• 【小动物FDG‑PET / CT和CT对原位SCID小鼠模型的顺铂和厄洛替尼抗肺癌功效进行非侵入性监测。】 复制标题 收藏 收藏
    DOI:10.3892/or.2018.6818 复制DOI
    作者列表:Otani T,Kondo K,Takizawa H,Kajiura K,Fujino H,Otsuka H,Miyoshi H
    BACKGROUND & AIMS: :We established patient‑like models of lung cancer metastasis by orthotopically implanting human non‑small cell lung cancer cell lines into SCID mice. We evaluated the utilities of small‑animal computed tomography (CT) and positron‑emission tomography‑computed tomography (PET/CT) in these models to non‑invasively and repeatedly monitor the anticancer effects of cisplatin and erlotinib. We orthotopically implanted three non‑small cell lung cancer cell lines, A549, FT821 and PC‑9, into SCID mice. These mice were then divided into three groups: Control, cis‑diamminedichloroplatinum (II) (CDDP) (7‑mg/kg CDDP, single administration intraperitoneally), and erlotinib (25 mg/kg erlotinib/day, oral administration 5 days/week). After treatment initiation, we repeatedly performed PET/CT and CT measurements and assessed anticancer effects based on tumor volumes and FDG uptake. A549 tumors were not affected by CDDP or erlotinib. FT821 tumors were highly responsive to CDDP. PC‑9 tumors, which have an epidermal growth factor receptor mutation, were highly responsive to erlotinib. Histological results and metastatic rates correlated with the anticancer effects shown by CT. In our orthotopic SCID mouse lung cancer models, 18FDG‑PET/CT and CT imaging non‑invasively and repeatedly monitored the efficacies of cisplatin and erlotinib against not only implanted tumors, but also mediastinal lymph node metastases.
    背景与目标: :我们通过将人非小细胞肺癌细胞系原位移植到SCID小鼠中,建立了类似于肺癌的患者转移模型。我们在这些模型中评估了小动物计算机断层扫描(CT)和正电子发射断层扫描计算机断层扫描(PET / CT)的实用性,以无创且反复监测顺铂和厄洛替尼的抗癌作用。我们将三种非小细胞肺癌细胞系A549,FT821和PC‑9原位移植到SCID小鼠中。然后将这些小鼠分为三组:对照组,顺二氨二氯铂(II)(CDDP)(7‑mg / kg CDDP,腹膜内单次给药)和厄洛替尼(25 mg / kg厄洛替尼/天,口服5天/周)。治疗开始后,我们反复进行PET / CT和CT测量,并根据肿瘤体积和FDG摄取评估抗癌作用。 A549肿瘤不受CDDP或厄洛替尼的影响。 FT821肿瘤对CDDP高度敏感。具有表皮生长因子受体突变的PC‑9肿瘤对厄洛替尼具有高响应性。组织学结果和转移率与CT显示的抗癌作用相关。在我们的原位SCID小鼠肺癌模型中,18FDG‑PET / CT和CT成像无创且反复监测了顺铂和厄洛替尼不仅对植入的肿瘤,而且对纵隔淋巴结转移的疗效。
  • 【对于晚期胰腺癌患者,KRAS突变状态不能预测厄洛替尼抗EGFR治疗的客观反应。】 复制标题 收藏 收藏
    DOI:10.1007/s00535-013-0767-4 复制DOI
    作者列表:Boeck S,Jung A,Laubender RP,Neumann J,Egg R,Goritschan C,Ormanns S,Haas M,Modest DP,Kirchner T,Heinemann V
    BACKGROUND & AIMS: BACKGROUND:It has not yet been defined if KRAS has a prognostic value or is a predictive biomarker for the efficacy of erlotinib in advanced pancreatic cancer (PC). METHODS:AIO-PK0104 was a phase III trial comparing gemcitabine/erlotinib followed by capecitabine with capecitabine/erlotinib followed by gemcitabine in advanced PC. For this post hoc subgroup analysis, biomarker data on the KRAS exon 2 mutation status were correlated with objective response to 1st-line therapy and with overall survival after start of 2nd-line chemotherapy (OSc). RESULTS:KRAS codon 12 was mutated in 121 of 173 (70 %) patients. The KRAS status showed no association with objective response (p = 0.40), but KRAS wildtype patients had an improved OS (HR 1.68, p = 0.005). A trend for a survival benefit was also observed during (non-erlotinib containing) 2nd-line chemotherapy, with a HR of 1.47 (p = 0.10) for the OSc. CONCLUSION:This post hoc analysis of AIO-PK0104 supports the assumption that KRAS is rather a prognostic than a predictive biomarker in PC.
    背景与目标: 背景:尚未确定KRAS对厄洛替尼在晚期胰腺癌(PC)中的疗效是否具有预后价值或是否为预测性生物标志物。
    方法:AIO-PK0104是一项III期试验,在晚期PC机中比较吉西他滨/厄洛替尼,卡培他滨,卡培他滨/厄洛替尼,吉西他滨。对于此事后亚组分析,有关KRAS外显子2突变状态的生物标记数据与对一线治疗的客观反应以及与二线化疗(OSc)开始后的总体生存率相关。
    结果:在173名患者中,有121名(70%)患者的KRAS密码子12被突变。 KRAS状态显示与客观反应无关(p = 0.40),但KRAS野生型患者的OS改善(HR 1.68,p = 0.005)。在(不含厄洛替尼的)二线化疗期间也观察到生存获益的趋势,OSc的HR为1.47(p = 0.10)。
    结论:AIO-PK0104的事后分析支持以下假设:KRAS在PC中是一种预后指标,而不是预测性生物指标。
  • 【厄洛替尼和索拉非尼在原位肝细胞癌大鼠模型中的作用。】 复制标题 收藏 收藏
    DOI:10.1016/j.jhep.2012.04.034 复制DOI
    作者列表:Sieghart W,Pinter M,Dauser B,Rohr-Udilova N,Piguet AC,Prager G,Hayden H,Dienes HP,Dufour JF,Peck-Radosavljevic M
    BACKGROUND & AIMS: BACKGROUND & AIMS:The combination of erlotinib with sorafenib is currently being investigated in a phase III RCT. We studied the effect of erlotinib and sorafenib on HCC in a preclinical model. METHODS:The Morris Hepatoma (MH) and HepG2 cells were treated in vitro with sorafenib (1-10 μM) and erlotinib (1-5 μM) and evaluated for tumor cell viability, apoptosis, and target regulation. Antiangiogenic effects were studied by measuring VEGF levels, endothelial cell viability, apoptosis, migration, and the aortic ring assay. In vivo, MH cells were implanted into the liver of syngeneic rats and treated with vehicle, sorafenib 5-10mg/kg, erlotinib 10mg/kg, and respective combinations. RESULTS:In vitro, erlotinib downregulated p-ERK but showed no significant effect on tumor cell viability in MH and HEPG2 cells. Despite a similar target regulation, sorafenib significantly reduced cell viability of HCC cells by induction of apoptosis, in a dose-dependent manner (11 ± 5%; 20 ± 10%; 51 ± 5% for sorafenib 1, 5, 10 μM). No additional effect was observed upon combination with erlotinib. Of note, erlotinib treatment resulted in endothelial cell migration and vascular sprouting of aortic rings through induction of VEGF mRNA and protein levels in endothelial and tumor cells, which was blocked by sorafenib. In vivo, erlotinib had no single agent antitumor activity, raised serum-VEGF levels, and lacked a synergistic effect in combination with sorafenib. CONCLUSIONS:Erlotinib had no antitumor effect on HCC in vitro nor in vivo, but induced VEGF, which may reflect a resistance mechanism to erlotinib monotherapy. No improvement of sorafenib efficacy was observed upon combination with erlotinib.
    背景与目标: 背景与目的:厄洛替尼与索拉非尼的组合目前正在III期RCT中进行研究。我们在临床前模型中研究了厄洛替尼和索拉非尼对肝癌的影响。
    方法:用索拉非尼(1-10μM)和厄洛替尼(1-5μM)体外处理Morris肝癌(MH)和HepG2细胞,并评估其肿瘤细胞活力,凋亡和靶标调控。通过测量VEGF水平,内皮细胞活力,凋亡,迁移和主动脉环测定研究了抗血管生成作用。在体内,将MH细胞植入同系大鼠的肝脏中,并用溶媒,索拉非尼5-10mg / kg,厄洛替尼10mg / kg及其各自的组合进行处理。
    结果:在体外,厄洛替尼下调了p-ERK,但对MH和HEPG2细胞中的肿瘤细胞存活率没有显着影响。尽管有类似的靶标调节,索拉非尼仍通过剂量依赖性方式(11±5%; 20±10%;索拉非尼1、5、10μM为51±5%)诱导凋亡,从而显着降低HCC细胞的细胞活力。与厄洛替尼合用时未观察到其他作用。值得注意的是,厄洛替尼治疗通过诱导内皮细胞和肿瘤细胞中的VEGF mRNA和蛋白水平诱导内皮细胞迁移和主动脉环血管萌芽,而索拉非尼则阻止了该过程。在体内,厄洛替尼没有单药抗肿瘤活性,血清VEGF水平升高,与索拉非尼联合使用缺乏协同作用。
    结论:厄洛替尼在体外和体内对肝癌均无抗肿瘤作用,但可诱导VEGF,可能反映了对厄洛替尼单药治疗的耐药机制。与厄洛替尼联合使用时未观察到索拉非尼功效的改善。
  • 【在癌症治疗中靶向HER1 / EGFR:厄洛替尼的经验。】 复制标题 收藏 收藏
    DOI:10.2217/14796694.1.4.449 复制DOI
    作者列表:Giaccone G
    BACKGROUND & AIMS: :Research into the role of the human epidermal receptor growth factor receptor 1/epidermal growth factor receptor (HER1/EGFR) in tumorigenesis has generated a new class of anticancer drugs. One such agent, erlotinib (Tarceva), is a potent, selective and reversible inhibitor of HER1/EGFR tyrosine kinase activity. Erlotinib has demonstrated the clinical activity in a variety of solid tumors, and has recently demonstrated improvements in survival in large Phase III trials, in non-small-cell lung cancer and pancreatic cancer.
    背景与目标: 人表皮生长因子受体1 /表皮生长因子受体(HER1 / EGFR)在肿瘤发生中的作用研究已经产生了新的一类抗癌药物。一种这样的药物,厄洛替尼(厄洛替尼)是有效的,选择性的和可逆的HER1 / EGFR酪氨酸激酶活性抑制剂。厄洛替尼已经证明了在各种实体瘤中的临床活性,并且最近在非小细胞肺癌和胰腺癌的大型III期临床试验中证明了生存率的提高。
  • 【在先前接受化学疗法治疗的一项扩大的访问计划研究中,厄洛替尼对台湾NSCLC患者的高疗效。】 复制标题 收藏 收藏
    DOI:10.1016/j.lungcan.2008.02.023 复制DOI
    作者列表:Perng RP,Yang CH,Chen YM,Chang GC,Lin MC,Hsieh RK,Chu NM,Lai RS,Su WC,Tsao CJ,Hsia TC,Chen HC,Chen CH,Huang MS,Wang JL,Ho ML,Chung CY,Yu CJ,Chang WC,Kuo HP,Yu CT,Lin ZZ,Kao WY
    BACKGROUND & AIMS: PURPOSE:Erlotinib is the first epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) which has demonstrated a survival benefit in non-small-cell lung cancer (NSCLC) patients. An open label phase II study was conducted in Taiwanese patients with NSCLC to evaluate its efficacy. METHODS:Patients with proven stage IIIB/IV NSCLC who had received at least one line of standard chemotherapy or radiotherapy were enrolled into this study. All patients were given oral erlotinib, 150mg/day till disease progression. RESULTS:From May 2005 to July 2006, 300 patients were entered from 14 hospitals in Taiwan. This analysis was based on 299 patients who received at least one dose of erlotinib. The best response rates were a 29% partial response and 44% stable disease in 273 patients who had response data available. Non-smoking (p=0.033), adenocarcinoma/BAC (p=0.0027), female (p=0.0013), aged less than 65 years (p=0.0115), stage IV (p=0.0492), patients with skin rash (p=0.0216), and a higher grade of skin rash (p=0.003) were significantly correlated with response to treatment. Skin rash was a common adverse event (any grade: 84%, Gr 3-4: 16%). The median time to disease progression was 5.6 months. Cox regression model for progression free survival showed patients most at risk of early progression were males of low performance status having squamous cell carcinoma. CONCLUSIONS:This was the largest multicenter prospective clinical study of NSCLC in Taiwan. The results demonstrated the excellent response rates, time-to-progression and overall survival of erlotinib in a large population of Taiwanese NSCLC patients who had been previously treated with chemotherapy or radiotherapy.
    背景与目标: 目的:厄洛替尼是第一种表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI),已证明在非小细胞肺癌(NSCLC)患者中具有生存获益。在台湾的NSCLC患者中进行了一项开放标签的II期研究,以评估其疗效。
    方法:IIIB / IV期NSCLC阶段已被证实接受过至少一线标准化疗或放疗的患者被纳入本研究。所有患者均口服厄洛替尼,剂量为150mg /天,直至疾病进展。
    结果:从2005年5月到2006年7月,来自台湾14所医院的300名患者进入了研究。该分析基于299名接受至少一剂厄洛替尼的患者。最好的缓解率是在有可用响应数据的273例患者中,部分缓解率为29%,疾病稳定率为44%。非吸烟(p = 0.033),腺癌/ BAC(p = 0.0027),女性(p = 0.0013),年龄小于65岁(p = 0.0115),IV期(p = 0.0492),皮疹患者(p = 0.0216),较高等级的皮疹(p = 0.003)与治疗反应显着相关。皮疹是常见的不良事件(任何等级:84%,Gr 3-4:16%)。疾病进展的中位时间为5.6个月。无进展生存期的Cox回归模型显示,处于早期进展风险最大的患者是表现为鳞状细胞癌的低性能男性。
    结论:这是台湾地区最大的非小细胞肺癌多中心前瞻性临床研究。结果表明,在先前接受过化学疗法或放射疗法治疗的大量台湾NSCLC患者中,厄洛替尼具有出色的缓解率,进展时间和总体生存率。
  • 【氮杂胞苷和厄洛替尼对急性髓性白血病具有协同作用。】 复制标题 收藏 收藏
    DOI:10.1038/onc.2012.469 复制DOI
    作者列表:Lainey E,Wolfromm A,Marie N,Enot D,Scoazec M,Bouteloup C,Leroy C,Micol JB,De Botton S,Galluzzi L,Fenaux P,Kroemer G
    BACKGROUND & AIMS: :The term myelodysplastic syndrome (MDS) identifies a heterogeneous group of clonal disorders originating from bone marrow stem cells that often progress to acute myeloid leukemia (AML). The reference treatments for MDS include the DNA methyltransferase inhibitors azacytidine and decitabine. Recently, the epidermal growth factor receptor (EGFR) inhibitor erlotinib has been shown to exert antileukemic activity in vitro and in vivo, independent of the EGFR. Thanks to this feature, erlotinib is currently being tested as an antileukemic drug in clinical trials. Here, we report that azacytidine and erlotinib mediate synergistic antineoplastic effects in several primary or secondary (post-MDS) AML cell lines. The combination of azacytidine and erlotinib blocked cell-cycle progression and induced caspase-dependent apoptosis more consistently than either of the two agents alone. These effects were not a consequence of cellular differentiation and could be discriminated from each other, as the former depended on caspases whereas the latter did not. The synergy between azacitidine and erlotinib, which involved the proteasomal degradation of the anti-apoptotic Bcl-2 family members MCL-1 and BCL2L10 and the upregulation of their pro-apoptotic counterpart PUMA, was abolished when azacytidine was replaced by decitabine but persisted when erlotinib was substituted with gefitinib, another EGFR inhibitor. Of note, the intracellular accumulation of azacytidine was exacerbated by both erlotinib and gefitinib, pointing to a pharmacokinetic mechanism of synergy. In approximately half of the cases studied, marrow and circulating blasts from MDS and AML patients, respectively, exhibited hyperadditive cytotoxic responses to the combination of azacytidine and erlotinib. These results strongly suggest that the combination of azacytidine and erlotinib may exert clinically relevant antileukemic effects.
    背景与目标: :骨髓增生异常综合症(MDS)一词是由骨髓干细胞引起的一组异类克隆性疾病,通常会发展为急性髓细胞性白血病(AML)。 MDS的参考治疗方法包括DNA甲基转移酶抑制剂氮胞苷和地西他滨。最近,表皮生长因子受体(EGFR)抑制剂埃洛替尼已显示出在体内和体外发挥抗白血病作用,与EGFR无关。由于此功能,厄洛替尼目前正在临床试验中作为抗白血病药物进行测试。在这里,我们报告氮杂胞苷和厄洛替尼在几种原发性或继发性(MDS后)AML细胞系中介导协同抗肿瘤作用。氮杂胞苷和厄洛替尼的组合比单独使用两种药物中的任何一种都能更一致地阻断细胞周期进程并诱导胱天蛋白酶依赖性凋亡。这些作用不是细胞分化的结果,可以相互区分,因为前者依赖于胱天蛋白酶,而后者则不依赖于胱天蛋白酶。阿扎胞苷与厄洛替尼之间的协同作用涉及抗凋亡的Bcl-2家族成员MCL-1和BCL2L10的蛋白酶体降解以及它们的促凋亡对应物PUMA的上调,但当阿西替丁被地西他滨替代时,该协同作用被废止,但当厄洛替尼被持久化时,这种协同作用仍然存在。被另一种EGFR抑制剂吉非替尼(gefitinib)取代。值得注意的是,厄洛替尼和吉非替尼都加剧了氮杂胞苷的细胞内蓄积,这表明了协同作用的药代动力学机制。在大约一半的研究案例中,分别来自MDS和AML患者的骨髓和循环母细胞对氮杂胞苷和厄洛替尼的组合表现出高加性细胞毒性反应。这些结果强烈表明氮杂胞苷和厄洛替尼的组合可能发挥临床相关的抗白血病作用。
  • 【吉非替尼和厄洛替尼在非小细胞肺癌患者中的不良反应和疗效比较:回顾性分析。】 复制标题 收藏 收藏
    DOI:10.1007/s12032-012-0349-y 复制DOI
    作者列表:Yoshida T,Yamada K,Azuma K,Kawahara A,Abe H,Hattori S,Yamashita F,Zaizen Y,Kage M,Hoshino T
    BACKGROUND & AIMS: :Previous studies have demonstrated that both gefitinib and erlotinib are markedly effective for the treatment of non-small-cell lung cancer (NSCLC) with somatic activating mutations of the epidermal growth factor receptor gene (EGFR-mt). These agents are considered to act on EGFR through the same mechanism. However, the efficacy of these agents against EGFR wild-type (-wt) NSCLC remains unclear, and the frequency of adverse events (AEs) appears to differ between them at each approved dose. Here, we conducted a retrospective analysis of AEs and drug efficacy in patients with NSCLC whose EGFR mutation status had been confirmed and who all received 250 mg gefitinib or 150 mg erlotinib once daily. The erlotinib group (n = 35) had more AEs, including rash, fatigue, stomatitis, anorexia and constipation. On the other hand, liver dysfunction and nail change were more frequent in the gefitinib group (n = 107). AEs of ≥grade 2, including rash, fatigue and nausea, were more frequent in the erlotinib group. The erlotinib group also showed more of a tendency to require dose reduction due to AEs. With regard to treatment efficacy for patients with EGFR-wt, there was no significant difference in progression-free survival between the two drug groups. However, this study has several limitations as of the nature of retrospective design; our data suggest that gefitinib and erlotinib might have almost equal efficacy for patients with EGFR-wt NSCLC, as is the case for patients with EGFR-mt tumors, although erlotinib appears to have higher toxicity than gefitinib at each approved dose.
    背景与目标: :以前的研究表明,吉非替尼和厄洛替尼均对具有表皮生长因子受体基因(EGFR-mt)的体细胞激活突变的非小细胞肺癌(NSCLC)具有显着疗效。这些试剂被认为通过相同的机制作用于EGFR。但是,这些药物对EGFR野生型(-wt)NSCLC的疗效仍不清楚,并且在每次批准的剂量下,它们之间的不良事件(AEs)频率也有所不同。在这里,我们对NSCLC患者的AEs和药物疗效进行了回顾性分析,这些患者的EGFR突变状态已得到确认,并且均每天接受250 mg吉非替尼或150 mg厄洛替尼治疗。厄洛替尼组(n = 35)具有更多的不良事件,包括皮疹,疲劳,口腔炎,厌食和便秘。另一方面,吉非替尼组(n = 107)更常出现肝功能障碍和指甲更换。厄洛替尼组≥2级的AE,包括皮疹,疲劳和恶心。埃洛替尼组还显示出更多由于AE导致需要减少剂量的趋势。关于EGFR-wt患者的治疗效果,两组药物的无进展生存期无显着差异。然而,由于回顾性设计的性质,该研究存在一些局限性。我们的数据表明,吉非替尼和厄洛替尼对EGFR-wt NSCLC患者的疗效几乎相同,而EGFR-mt肿瘤患者也是如此,尽管在每个批准的剂量下厄洛替尼似乎比吉非替尼具有更高的毒性。
  • 【EGCG和厄洛替尼联合经典化学疗法对JAR细胞的体外评估。】 复制标题 收藏 收藏
    DOI:10.1007/s11626-017-0145-2 复制DOI
    作者列表:Telli E,Genç H,Tasa BA,Sinan Özalp S,Tansu Koparal A
    BACKGROUND & AIMS: :Gestational Trophoblastic Neoplasia (GTN) is a term used for a group of malignant gynecological tumors including choriocarcinoma. Low-risk neoplasias can be cured using single agents Methotrexate (MTX) and actinomycin-D (ACD), but in certain cases, decreased responsiveness and serious side effects occur. Therefore, researchers have been attempting to find new treatment modalities. One of the most popular way for increasing cancer patient survival rates is supporting treatment with adjuvant molecules or chemosensitizers. For this purpose, we investigated epigallocatechin-3-gallate (EGCG), a green tea cathecin, and Erlotinib, an EGFR tyrosine kinase inhibitor, as single agents and combined with MTX or ACD. In accordance with this, JAR (human placenta choriocarcinoma) cell line was used as an in vitro model and MTT, LDH, caspase-3 activation, RT-PCR, and Western Blot analyses were performed to investigate the effects of the test materials. Our studies demonstrate that combination of Erlotinib and EGCG with MTX and ACD decreases JAR cell proliferation and metastatic HER2 protein synthesis and increases caspase-3 activation compared to ACD or MTX alone. In addition, significant increase was observed in the apoptotic Bax gene, but no notable protein synthesis occurred in the Western Blot analysis, which suggests that combination of Erlotinib and EGCG with classical chemotherapeutics ACD or MTX may lead the JAR cells to apoptosis, but not by a mitochondrial pathway. All the results indicate that the synergetic effect of Erlotinib and EGCG with classical chemotherapeutics may help to increase patient survival rates of choriocarcinoma, but the detailed mechanism needs further investigation.
    背景与目标: 妊娠滋养细胞肿瘤(GTN)是一个术语,用于表示包括绒癌在内的一系列恶性妇科肿瘤。可以使用甲氨蝶呤(MTX)和放线菌素D(ACD)单一药物治愈低危的肿瘤,但在某些情况下,会降低反应性和严重的副作用。因此,研究人员一直在尝试寻找新的治疗方式。增加癌症患者存活率的最流行方法之一是支持使用辅助分子或化学增敏剂进行治疗。为此,我们研究了绿茶儿茶素表没食子儿茶素-3-没食子酸酯(EGCG)和EGFR酪氨酸激酶抑制剂厄洛替尼作为单一药物并与MTX或ACD联合使用。据此,将JAR(人胎盘绒毛膜癌)细胞系用作体外模型,并进行MTT,LDH,caspase-3激活,RT-PCR和Western Blot分析以研究测试材料的作用。我们的研究表明,与单独使用ACD或MTX相比,厄洛替尼和EGCG与MTX和ACD的组合可降低JAR细胞增殖和转移性HER2蛋白的合成,并增加caspase-3激活。此外,凋亡的Bax基因显着增加,但在Western Blot分析中未发现明显的蛋白质合成,这表明厄洛替尼和EGCG与经典化学疗法ACD或MTX的组合可能导致JAR细胞凋亡,但并非通过线粒体途径。所有结果表明,厄洛替尼和EGCG与经典化学疗法的协同作用可能有助于提高绒毛膜癌的患者生存率,但详细的机制尚需进一步研究。
  • 【转移性胰腺癌中表皮生长因子受体和胰岛素样生长因子受体-1信号的双重阻断:吉西他滨,厄洛替尼和西克斯妥单抗与吉西他滨加厄洛替尼的Ib期和随机II期试验(SWO】 复制标题 收藏 收藏
    DOI:10.1002/cncr.28744 复制DOI
    作者列表:Philip PA,Goldman B,Ramanathan RK,Lenz HJ,Lowy AM,Whitehead RP,Wakatsuki T,Iqbal S,Gaur R,Benedetti JK,Blanke CD
    BACKGROUND & AIMS: BACKGROUND:Targeting a single pathway in pancreatic adenocarcinoma (PC) is unlikely to affect its natural history. We tested the hypothesis that simulataneous targeting of the epidermal growth factor receptor (EGFR) and insulin-like growth factor receptor-1 (IGF-1R) pathways would significantly improve progression-free survival (PFS) by abrogating reciprocal signaling that promote drug resistance METHODS:This was a phase Ib/II study testing cixutumumab, combined with erlotinib and gemcitabine (G) in patients with untreated metastatic PC. The control arm was erlotinib plus G. The primary end point was PFS. Eligibility included performance status 0/1 and normal fasting blood glucose. Polymorphisms in genes involved in G metabolism and in the EGFR pathway were also studied RESULTS:The phase I results (n = 10) established the safety of cixutumumab 6 mg/kg/week intravenously, erlotinib 100 mg/day orally, and G 1000 mg/m(2) intravenously on days 1, 8, and 15 of a 28-day cycle. In the RP2 portion (116 eligible patients; median age, 63), the median PFS and overall survival (OS) were 3.6 and 7.0 months, respectively, on the cixutumumab arm, and 3.6 and 6.7 months, respecively, on the control arm. Major grades 3 and 4 toxicities with cixutumumab and control were elevation of transaminases, 12% and 6%, respectively; fatigue, 16% and 12%, respectively; gastrointestinal, 35% and 28%, respectively; neutropenia, 21% and 10%, respectively; and thrombocytopenia, 16% and 7%, respecively. Grade 3/4 hyperglycemia was seen in 16% of patients on cixutumumab. Grade 3 or 4 skin toxicity was similar in both arms of the study (< 5%). No significant differences in PFS by genotype were seen for any of the polymorphisms. CONCLUSIONS:Adding the IGF-1R inhibitor cixutumumab to erlotinib and G did not lead to longer PFS or OS in metastatic PC.
    背景与目标: 背景:针对胰腺腺癌(PC)的单一途径,不太可能影响其自然病史。我们测试了这样的假设,即表皮生长因子受体(EGFR)和胰岛素样生长因子受体1(IGF-1R)途径的同时靶向将通过废除促进耐药性的相互信号来显着改善无进展生存期(PFS)
    方法:这是一项Ib / II期研究,测试西妥木单抗联合厄洛替尼和吉西他滨(G)用于未经治疗的转移性PC患者。对照组为厄洛替尼加G。主要终点为PFS。资格包括表现状态0/1和正常的空腹血糖。还研究了参与G代谢和EGFR途径的基因的多态性
    结果:第一阶段的结果(n = 10)建立了西妥昔单抗6 mg / kg /周静脉内,厄洛替尼100 mg /天口服和G 1000 mg / m(2)在第1、8和15天静脉内的安全性28天的周期。在RP2部分(116名符合条件的患者;中位年龄为63岁)中,西妥昔单抗组的中位PFS和总生存期(OS)分别为3.6和7.0个月,对照组分别为3.6和6.7个月。西昔单抗和对照的主要3级和4级毒性分别是转氨酶升高,分别为12%和6%。疲劳分别为16%和12%;胃肠道,分别为35%和28%;中性粒细胞减少症分别为21%和10%;和血小板减少症分别为16%和7%。在16%的西妥昔单抗患者中发现3/4级高血糖。在研究的两个方面,3级或4级皮肤毒性相似(<5%)。对于任何多态性,未发现按基因型划分的PFS差异显着。
    结论:在厄洛替尼和G中加入IGF-1R抑制剂西克斯妥单抗不能导致转移性PC患者更长的PFS或OS。
  • 【比较吉非替尼和厄洛替尼作为晚期非小细胞肺癌三线治疗的疗效。】 复制标题 收藏 收藏
    DOI:10.1016/j.ejca.2012.07.014 复制DOI
    作者列表:Shao YY,Shau WY,Lin ZZ,Chen HM,Kuo R,Yang JC,Lai MS
    BACKGROUND & AIMS: PURPOSE:The epidermal growth factor receptor inhibitors, gefitinib and erlotinib, are used as standard salvage therapy for advanced non-small-cell lung cancer (NSCLC). The aim of the present study was to compare their efficacies in this population. PATIENTS AND METHODS:The Taiwan Cancer Registry and the National Health Insurance claim databases were searched for newly diagnosed patients with NSCLC from 2004 to 2007 who received gefitinib or erlotinib as third-line therapy. Overall survival (OS) and time to treatment failure (TTF) were determined from registered parameters. Treatment efficacies were compared by the log-rank test in total population and subsets with different clinical characteristics. The Cox's proportion hazard model was used to estimate the adjusted hazard ratios in multivariate analyses. RESULTS:A total of 984 patients who received gefitinib (67%) or erlotinib (33%) were included. Patients receiving gefitinib or erlotinib had similar OS (median, 10.2 versus 9.9 months, p=0.524) and TTF (median, 5.5 versus 3.4 months, p=0.103). In multivariate analyses, both treatment groups had similar risk of overall mortality (adjusted hazard ratio [HR]=1.04, p=0.629) and treatment failure (adjusted HR=0.94, p=0.417). Comparing the treatments in subgroups based on age, tumour histology and gender also revealed no differences in OS and TTF. For patients who received gefitinib or erlotinib for more than 3 or 6 months, there was no difference in TTF but patients who received erlotinib had longer OS. CONCLUSIONS:Gefitinib and erlotinib had similar efficacies as salvage therapy for advanced NSCLC in Taiwan.
    背景与目标: 目的:表皮生长因子受体抑制剂吉非替尼和厄洛替尼被用作晚期非小细胞肺癌(NSCLC)的标准挽救疗法。本研究的目的是比较他们在这一人群中的疗效。
    病人和方法:在台湾癌症登记处和国家健康保险索赔数据库中搜索2004年至2007年新诊断的接受吉非替尼或厄洛替尼作为三线治疗的非小细胞肺癌患者。根据注册参数确定总生存期(OS)和治疗失败时间(TTF)。通过对数秩检验比较总人口和具有不同临床特征的亚组的治疗效果。使用Cox比例风险模型估算多元分析中调整后的风险比率。
    结果:共纳入984例接受吉非替尼(67%)或厄洛替尼(33%)治疗的患者。接受吉非替尼或厄洛替尼的患者的OS(中位10.2对9.9个月,p = 0.524)和TTF(中位5.5对3.4个月,p = 0.103)相似。在多变量分析中,两个治疗组的总死亡率(调整后的危险比[HR] = 1.04,p = 0.629)和治疗失败(调整后的HR = 0.94,p = 0.417)的风险相似。根据年龄,肿瘤组织学和性别对亚组的治疗方法进行比较,还发现OS和TTF均无差异。对于接受吉非替尼或厄洛替尼治疗超过3或6个月的患者,TTF没有差异,但接受厄洛替尼的患者的OS更长。
    结论:吉非替尼和厄洛替尼的疗效与台湾晚期NSCLC的挽救疗法相似。
  • 【厄洛替尼单药治疗老年患者非小细胞肺癌一线治疗:病例系列讨论。】 复制标题 收藏 收藏
    DOI:10.1159/000106097 复制DOI
    作者列表:Reck M
    BACKGROUND & AIMS: BACKGROUND:Non-small-cell lung cancer (NSCLC) predominantly occurs in the elderly, a group that has been historically undertreated for various reasons such as perceived frailty and comorbidity. CASE REPORTS:A series of 5 cases is presented, illustrating the value of erlotinib as a first-line therapy option in elderly patients with adenocarcinoma, who might otherwise have been unsuitable for treatment. A summary of each case is given, along with a discussion of some interesting factors and their clinical relevance to NSCLC therapy. Dose adjustment to manage adverse events is also addressed. CONCLUSION:Erlotinib is an effective and well-tolerated treatment option for NSCLC and could offer an alternative for patients unsuitable for or not wishing to receive chemotherapy.
    背景与目标: 背景:非小细胞肺癌(NSCLC)主要发生在老年人中,该群体由于各种原因(例如感觉虚弱和合并症)在历史上一直得不到充分治疗。
    病例报告:提出了一系列5例病例,说明厄洛替尼作为老年腺癌患者的一线治疗选择的价值,否则他们可能不适合治疗。给出每个病例的摘要,并讨论一些有趣的因素及其与NSCLC治疗的临床相关性。还讨论了管理不良事件的剂量调整。
    结论:厄洛替尼是一种有效且耐受良好的非小细胞肺癌的治疗选择,可为不适合或不希望接受化疗的患者提供替代方案。
  • 【孕酮受体膜成分1导致埃洛替尼耐药,并在肺腺癌细胞中引发Wnt /β-catenin和NF-κB通路的串扰。】 复制标题 收藏 收藏
    DOI:10.1038/s41598-020-61727-3 复制DOI
    作者列表:Lin Y,Higashisaka K,Shintani T,Maki A,Hanamuro S,Haga Y,Maeda S,Tsujino H,Nagano K,Fujio Y,Tsutsumi Y
    BACKGROUND & AIMS: :In non-small-cell lung cancer, mutation of epidermal growth factor receptor (EGFR) stimulates cell proliferation and survival. EGFR tyrosine kinase inhibitors (EGFR-TKIs) such as erlotinib are used as first-line therapy with drastic and immediate effectiveness. However, the disease eventually progresses in most cases within a few years due to the development of drug resistance. Here, we explored the role of progesterone membrane component 1 (PGRMC1) in acquired resistance to erlotinib and addressed the molecular mechanism of EGFR-TKI resistance induced by PGRMC1. The erlotinib-sensitive cell line PC9 (derived from non-small-cell lung cancer) and the erlotinib-resistant cell line PC9/ER were used. In proteomic and immunoblotting analyses, the PGRMC1 level was higher in PC9/ER cells than in PC9 cells. WST-8 assay revealed that inhibition of PGRMC1 by siRNA or AG-205, which alters the spectroscopic properties of the PGRMC1-heme complex, in PC9/ER cells increased the sensitivity to erlotinib, and overexpression of PGRMC1 in PC9 cells reduced their susceptibility to erlotinib. In the presence of erlotinib, immunoprecipitation assay showed that AG-205 suppressed the interaction between EGFR and PGRMC1 in PC9/ER cells. AG-205 decreased the expression of β-catenin, accompanied by up-regulation of IκBα (also known as NFKBIA). Furthermore, AG-205 reduced the expression of β-TrCP (also known as BTRC), suggesting that PGRMC1 enhanced the crosstalk between NF-κB (also known as NFKB) signaling and Wnt/β-catenin signaling in an erlotinib-dependent manner. Finally, treatment with the Wnt/β-catenin inhibitor XAV939 enhanced the sensitivity of PC9/ER cells to erlotinib. These results suggest that PGRMC1 conferred resistance to erlotinib through binding with EGFR in PC9/ER cells, initiating crosstalk between the Wnt/β-catenin and NF-κB pathways.
    背景与目标: 在非小细胞肺癌中,表皮生长因子受体(EGFR)的突变会刺激细胞增殖和存活。 EGFR酪氨酸激酶抑制剂(EGFR-TKI)(例如埃洛替尼)被用作一线治疗,具有明显而即时的效果。然而,由于耐药性的发展,该疾病最终在大多数情况下在几年内发展。在这里,我们探讨了孕酮膜成分1(PGRMC1)在对埃洛替尼的获得性耐药中的作用,并探讨了PGRMC1诱导的EGFR-TKI耐药的分子机制。使用了对埃洛替尼敏感的细胞系PC9(源自非小细胞肺癌)和对埃洛替尼耐药的细胞系PC9 / ER。在蛋白质组学和免疫印迹分析中,PC9 / ER细胞中的PGRMC1水平高于PC9细胞中的PGRMC1水平。 WST-8分析表明,在PC9 / ER细胞中,siRNA或AG-205对PGRMC1的抑制会改变PGRMC1-血红素复合物的光谱性质,从而增加了对厄洛替尼的敏感性,而在PC9细胞中过表达PGRMC1则降低了其对ERG的敏感性。厄洛替尼。在存在厄洛替尼的情况下,免疫沉淀分析表明AG-205抑制了PC9 / ER细胞中EGFR与PGRMC1之间的相互作用。 AG-205会降低β-catenin的表达,并伴随IκBα(也称为NFKBIA)的上调。此外,AG-205降低了β-TrCP(也称为BTRC)的表达,这表明PGRMC1以依洛替尼依赖性的方式增强了NF-κB(也称为NFKB)信号传导和Wnt /β-catenin信号传导之间的串扰。最后,用Wnt /β-catenin抑制剂XAV939处理可增强PC9 / ER细胞对厄洛替尼的敏感性。这些结果表明,PGRMC1通过与PC9 / ER细胞中的EGFR结合而赋予了对厄洛替尼的抗性,从而引发Wnt /β-catenin与NF-κB通路之间的串扰。
  • 【厄洛替尼和吉非替尼治疗非小细胞肺癌患者的比较研究。】 复制标题 收藏 收藏
    DOI:10.4103/ijmr.IJMR_1896_17 复制DOI
    作者列表:Thomas P,Vincent B,George C,Joshua JM,Pavithran K,Vijayan M
    BACKGROUND & AIMS: Background & objectives:Tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) have been evaluated in patients with advanced non-small cell lung cancer (NSCLC). Erlotinib and gefitinib are the first-generation EGFR-TKIs for patients with NSCLC. However, there is a paucity of studies comparing the effectiveness of these two drugs. Hence, this study was aimed to compare the effectiveness and safety of erlotinib and gefitinib in NSCLC patients. Methods:This study included 71 NSCLC patients who received EGFR-TKIs between 2013 and 2016. Adverse drug reaction of both erlotinib (n=37) and gefitinib (n=34) was determined and graded according to Common Terminology Criteria for Adverse Events grading system. Effectiveness was measured using response evaluation criteria in solid tumours and progression-free survival (PFS). Pharmacoeconomic analysis was performed by cost-effective analysis. Results:When comparing safety profile, both the drugs had similar adverse events except for dermal side effects such as acneiform eruption (51.4%), rash (54.05%) and mucositis (59.5%) for erlotinib and 20.6, 26.5 and 29.4 per cent for gefitinib, respectively. The PFS of the two drugs was compared to differentiate the effectiveness of erlotinib and gefitinib. There was no significant difference between the effectiveness of the two drugs. The pharmacoeconomic analysis showed that gefitinib was more cost-effective than erlotinib. Interpretation & conclusions:This study showed that erlotinib and gefitinib had similar effectiveness but gefitinib had a better safety profile compared to erlotinib. Therefore, gefitinib could be considered a better option for NSCLC patients compared to erlotinib. However, further studies need to be done with a large sample to confirm these findings.
    背景与目标: 背景与目的:已针对晚期非小细胞肺癌(NSCLC)患者评估了靶向表皮生长因子受体(EGFR)的酪氨酸激酶抑制剂(TKI)。厄洛替尼和吉非替尼是用于NSCLC患者的第一代EGFR-TKI。但是,很少有研究比较这两种药物的有效性。因此,本研究旨在比较厄洛替尼和吉非替尼在非小细胞肺癌患者中的有效性和安全性。
    方法:该研究纳入了2013年至2016年间接受EGFR-TKI的71例NSCLC患者。根据不良事件通用术语标准分级系统,确定了厄洛替尼(n = 37)和吉非替尼(n = 34)的不良药物反应并进行了分级。使用对实体瘤和无进展生存期(PFS)的反应评估标准来评估有效性。药物经济学分析是通过成本效益分析进行的。
    结果:比较安全性时,两种药物都有相似的不良事件,除了皮肤副作用如埃洛替尼的痤疮样皮疹(51.4%),皮疹(54.05%)和粘膜炎(59.5%)以及厄洛替尼的20.6、26.5和29.4%吉非替尼。比较了两种药物的PFS,以区分厄洛替尼和吉非替尼的疗效。两种药物的有效性之间没有显着差异。药物经济学分析表明,吉非替尼比厄洛替尼更具成本效益。
    解释与结论:这项研究表明,与厄洛替尼相比,厄洛替尼和吉非替尼具有相似的疗效,但吉非替尼具有更好的安全性。因此,与厄洛替尼相比,吉非替尼被认为是非小细胞肺癌患者的更好选择。但是,需要对大量样本进行进一步的研究以证实这些发现。
  • 【玻璃体内给予贝伐单抗治疗厄洛替尼失败的肺腺癌患者的脉络膜转移。】 复制标题 收藏 收藏
    DOI:10.1016/j.lungcan.2012.02.020 复制DOI
    作者列表:Lai CL,Fan KS,Lee YH,Chen HC,Fan WH
    BACKGROUND & AIMS: :Choroidal metastasis is uncommon and usually identified in a relatively advanced cancer status. The median survival after diagnosing choroid metastasis in lung cancer patients was only 1.9 months. Once failed to systemic treatment, there was no effective local treatment for saving visual acuity. The off-label use of intravitreal bevacizumab was popular in treating VEGF-mediated chorioretinal diseases worldwide. We here demonstrate a dramatic and durable response to intravitreal bevacizumab. Unlike the previous similar reports, our patient had failed both first- and second-line therapies.
    背景与目标: :脉络膜转移并不常见,通常在相对晚期的癌症状态下发现。诊断肺癌患者脉络膜转移后的中位生存期仅为1.9个月。一旦全身治疗失败,就没有有效的局部治疗来挽救视力。玻璃体内贝伐单抗的标签外使用广泛用于治疗VEGF介导的脉络膜视网膜疾病。我们在这里展示了对玻璃体内贝伐单抗的戏剧性和持久性反应。与之前的类似报道不同,我们的患者在一线和二线治疗均失败。
  • 【厄洛替尼抗非小细胞肺癌患者脑转移的有效性。】 复制标题 收藏 收藏
    DOI:10.1097/COC.0b013e3182438c91 复制DOI
    作者列表:Bai H,Han B
    BACKGROUND & AIMS: BACKGROUND:Brain metastases commonly occur in non-small cell lung cancer (NSCLC), and patient prognosis is poor. Erlotinib, a specific inhibitor of epidermal growth factor receptor-associated tyrosine kinase, has shown antitumor activity in advanced NSCLC. This study evaluates erlotinib in the treatment for brain metastases from NSCLC. PATIENTS AND METHODS:We retrospectively reviewed 40 NSCLC patients with brain metastases. All were treated with oral erlotinib and followed until disease progression, death, or intolerable side effects. EGFR mutations within surgical specimens were retrospectively examined in 9 patients. RESULTS:For intracranial diseases, partial response (PR) was observed in 4 patients (10%), stable disease (SD) in 21 (52.5%), and progressive disease in 15 (37.5%), with an objective response rate of 10% and a disease control rate (DCR) of 62.5%. For extracranial diseases, DCR was observed in 17 patients (42.5%) (3 PRs+14 SDs) and progressive disease in 23 patients (57.5%). DCR within brain lesions in patients with activating EGFR mutations was 80% (1 PR+3 SDs), compared with 25% (1 SD) in patients with negative EGFR mutation. The median progression-free survival and median survival were 3.0 months and 9.2 months, respectively. There were no clinical factors associated with the response to erlotinib and survival as well (all P>0.05), whereas only the DCR in the brain was related to survival in multivariate analysis (P=0.000). CONCLUSIONS:Erlotinib is modestly active and well-tolerated by NSCLC patients with brain metastases. Erlotinib seems to be more effective in patients with activating EGFR mutations. Erlotinib may be an alternative to traditional treatments in this patient population.
    背景与目标: 背景:脑转移通常发生在非小细胞肺癌(NSCLC)中,患者预后较差。厄洛替尼是一种与表皮生长因子受体相关的酪氨酸激酶的特异性抑制剂,已在晚期NSCLC中显示出抗肿瘤活性。这项研究评估了厄洛替尼在治疗非小细胞肺癌脑转移中的作用。
    方法回顾性分析40例NSCLC脑转移患者。所有患者均接受口服厄洛替尼治疗,直至疾病进展,死亡或无法忍受的副作用为止。回顾性分析了9例患者的手术标本中的EGFR突变。
    结果:对于颅内疾病,4例患者(10%)观察到部分反应(PR),21例(52.5%)观察到稳定疾病(SD),15例(37.5%)观察到进展性疾病,客观缓解率为10 ,疾病控制率(DCR)为62.5%。对于颅外疾病,在17例患者(42.5%)(3 PRs 14 SDs)中观察到DCR,在23例患者中(57.5%)观察到进行性疾病。 EGFR活化突变患者脑部病变的DCR为80%(1 PR 3 SDs),而EGFR突变阴性患者脑部DCR为25%(1 SD)。中位无进展生存期和中位生存期分别为3.0个月和9.2个月。在多变量分析中,也没有与厄洛替尼反应和生存相关的临床因素(所有P> 0.05),而只有脑中的DCR与生存有关(P = 0.000)。
    结论:厄洛替尼在患有脑转移的非小细胞肺癌患者中适度活跃,且耐受性良好。厄洛替尼似乎在激活EGFR突变的患者中更有效。在该患者人群中,厄洛替尼可能是传统治疗的替代方法。

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