer and this study has explored the possibility for the use of ZD1839 as a radiosensitiser in this scenario. The effect of combination treatment with ZD1839 (0.01 microM) and ionising radiation in the established bladder cancer cell lines MGH-U1 and its radiosensitive mutant clone S40b was measured by clonogenic assays. A highly significant radiosensitising effect was seen in both cell lines (P < 0.001 for MGH-U1 and S40b cell lines). This effect was independent of the concentration of the drug and the duration of exposure prior to treatment with ionising radiation. Cell cycle kinetics of both cell lines was not significantly altered with ZD1839 (0.01 microM) as a single agent. A modest induction of apoptosis was observed with ZD1839 (0.01 microM) as a single agent, but a marked induction was observed with the combination treatment of ZD1839 and ionising radiation. These results suggest a potentially important role for ZD1839 in combination with radiotherapy in the treatment of muscle invasive bladder cancer. 相似文献
15.
The effects of ZD1839 (Iressa), a highly selective EGFR tyrosine kinase inhibitor, as a radiosensitiser in bile duct carcinoma cell lines 总被引:1,自引:0,他引:1
Miyata H Sasaki T Kuwahara K Serikawa M Chayama K 《International journal of oncology》2006,28(4):915-921
The signaling pathway that is initiated by binding of epidermal growth factor receptor (EGFR) and results in sustained signaling through PI3K plays an important role in a tumor's response to ionizing radiation. The current in vitro study explored both the effects of ZD1839 (Iressa), a highly selective EGFR tyrosine kinase inhibitor, as a radiosensitiser for bile duct carcinoma cell lines and ZD1839's general effects on cell growth in the same two lines. Secondly, we ensured suppression of radiation-induced phosphorylation of EGFR by ZD1839 using an immunoprecipitation technique. Furthermore, we examined radiation-induced phosphorylation of ERK, p38, JNK, and AKT with or without inhibitor with use of Western blot techniques and performed clonogenic assays to confirm radiosensitivity in the presence of a drug. ZD1839 inhibited cell growth of both cell lines and suppressed radiation-induced phosphorylation of EGFR. After exposure to radiation, there was an increase in phosphorylation of AKT as shown by Western blot. Treatment with either ZD1839 or LY294002 (the latter, a PI3K inhibitor) suppressed phosphorylation of AKT by Western blot. Both ZD1839 and LY294002 significantly suppressed colony formation by clonogenic assay; however, U0126 (a MEK1/2 inhibitor), SB203580 (a p38 inhibitor), and SP600125 (a JNK inhibitor) had no effect on colony formation. These results suggest that AKT may be a useful target molecule for enhancement of radiotherapy effect and that ZD1839 may have an important role in combination with radiotherapy for patients with bile duct carcinoma. 相似文献
16.
Zhibo Yang Rozita Bagheri-Yarmand Rui-An Wang Liana Adam Vali Vassiliki Papadimitrakopoulou Gary L Clayman Adel El-Naggar Reuben Lotan Christopher J Barnes Waun Ki Hong Rakesh Kumar 《Clinical cancer research》2004,10(2):658-667
PURPOSE: Abnormalities in the expression and signaling pathways downstream of the epidermal growth factor receptor (EGFR) contribute to the progression, invasion, and maintenance of the malignant phenotype in human cancers, including those of the head and neck and breast. Accordingly, agents such as the EGFR tyrosine kinase inhibitor (EGFR-TKI) ZD1839 (Iressa) are promising, biologically based treatments that are in various stages of preclinical and clinical development. The process of tumor progression requires, among other steps, increased transformation, directional migration, and enhanced cell survival; this study explored the effect of ZD1839 on the stimulation of c-Src and p21-activated kinase 1 (Pak1), which are vital for transformation, directional motility, and cell survival of cancer cells. EXPERIMENTAL DESIGN: We examined the effect of ZD1839 on biochemical and functional assays indicative of directional motility and cell survival, using human head and neck squamous cancer cells and breast cancer cells. RESULTS: ZD1839 effectively inhibited c-Src activation and Pak1 activity in exponentially growing cancer cells. In addition, ZD1839 suppressed EGF-induced stimulation of EGFR autophosphorylation on Y1086 and Grb2-binding Y1068 sites, c-Src phosphorylation on Y215, and Pak1 activity. ZD1839 also blocked EGF-induced cytoskeleton remodeling, redistribution of activated EGFR, and in vitro invasiveness of cancer cells. CONCLUSIONS: These studies suggest that the EGFR-TKI ZD1839 may cause potent inhibition of the Pak1 and c-Src pathways and, therefore, have potential to affect the invasiveness of human cancer cells deregulated in these growth factor receptor pathways. 相似文献
17.
Tetsuya Okano Tadashi Kondo Kiyonaga Fujii Toshihide Nishimura Toshimi Takano Yuichiro Ohe Koji Tsuta Yoshihiro Matsuno Akihiko Gemma Harbumi Kato Shoji Kudoh Setsuo Hirohashi 《Clinical cancer research》2007,13(3):799-805
PURPOSE: We aimed to identify candidate proteins for tumor markers to predict the response to gefitinib treatment. EXPERIMENTAL DESIGN: We did two-dimensional difference gel electrophoresis to create the protein expression profile of lung adenocarcinoma tissues from patients who showed a different response to gefitinib treatment. We used a support vector machine algorithm to select the proteins that best distinguished 31 responders from 16 nonresponders. The prediction performance of the selected spots was validated by an external sample set, including six responders and eight nonresponders. The results were validated using specific antibodies. RESULTS: We selected nine proteins that distinguish responders from nonresponders. The predictive performance of the nine proteins was validated examining an additional six responders and eight nonresponders, resulting in positive and negative predictive values of 100% (six of six) and 87.5% (seven of eight), respectively. The differential expression of one of the nine proteins, heart-type fatty acid-binding protein, was successfully validated by ELISA. We also identified 12 proteins as a signature to distinguish tumors based on their epidermal growth factor receptor gene mutation status. CONCLUSIONS: Study of these proteins may contribute to the development of personalized therapy for lung cancer patients. 相似文献
18.
Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by coadministration of ZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase. 总被引:22,自引:0,他引:22
F M Sirotnak M F Zakowski V A Miller H I Scher M G Kris 《Clinical cancer research》2000,6(12):4885-4892
The blockade of epidermal growth factor receptor (EGFR) function with monoclonal antibodies has major antiproliferative effects against human tumors in vivo. Similar antiproliferative effects against some of these same tumors have also been observed with specific inhibitors of the EGFR-associated tyrosine kinase. One such inhibitor, the p.o. active ZD1839 (Iressa), has pronounced antiproliferative activity against human tumor xenografts. We now show that coadministration of ZD1839, as with anti-EGFR, will enhance the efficacy of cytotoxic agents against human vulvar (A431), lung (A549 and SK-LC-16 NSCL and LX-1), and prostate (PC-3 and TSU-PR1) tumors. Oral ZD1839 (five times daily x 2) and cytotoxic agents (i.p. every 3-4 days x 4) were given for a period of 2 weeks to mice with well-established tumors. On this schedule, the maximum tolerated dose (150 mg/kg) of ZD1839 induced partial regression of A431, a tumor that expresses high levels of EGFR, 70-80% inhibition among tumors with low but highly variable levels of EGFR expression (A549, SKLC-16, TSU-PR1, and PC-3), and 50-55% inhibition against the LX-1 tumor, which expresses very low levels of EGFR. ZD1839 was very effective in potentiating most cytotoxic agents in combination treatment against all of these tumors, irrespective of EGFR status, but dose reduction of ZD1839 below its single-agent maximum tolerated dose was required for optimum tolerance. The pronounced growth inhibitory action of the platinums, cisplatin and carboplatinum, as single agents against A431 vulvar, A549 and LX-1 lung, and TSU-PR1 and PC-3 prostate tumors was increased several-fold when ZD1839 was added, with some regression of A431 and PC-3 tumors. Although the taxanes, paclitaxel or docetaxel, as single agents markedly inhibited the growth of A431, LX-1, SK-LC-16, TSU-PR1, and PC-3, when combined with ZD1839, partial or complete regression was usually seen. Against A549, the growth inhibition of doxorubicin was increased 10-fold (>99%) with ZD1839. The folate analogue, edatrexate, was highly growth inhibitory against A549, LX-1, and TSU-PR1, whereas edatrexate combined with ZD1839 resulted in partial or complete regression in these tumors. Against the A431 tumor, paclitaxel alone either was highly growth inhibitory or induced some regression, but when combined with ZD1839, pronounced regression was obtained. Combination with gemcitabine neither added nor detracted from baseline cytotoxic efficacy, whereas ZD1839 combined with vinorelbine was poorly tolerated. Overall, these results suggest that potentiation of cytotoxic treatment with ZD1839 does not require high levels of EGFR expression in the target tumors. They also suggest significant clinical benefit from ZD1839 in combination with a variety of widely used cytotoxic agents. 相似文献
19.
ZD1839 ("Iressa") is an orally active, selective epidermal growth factor (EGF) receptor-tyrosine kinase inhibitor. We evaluated the antitumor activity of ZD1839 in combination with HSP90 antagonist, 17-AAG in malignant human glioma cell lines. ZD1839 independently produced a dose-dependent inhibition of cellular proliferation in glioma cells grown in culture with time- and dose-dependent accumulation of cells in G(1) phase of the cell cycle on flow cytometric analysis, although the concentrations required for optimal efficacy were at or above the limits of clinically achievable levels. Because the heat shock protein (HSP) is involved in the conformational maturation of a number of signaling proteins critical to the proliferation of malignant glioma cells, we hypothesized that the HSP90 inhibitor 17-AAG would potentiate ZD 1839-mediated glioma cytotoxicity by decreasing the activation status of EGF receptor, as well as down regulating the levels of other relevant signaling effectors. We, therefore, examined the effects of ZD1839 and 17-AAG, alone and in combination, on signal transduction and apoptosis in a series of malignant glioma cell lines. Simultaneous exposure to these inhibitors significantly induced cell death and quantitative analysis revealed that interaction between ZD1839 and 17-AAG-induced cytotoxicity was synergistic, leading to a pronounced increase in active caspase-3 and PARP cleavage. No significant growth inhibition or caspase activation was seen in control cells. The enhanced cytotoxicity of this combination was associated with diminished Akt activation and a significant downregulation of EGFR receptor, Raf-1 and mitogen activated protein kinase (MAPK). Cells exposed to 17-AAG and ZD1839 displayed a significant reduction in cell cycle regulatory proteins, such as CDK4 and CDK6. Taken together, these findings suggest that ZD1839, an EGF receptor tyrosine kinase inhibitor, plays a critical role in regulating the apoptotic response to 17-AAG and that multi-site targeting of growth signaling and cell survival pathways could provide a potent strategy to treat patients with malignant gliomas. 相似文献
20.
Kirby AM A'Hern RP D'Ambrosio C Tanay M Syrigos KN Rogers SJ Box C Eccles SA Nutting CM Harrington KJ 《British journal of cancer》2006,94(5):631-636
To assess the level of activity and toxicity of gefitinib (ZD1839, Iressatrade mark) in a population of patients with locally recurrent and/or metastatic head and neck cancer. Patients were recruited into an expanded access programme through the multidisciplinary head and neck clinics at the Royal Marsden and St George's Hospitals. Patients were required to have received at least one course of standard systemic chemotherapy or radiation therapy, or be medically unfit for chemotherapy. Patients were commenced on single-agent gefitinib at a dose of 500 mg day(-1). Clinical, symptomatic and radiological response, time to progression (TTP), survival and toxicity were recorded. A total of 47 patients were enrolled (35 male and 12 female) with a median age of 62 years (range 18-93 years). The observed clinical response rate was 8% with a disease control rate (complete response, partial response, stable disease) of 36%. In all, 34% of patients experienced an improvement in their symptoms. The median TTP and survival were 2.6 and 4.3 months, respectively. Acneiform folliculitis was the most frequent toxicity observed (76%) but the majority of cases were grade 1 or 2. Only four patients experienced grade 3 toxicity of any type (all cases of folliculitis). Gefitinib was well tolerated and yielded symptomatic improvement in one-third of patients. However, this agent appeared to possess limited antitumour activity in this group of patients with head and neck cancer in whom the objective response rate, median TTP and survival were all lower than has been reported in a previous study. 相似文献