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Mariarosaria Boccellino Lucio Quagliuolo Concetta Alaia Anna Grimaldi Raffaele Addeo Giovanni Francesco Nicoletti 《Current medical research and opinion》2016,32(11):1839-1848
The presence of an aberrantly activated epidermal growth factor receptor (EGFR) in many epithelial tumors, due to its overexpression, activating mutations, gene amplification and/or overexpression of receptor ligands, represent the fundamental basis underlying the use of EGFR tyrosine kinase inhibitors (EGFR-TKIs). Drugs inhibiting the EGFR have different mechanisms of action; while erlotinib and gefitinib inhibit the intracellular tyrosine kinase, monoclonal antibodies like cetuximab and panitumumab bind the extracellular domain of the EGFR both activating immunomediated anti-cancer effect and inhibiting receptor function. On the other hand, interleukin-8 has tumor promoting as well as neo-angiogenesis enhancing effects and several attempts have been made to inhibit its activity. One of these is based on the use of the old sulfone antibiotic dapsone that has demonstrated several interleukin-8 system inhibiting actions. Erlotinib typically gives a rash that has recently been proven to come out via up-regulated keratinocyte interleukin-8 synthesis with histological features reminiscent of typical neutrophilic dermatoses. In this review, we report experimental evidence that shows the use of dapsone to improve quality of life in erlotinib-treated patients by ameliorating rash as well as short-circuiting a growth-enhancing aspect of erlotinib based on increased interleukin-8 secretion. 相似文献
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Epidermal growth factor receptor tyrosine kinase inhibitors 总被引:8,自引:0,他引:8
Wakeling AE 《Current opinion in pharmacology》2002,2(4):382-387
Clinical trials of selective small-molecule inhibitors of epidermal growth factor receptor tyrosine kinase activity have shown that these targeted inhibitors of proliferative signal transduction provide well-tolerated antitumour activity in patients. Preclinical pharmacology studies illustrate the potential use of these new cancer therapeutics in combination with chemotherapy, radiotherapy and hormone therapy, and in chemoprevention, in a spectrum of solid human tumours. 相似文献
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《Expert opinion on therapeutic patents》2013,23(5):713-718
Amgen disclosed a series of 4-heteroaryloxy quinoline/quinazoline compounds as multiple kinase inhibitors, including hepatocyte growth factor (HGF) receptor tyrosine kinase c-Met and vascular endothelial growth factor (VEGF) receptor tyrosine kinase. These compounds are stated to have wide therapeutic applications for the treatment of a variety of cancers, hypertension, arteriosclerosis, myocardial infarction and rheumatoid arthritis. 相似文献
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Sülsen VP Frank FM Cazorla SI Barrera P Freixa B Vila R Sosa MA Malchiodi EL Muschietti LV Martino VS 《International journal of antimicrobial agents》2011,37(6):536-543
In this study, the antiprotozoal activity of the sesquiterpene lactone psilostachyin C was investigated. This natural compound was isolated from Ambrosia scabra by bioassay-guided fractionation and was identified by spectroscopic techniques. Psilostachyin C exerted in vitro trypanocidal activity against Trypanosoma cruzi epimastigotes, trypomastigotes and amastigotes, with 50% inhibitory concentration (IC(50)) values of 0.6, 3.5 and 0.9 μg/mL, respectively, and displayed less cytotoxicity against mammalian cells, with a 50% cytotoxic concentration (CC(50)) of 87.5 μg/mL. Interestingly, this compound induced ultrastructural alterations, as seen by transmission electron microscopy, in which vacuolisation and a structural appearance resembling multivesicular bodies were observed even at a concentration as low as 0.2 μg/mL. In an in vivo assay, a significant reduction in the number of circulating parasites was found in T. cruzi-infected mice treated with psilostachyin C for 5 days compared with untreated mice (7.4 ± 1.2 × 10(5)parasites/mL vs. 12.8 ± 2.0 × 10(5)parasites/mL) at the peak of parasitaemia. According to these results, psilostachyin C may be considered a promising template for the design of novel trypanocidal agents. In addition, psilostachyin C inhibited the growth of Leishmania mexicana and Leishmania amazonensis promastigotes (IC(50)=1.2 μg/mL and 1.5 μg/mL, respectively). 相似文献
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Increasing knowledge of the structure and function of the epidermal growth factor receptor (EGFR) subfamily of tyrosine kinases and of their role in the initiation and progression of various cancers has, in recent years, provided the impetus for a substantial research effort aimed at developing new anticancer therapies that target specific components of the EGFR signal transduction pathway. Selective compounds have been developed that target either the extracellular ligand-binding region of the EGFR or the intracellular tyrosine kinase region, resulting in interference with the signalling pathways that modulate mitogenic and other cancer-promoting responses (e.g. cell motility, cell adhesion, invasion and angiogenesis). Potential new anticancer agents that target the extracellular ligand-binding region of the receptor include a number of monoclonal antibodies, immunotoxins and ligand-binding cytotoxic agents. Agents that target the intracellular tyrosine kinase region include small molecule tyrosine kinase inhibitors (TKIs), which act by interfering with ATP binding to the receptor, and various other compounds that act at substrate-binding regions or downstream components of the signalling pathway. Currently, the most advanced of the newer therapies undergoing clinical development are antireceptor monoclonal antibodies (e.g. trastuzumab and cetuximab) and a number of small molecule EGFR-TKIs principally of the quinazoline and pyrazolo-pyrrolo-pyridopyrimidine inhibitor structural classes. The latter group of compounds offers several advantages in cancer chemotherapy, including the possibility of inhibiting specific deregulated pathways in cancer cells while having minimal effects on normal cell function. They also have favourable pharmacokinetic and pharmacodynamic properties and low toxicity, and some TKIs such as the reversible inhibitor ZD1839 ('Iressa') are now undergoing phase II to III clinical trials. In addition, the accumulation of evidence from laboratory studies strongly suggests that EGFR-selective TKIs will have synergistic effects with other antitumour agents or therapy such as cytostatic agents, conventional cytotoxic drugs and radiotherapy. As our knowledge of signal transduction pathways in cancer increases, it is hoped that further advances in this area will allow the therapeutic potential of these compounds as anticancer agents to be realised. 相似文献
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《Expert opinion on therapeutic patents》2013,23(7):885-897
Importance of the field: Platelet-derived growth factor receptor (PDGFR) is a compelling target for developing therapeutic agents to treat diseases associated with overactivated platelet-derived growth factor (PDGF) signaling and has proved to be particularly encouraging for cancer treatment. The efforts in this area have been greatly enhanced by the approval of tyrosine kinase inhibitors with PDGFR inhibitory activity such as imatinib, sunitinib and sorafenib.Areas covered in this review: This review surveys the small molecule PDGFR inhibitors reported in patent literature over the past 5 years (2005 – 2009).What the reader will gain: The reader will gain an overview of the chemical scaffolds and the activity/selectivity of the newly discovered PDGFR inhibitors.Take home message: Targeting PDGFR kinase with small molecule inhibitors has remained a very active area. Many new and novel PDGFR inhibitors with different selectivity profiles are being discovered and evaluated. In cancer therapy, the identification of novel and potent PDGFR inhibitors with preferred kinase inhibitory profiles that deliver superior antitumor efficacy, yet have manageable side effects and toxicities, will continue to be the key for success. Additionally, interest in targeting PDGF signaling for intervention of various vascular diseases and fibrotic conditions is expected to continue to grow. 相似文献
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Ciardiello F 《Drugs》2000,60(Z1):25-32; discussion 41-2
The epidermal growth factor receptor (EGFR)-driven autocrine growth pathway has been implicated in the development and progression of the majority of the most common human epithelial cancers, making the blockade of this growth pathway a promising anticancer therapeutic strategy. Different approaches have been developed to block EGFR activation and/or function in cancer cells. In the past 15 years, various anti-EGFR blocking monoclonal antibodies (MAb), recombinant proteins containing transforming growth factor-alpha (TGFalpha) or EGF fused to toxins, and tyrosine kinase inhibitors (TKIs) have been generated and their biological and potentially therapeutic properties characterised. One of these agents, MAb IMC-C225, a chimeric human-mouse IgG1 MAb, is the first anti-EGFR agent to enter phase II to III clinical trials in patients with cancer. Several small compounds that block the ligand-induced activation of the EGFR tyrosine kinase have been developed. Among these EGFR-TKIs, various quinazoline-derived agents have been synthesised and have shown promising activity as anticancer agents in preclinical models. ZD1839 ('Iressa'), an anilinoquinazoline, is an orally active, selective EGFR-TKI which is currently under clinical evaluation in phase II to III clinical trials in patients with cancer. Preclinical data for ZD1839 strongly support the possibility of potentiating the antitumour activity of conventional chemotherapy with agents that selectively block the EGFR. 相似文献
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靶向血小板源生长因子受体酪氨酸激酶抑制剂的临床研究进展 总被引:2,自引:0,他引:2
随着血小板源生长因子(platelet-derived growth factor,PDCF)及其受体(platelet-derived growth factor receptor,PDGFR)在抗肿瘤作用中研究的深入,通过阻断PDGF/PDGFR信号转导通路来抑制肿瘤的生长,为治疗肿瘤提供了新的方法和策略。本文对进入临床研究的PDGFR激酶抑制剂的研究进展作一综述。 相似文献
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Rubin R Harrison R Chen XF Corzitotto J Hoek JB Hallak H 《Biochemical pharmacology》2004,68(10):2009-2017
Ethanol inhibits insulin and insulin-like growth factor-I (IGF-I) signaling in a variety of cell types leading to reduced mitogenesis and impaired survival. This effect is associated with inhibition of insulin receptor (IR) and insulin-like growth factor-I receptor (IGF-IR) autophosphorylation, which implicates these receptors as direct targets for ethanol. It was demonstrated previously that ethanol inhibits the autophosphorylation and kinase activity of the purified cytoplasmic tyrosine kinase domain of the IR. We performed computer modeling of the ethanol interaction with the IR and IGF-IR kinases (IRK and IGF-IRK). The analysis predicted binding of alcohols within the hydrophobic pocket of the kinase activation cleft, with stabilization at specific polar residues. Using IGF-IRK purified from baculovirus-infected insect cells, ethanol inhibited peptide substrate phosphorylation by non-phosphorylated IGF-IRK, but had no effect on the autophosphorylated enzyme. In common with the IRK, ethanol inhibited IGF-IRK autophosphorylation. In cerebellar granule neurons, ethanol inhibited autophosphorylation of the apo-IGF-IR, but did not reverse IGF-IR phosphorylation after IGF-I stimulation. In summary, the findings demonstrate direct inhibition of IGF-IR tyrosine kinase by ethanol. The data are consistent with a model wherein ethanol prevents the initial phase of IRK and IGF-IRK activation, by inhibiting the engagement of the kinase activation loop. 相似文献
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人表皮生长因子受体1和2(EGFR和HER2)与多种恶性肿瘤的发生和发展密切相关,成为抗肿瘤药物作用的靶点,针对这两个靶点的药物开发已成为抗肿瘤药物的研究热点之一,已有一系列相关药物应用于临床治疗。拉帕替尼是近年开发的针对EGFR和HER的双靶点抗肿瘤新药物,已在部分国家或地区上市,目前主要联合卡培他滨用于先期接受过蒽酮类抗生素、紫杉醇和曲妥珠单抗的HER2阳性乳腺癌的治疗,对于晚期或转移性乳腺癌疗效显著。本文主要综述了拉帕替尼的抗癌机制、临床研究进展和应用前景。 相似文献
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Xiu-Qing Lv Gang Feng Ying-Qian Liu Xiang Nan Liu Yang 《Medicinal chemistry research》2014,23(7):3347-3352
The insecticidal activity of a natural compound combretastatin A-4 (CA-4) was assessed in in vivo assays against Spodoptera litura. CA-4, mixed into an artificial diet, caused various effects, depending on the concentration used. Compared with controls, food intake was lower, larval growth was reduced and larval development prolonged. Pupae weight was reduced, and adult morphology was also affected. Relative to the untreated group, treated groups showed higher mortality at larval and pupal stages, which was generally caused by moult disruption. Results of this study with CA-4 resemble those found in treatment with insect growth regulators. This study indicated that CA-4 merits further study as a lead compound in a novel class of potential insect-control agents or for managing field populations of Lepidoptera pests on cruciferous crops. 相似文献
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Ciardiello F De Vita F Orditura M De Placido S Tortora G 《Expert opinion on emerging drugs》2003,8(2):501-514
The epidermal growth factor receptor (EGFR) is a cell membrane receptor that plays a key role in cancer development and progression. Ligand-activated EGFR-dependent signalling is involved in cell proliferation, apoptosis, angiogenesis and metastatic spread. Targeting the EGFR, therefore, represents a promising molecular approach in cancer treatment. Several anti-EGFR agents are in clinical development. Three drugs are currently in Phase II and III development as single agents, or in combination with other anticancer modalities: IMC-225 (cetuximab/Erbitux; ImClone), a chimaeric human-mouse monoclonal IgG(1) antibody, which blocks ligand binding and functional activation of the EGFR; OSI-774 (erlotinib/Tarceva; Genentech/OSI/Roch) and ZD1839 (gefitinib/Iressa; AstraZeneca), two small molecule EGFR-selective inhibitors of tyrosine kinase enzymatic activity, which prevent EGFR autophosphorylation and activation. Iressa is the first EGFR-targeting agent to be registered as an anticancer drug in Japan, in Australia and in the US for the third-line treatment of chemoresistant non-small cell lung cancer (NSCLC) patients. This review will focus on the preclinical background and on the results from the first series of clinical trials with these drugs. Furthermore, continuing clinical trials and a series of open clinical issues for the development of optimal strategies of using EGFR-targeting agents will be discussed. 相似文献
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目前表皮生长因子受体(EGFR)的酪氨酸激酶抑制剂(TKI)在治疗非小细胞肺癌中得到广泛应用。本文回顾了影响酪氨酸激酶抑制剂药效的EGFR基因多态性以及相关的EGFR基因突变位点对酪氨酸激酶抑制剂吉非替尼治疗非小细胞肺癌的药效发挥产生何种影响的相关研究,说明EGFR的基因多态性对酪氨酸激酶抑制剂的药效发挥产生了重要的作用。 相似文献
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Kakutani R Adachi Y Kajiura H Takata H Kuriki T Ohno N 《International immunopharmacology》2012,12(1):80-87
Natural killer (NK) cells, innate immune effectors that mediate rapid responses to various antigens, play an important role in potentiating host defenses through the clearance of tumor cells and virally infected cells. By using enzymatically synthesized glycogen (ESG) with the same characteristics as natural glycogen, we examined whether orally administered glycogen enhances the innate defense of tumor-implanted mice and the cytotoxicity of NK cells. Oral administration of ESG led to the suppression of tumor proliferation and the prolongation of survival times of tumor-bearing mice. Splenic NK activities of BALB/c mice treated orally with ESG were significantly higher than those of water-treated mice, which were used as a negative control. In addition, intraduodenal injections of ESG gradually and markedly lowered splenic sympathetic nerve activity, which has an inverse correlation with NK activity. Furthermore, ESG activated Peyer's patch cells to induce the production of macrophage inflammatory protein-2 (MIP-2), interleukin-6 (IL-6), and immunoglobulin A (IgA) from these cells. These results demonstrated that orally administrated glycogen significantly enhanced the cytotoxicity of NK cells by acting on Peyer's patch cells and autonomic nerves, and eventually induced the potentiation of host defenses. We propose that glycogen functions not only as an energy source for life support but also as an oral adjuvant for immunopotentiation. 相似文献
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表皮生长因子受体酪氨酸激酶抑制剂在肿瘤治疗中的应用 总被引:4,自引:1,他引:4
表皮生长因子受体 (EGFR)酪氨酸激酶 ,是细胞外信号传递到细胞内的重要枢纽 ,它在信号传导、细胞增殖、分化以及各种调节机制中发挥重要作用 ,在多种癌细胞中过度表达。许多研究表明 ,抑制EGFR酪氨酸激酶活性 ,可抑制肿瘤生长。目前 ,已有几种EGFR酪氨酸激酶抑制剂进入了临床试验。本文对几种EGFR酪氨酸激酶小分子抑制剂在肿瘤治疗中的研究进展做一综述。 相似文献