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1.
Eph receptors are a unique family of receptor tyrosine kinases (RTK) that play critical roles in embryonic patterning, neuronal targeting, and vascular development during normal embryogenesis. Eph RTKs and their ligands, the ephrins, are also frequently overexpressed in a variety of cancers and tumor cell lines. In particular, one family member, EphA2, is overexpressed in breast, prostate, lung, and colon cancers. Unlike traditional oncogenes that often function only in tumor cells, recent data show that Eph receptors mediate cell-cell interactions both in tumor cells and in the tumor microenvironment, namely the tumor stroma and tumor vasculature. Thus, EphA2 receptors are attractive targets for drug design, as targeting these molecules could simultaneously inhibit several aspects of tumor progression. This review focuses on the multiple roles of EphA2 in cancer progression, the mechanisms by which EphA2 inhibition may halt this progression, and the pre-clinical results of EphA2 inhibition in various cancer model systems. 相似文献
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From single- to multi-target drugs in cancer therapy: when aspecificity becomes an advantage 总被引:1,自引:0,他引:1
Targeted therapies by means of compounds that inhibit a specific target molecule represent a new perspective in the treatment of cancer. In contrast to conventional chemotherapy which acts on all dividing cells generating toxic effects and damage of normal tissues, targeted drugs allow to hit, in a more specific manner, subpopulations of cells directly involved in tumor progression. Molecules controlling cell proliferation and death, such as Tyrosine Kinase Receptors (RTKs) for growth factors, are among the best targets for this type of therapeutic approach. Two classes of compounds targeting RTKs are currently used in clinical practice: monoclonal antibodies and tyrosine kinase inhibitors. The era of targeted therapy began with the approval of Trastuzumab, a monoclonal antibody against HER2, for treatment of metastatic breast cancer, and Imatinib, a small tyrosine kinase inhibitor targeting BCR-Abl, in Chronic Myeloid Leukemia. Despite the initial enthusiasm for the efficacy of these treatments, clinicians had to face soon the problem of relapse, as almost invariably cancer patients developed drug resistance, often due to the activation of alternative RTKs pathways. In this view, the rationale at the basis of targeting drugs is radically shifting. In the past, the main effort was aimed at developing highly specific inhibitors acting on single RTKs. Now, there is a general agreement that molecules interfering simultaneously with multiple RTKs might be more effective than single target agents. With the recent approval by FDA of Sorafenib and Sunitinib--targeting VEGFR, PDGFR, FLT-3 and c-Kit--a different scenario has been emerging, where a new generation of anti-cancer drugs, able to inhibit more than one pathway, would probably play a major role. 相似文献
3.
Receptor tyrosine kinases (RTKs) are cell surface transmembrane proteins responsible for intracellular signal transduction. They are expressed in several cell types and, after activation by growth factor binding, trigger a series of intracellular pathways, leading to a wide variety of cell responses (e.g., differentiation, proliferation, migration and invasion, angiogenesis, survival). Over-expression and/or structural alteration of RTKs family members are often associated to human cancers and tumor cells are known to use RTK transduction pathways to achieve tumor growth, angiogenesis and metastasis. Therefore, RTKs represent pivotal target in approaches of cancer therapy. A number of small molecules acting as RTK inhibitors have been synthesized by pharmaceutical companies and are under clinical trials, are being analyzed in animal models or have been successfully marketed. Ligand-dependent downregulation of RTKs is a critical step for modulating their activity and the adaptor Cbl has been indicated as the key protein involved in negative regulation of RTKs, such as EGF and HGF receptors. These data suggest novel potential pharmacological targets for the treatment of human malignancies associated to oncogenic activation of RTKs. 相似文献
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Sophia A. Shahin Ruining Wang Shirleen I. Simargi Altagracia Contreras Liliana Parra Echavarria Louise Qu Wei Wen Thanh Dellinger Juli Unternaehrer Fuyuhiko Tamanoi Jeffrey I. Zink Carlotta A. Glackin 《Nanomedicine : nanotechnology, biology, and medicine》2018,14(4):1381-1394
TWIST protein is critical to development and is activated in many cancers. TWIST regulates epithelial-mesenchymal transition, and is linked to angiogenesis, metastasis, cancer stem cell phenotype, and drug resistance. The majority of epithelial ovarian cancer (EOC) patients with metastatic disease respond well to first-line chemotherapy but most relapse with disease that is both metastatic and drug resistant, leading to a five-year survival rate under 20%. We are investigating the role of TWIST in mediating these relapses. We demonstrate TWIST-siRNA (siTWIST) and a novel nanoparticle delivery platform to reverse chemoresistance in an EOC model. Hyaluronic-acid conjugated mesoporous silica nanoparticles (MSN-HAs) carried siTWIST into target cells and led to sustained TWIST knockdown in vitro. Mice treated with siTWIST-MSN-HA and cisplatin exhibited specific tumor targeting and reduction of tumor burden. This platform has potential application for overcoming clinical challenges of tumor cell targeting, metastasis and chemoresistance in ovarian and other TWIST overexpressing cancers. 相似文献
6.
《Expert opinion on drug delivery》2013,10(12):1297-1309
Tumor vessels possess unique physiological features that might be exploited for improved drug delivery. The targeting of liposomal anticancer drugs to tumor vasculature is increasingly recognized as an effective strategy to obtain superior therapeutic efficacy with limited host toxicity compared with conventional treatments. This review introduces recent advances in the field of liposomal targeting of tumor vasculature, along with new approaches that can be used in the design and optimization of liposomal delivery systems. In addition, cationic liposome is focused on as a promising carrier for achieving efficient vascular targeting. The clinical implications are discussed of several approaches using a single liposomal anticancer drug formulation: dual targeting, vascular targeting (targeting tumor endothelial cells) and tumor targeting (targeting tumor cells). 相似文献
7.
《Expert opinion on therapeutic targets》2013,17(10):1073-1090
Importance of the field: Axl and/or Mer expression correlates with poor prognosis in several cancers. Until recently, the role of these receptor tyrosine kinases (RTKs) in development and progression of cancer remained unexplained. Studies demonstrating that Axl and Mer contribute to cell survival, migration, invasion, metastasis and chemosensitivity justify further investigation of Axl and Mer as novel therapeutic targets in cancer.Areas covered in this review: Axl and Mer signaling pathways in cancer cells are summarized and evidence validating these RTKs as therapeutic targets in glioblastoma multiforme, NSCLC, and breast cancer is examined. A discussion of Axl and/or Mer inhibitors in development is provided.What the reader will gain: Potential toxicities associated with Axl or Mer inhibition are addressed. We propose that the probable action of Mer and Axl inhibitors on cells within the tumor microenvironment will provide a therapeutic opportunity to target both tumor cells and the stromal components that facilitate disease progression.Take home message: Axl and Mer mediate multiple oncogenic phenotypes and activation of these RTKs constitutes a mechanism of chemoresistance in a variety of solid tumors. Targeted inhibition of these RTKs may be effective as anti-tumor and/or anti-metastatic therapy, particularly if combined with standard cytotoxic therapies. 相似文献
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目的 对比分析阿托伐他汀和瑞舒伐他汀所致药品不良反应,为临床安全、合理选择降脂药提供参考。方法 采用回顾性分析的方法,对福州市长乐区医院2010—2019年上报的怀疑阿托伐他汀和瑞舒伐他汀所致不良反应病例报告进行对比分析。分别从患者一般情况、用药情况、累及系统-器官损害、观察指标、不良反应发生时间分布、及转归等方面进行统计分析。结果 共筛选出89例阿托伐他汀所致的不良反应报告、38例瑞舒伐他汀所致的不良反应报告。阿托伐他汀以肝胆系统损害及骨骼肌系统损害多见,瑞舒伐他汀以肝胆系统及泌尿系统损害多见;阿托伐他汀涉及系统器官的不良反应表现较多,阿托伐他汀和瑞舒伐他汀出现的LFTs>3×ULN、CK>10×ULN、SAMS的比较差异均无统计学意义。阿托伐他汀不良反应多发生在用药4~18 d,而瑞舒伐他汀多发生在5~20 d。阿托伐他汀与瑞舒伐他汀引起的不良反应大部分为严重,经采取相应措施治疗后易于好转及治愈。结论 阿托伐他汀与瑞舒伐他汀引发的不良反应临床表现有所不同,但不良反应发生时间及主要不良反应观察指标相似,临床用药中应当根据实际情况进行使用,以保障用药安全。 相似文献
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The coordinated functional expression of epidermal growth factor receptor and c-Met in colorectal carcinoma metastasis 总被引:5,自引:0,他引:5
The process of metastasis is a highly selective, nonrandom process resulting in the clonal selection of a population of cells that is able to detach from the primary tumor, invade and survive in the circulation, arrest, extravasate, and ultimately survive and proliferate in the secondary organ-specific site. Tumor cell interactions with the microenvironment can profoundly influence the survival and proliferation of the cell at a secondary site. The epidermal growth factor receptor (EGFR) and the hepatocyte growth factor receptor (c-Met) are two such receptor tyrosine kinases (RTKs) that have been causally implicated in colorectal carcinoma (CRC) progression and metastasis. Activation of these RTKs can stimulate a number of specific pathways directly effecting tumor cell migration, survival and proliferation. The aberrant regulation of the RTKs is often noted in advanced CRC and its' liver metastases and can significantly effect the metastatic phenotype of tumor cells. 相似文献
10.
Protein tyrosine kinases have emerged as crucial targets for therapeutic intervention in cancer. More recently, growth factor ligands and their respective receptor tyrosine kinases (RTKs) have been shown to be required for tumor cell growth. This latter aspect includes tumor angiogenesis where the growth of tumors leads to compensatory effects on host cells in the tumor microenvironment leading to the growth of microvessels. The purpose of this review is to focus on synthetic chemical approaches to block RTKs associated with tumor angiogenesis as a means to limit the growth and spread of human tumors. 相似文献
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Breast cancer is the most common cancer and the second leading cause of cancer‐related death in women worldwide. In spite of huge advancements in early detection and ever‐increasing knowledge of breast cancer biology, approximately 30% of patients with early‐stage breast cancer experience disease recurrence. Most patients are chemosensitive and cancer free immediately after the treatment. About 50% to 70% of breast cancer patients, however, will relapse within 1 year. Such a relapse is usually concomitant with adenocarcinoma cells acquiring a chemoresistant phenotype. Both de novo and acquired chemoresistance are poorly understood and present a major burden in the treatment of breast cancer. Although, previously, chemoresistance was largely linked to genetic alterations within the cancer cells, recent investigations are indicating that chemoresistance can also be associated with the tumor microenvironment. Nowadays, it is widely believed that tumor microenvironment is a key player in tumor progression and response to treatment. In this study, we will review the interactions of breast tumor cells with their microenvironment, present the latest research on the resistance mediated by the stromal component in breast cancer, and discuss the potential therapeutic strategies that can be exploited to treat breast cancers by targeting tumor microenvironment. 相似文献
12.
Active targeting with particulate drug carriers in tumor therapy: fundamentals and recent progress 总被引:5,自引:0,他引:5
Drug therapy for the treatment of tumors is often limited by a narrow therapeutic index. One approach that overcomes this limitation is the active targeting of tumors with particulate drug carriers. The derivatization of particulate drug carriers with a ligand leads to the selective targeting of the particulate to selected cells, thereby focusing drug delivery. In addition, particulate drug carriers have a high loading capacity, do not need covalent conjugation of the drug and the formulation protects the entrapped drug from enzymatic inactivation. Despite these favorable properties, their therapeutic efficacy in animal models has been reported only in recent years. The use of internalizing ligands and the targeting of intravascular tumor cells and endothelial cells of tumor blood vessels have been instrumental in demonstrating the clinical effectiveness of particulate drug carriers in animal models. As a result, several actively targeted particulate carriers have now entered, or are about to enter, clinical investigation. Recent findings, for example, the identification of cell-penetrating peptides with restricted cell selectivity, suggest that further improvements in this approach are likely in the near future. 相似文献
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Enhanced activity of tyrosine kinase receptors (RTKs) has been implicated as a contributing factor in the development of malignant and nonmalignant proliferative diseases such as cancer and atherosclerosis. Several growth factors traducing mitogenic signals through RTKs are implicated in the development of tumor and cardiovascular diseases. Therefore, in recent years many efforts have been made to develop RTK small molecule inhibitors for the treatment of tumor and cardiovascular diseases. Recently, catechins, the main compounds of green tea leafs, have been identified as potent natural inhibitors of several RTKs. Furthermore, there is increasing evidence that catechins possess antiangiogenic properties. In summary, several animal and cell culture studies suggest that catechins are potential candidates for the clinical therapy of cancer and cardiovascular diseases. (c) 2002 Prous Science. All rights reserved. 相似文献
14.
Vaccines against cancers have not been as effective as vaccines against infectious diseases. However, recent studies have advanced our understanding of the stages of tumor cell development and of mechanisms of immune surveillance, immune suppression, and of tumor escape from the immune system. The development of animal models that mimic development of human cancers has helped advance the understanding of these processes and is aiding the development of greatly improved vaccines. Here we review the recent progress in developing vaccines and prophylactic approaches for pancreatic and colon cancers. Improved understanding of the expression of various oncogenes and tumor-associated antigens helps in selecting antigenic targets for stage-specific immune prevention. Identification of the earliest alterations in precancerous lesions and selection of epitopes unique to the aberrant cells and capable of triggering strong cytotoxic and helper T cell responses may aid the development of safe and effective vaccines for use in those at high risk of progressing to invasive cancers. The responses can be enhanced with carefully selected adjuvants to boost immunity and by selecting epitopes that are expressed on dendritic cells, thereby promoting T cell responses. Tumor resistance via loss of the targeted antigen can be mitigated by inclusion of multiple tumor epitopes in vaccine constructs. Tumor immune escape can be diminished by targeting various immunosuppressive mechanisms used by different tumors, such as tumor production of immunosuppressive cytokines (e.g., interleukin 10, and Transforming Growth Factor-beta, which can promote activity of immunosuppressive regulatory T cells), or by inhibiting production of inflammatory prostanoids with combined cyclooxygenase/lipoxygenase inhibitors. Finally, prevention of many cancers may be enhanced by carefully selecting and scheduling of vaccine administration in combination with other chemotherapeutic or chemopreventive agents. Preclinical and early clinical trials incorporating these principles are discussed. 相似文献
15.
Roussidis AE Theocharis AD Tzanakakis GN Karamanos NK 《Current medicinal chemistry》2007,14(7):735-743
Molecular therapies target key functional molecules in order to halter viable operation of cancer cells. Receptor tyrosine kinases (RTKs) constitute attractive targets, as quite often their abnormal signaling has been associated with tumor development and growth. Overexpression of growth factor receptors, including IGF, EGF, TGF-alpha, SCF and PDGF receptors, has been associated with poor prognosis in breast cancer. Therefore, a number of RTKs are already targets for novel designed drugs, which involve tyrosine kinase inhibitors and monoclonal antibodies. Despite the fact that c-Kit and PDGF-R have been effective targets in a number of cancers, the experimental results in breast have not yet clarified their importance. The expression and function of c-Kit in breast cancer is a quite controversial subject. Several studies propose that the loss of c-Kit expression has been associated with tumor progress, whereas other reports indicate not only its expression but also the implication of c-Kit in breast cancer. On the other hand, the expression of PDGF-R in breast cancer is not in question. A number of inhibitors against tyrosine kinases are currently in trials as to demonstrate their importance in breast cancer treatment. Imatinib (STI571), which is a selective tyrosine kinase inhibitor and particularly of c-Kit and PDGF-R, exhibited encouraging results in respect to its inhibitory effect in cell growth and invasion potential in a panel of human breast cancer cell lines. In this review, the importance of RTKs in human cancer and of c-Kit and PDGF-R as molecular targets in breast cancer treatment, in the view of their expression profiles and the in vitro effects of STI571 is discussed. 相似文献
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Noberini R De SK Zhang Z Wu B Raveendra-Panickar D Chen V Vazquez J Qin H Song J Cosford ND Pellecchia M Pasquale EB 《Chemical biology & drug design》2011,78(4):667-678
Eph receptor tyrosine kinases and ephrin ligands control many physiological and pathological processes, and molecules interfering with their interaction are useful probes to elucidate their complex biological functions. Moreover, targeting Eph receptors might enable new strategies to inhibit cancer progression and pathological angiogenesis as well as promote nerve regeneration. Because our previous work suggested the importance of the salicylic acid group in antagonistic small molecules targeting Eph receptors, we screened a series of salicylic acid derivatives to identify novel Eph receptor antagonists. This identified a disalicylic acid-furanyl derivative that inhibits ephrin-A5 binding to EphA4 with an IC(50) of 3 μm in ELISAs. This compound, which appears to bind to the ephrin-binding pocket of EphA4, also targets several other Eph receptors. Furthermore, it inhibits EphA2 and EphA4 tyrosine phosphorylation in cells stimulated with ephrin while not affecting phosphorylation of EphB2, which is not a target receptor. In endothelial cells, the disalicylic acid-furanyl derivative inhibits EphA2 phosphorylation in response to TNFα and capillary-like tube formation on Matrigel, two effects that depend on EphA2 interaction with endogenous ephrin-A1. These findings suggest that salicylic acid derivatives could be used as starting points to design new small molecule antagonists of Eph receptors. 相似文献
18.
Radiogenetic therapy: strategies to overcome tumor resistance 总被引:9,自引:0,他引:9
The aim of cancer gene therapy is to selectively kill malignant cells at the tumor site, by exploiting traits specific to cancer cells and/or solid tumors. Strategies that take advantage of biological features common to different tumor types are particularly promising, since they have wide clinical applicability. Much attention has focused on genetic methods that complement radiotherapy, the principal treatment modality, or that exploit hypoxia, the most ubiquitous characteristic of most solid cancers. The goal of this review is to highlight two promising gene therapy methods developed specifically to target the tumor volume that can be readily used in combination with radiotherapy. The first approach uses radiation-responsive gene promoters to control the selective expression of a suicide gene (e.g., herpes simplex virus thymidine kinase) to irradiated tissue only, leading to targeted cell killing in the presence of a prodrug (e.g., ganciclovir). The second method utilizes oxygen-dependent promoters to produce selective therapeutic gene expression and prodrug activation in hypoxic cells, which are refractive to conventional radiotherapy. Further refining of tumor targeting can be achieved by combining radiation and hypoxia responsive elements in chimeric promoters activated by either and dual stimuli. The in vitro and in vivo studies described in this review suggest that the combination of gene therapy and radiotherapy protocols has potential for use in cancer care, particularly in cases currently refractory to treatment as a result of inherent or hypoxia-mediated radioresistance. 相似文献
19.
The success of molecular target-based cancer therapy exampled by Herceptin targeting Her2 indicates that cancer immunotherapy involves identifying and targeting key molecular drivers of cancer. Recently, the human Cripto, a founding member of the epidermal growth factor-Cripto-FRL1-Cryptic (EGF-CFC) protein family has been demonstrated to be a unique molecule and could be targeted by anti-Cripto monoclonal antibodies for the treatment of cancer. Cripto plays an important role in embryonic development, tumorigenesis, cancer cell proliferation and survival. Cripto is upregulated in most epithelial cancers but is absent or weakly expressed in normal cells. Cripto expression is associated with tumorigenesis and invasion. Cripto is also involved in tumor metastasis, which is strongly supported by the recent discovery that the phenotypic changes of increased motility and invasiveness of cancer cells are reminiscent of the epithelial mesenchymal transition (EMT) that occurs during embryonic development. In this review, we emphasize that the EGF-like region of Cripto plays a critical role in Cripto signaling-mediated tumor growth and EMT. Therefore the EGF-like region should be regarded as a therapeutic point for monoclonal antibody (MAb) intervention. The mechanisms of action of these MAbs to the EGF-like region of Cripto are most likely through intervention of c-Src signaling. The CFC region of Cripto is another region to be targeted for treatment of cancer, as the Cripto can bind to activin B through the CFC region to stimulate cell proliferation. The MAbs to the CFC region block the binding of Cripto and activin B and result in an inhibition of cell growth. Therefore the MAbs to Cripto may be of value in the treatment of various cancers. 相似文献
20.
Felipe A Bielanska J Comes N Vallejo A Roig S Ramón Y Cajal S Condom E Hernández-Losa J Ferreres JC 《Current medicinal chemistry》2012,19(5):661-674
Potassium channels (KCh) are a diverse group of membrane proteins that participate in the control of the membrane potential. More than eighty different KCh genes have been identified, which are expressed in virtually all living cells. In addition to nerve and cardiac action potentials, these proteins are involved in a number of physiological processes, including cell volume regulation, apoptosis, immunomodulation and differentiation. Furthermore, many KCh have been reported to play a role in proliferation and cell cycle progression in mammalian cells, and an important number of studies report the involvement of KCh in cancer progression. The voltage dependent potassium (Kv) channels, in turn, form the largest family of human KCh, which comprises about 40 genes. Because Kv1.3 and Kv1.5 channels modulate proliferation of different mammalian cells, these proteins have been analyzed in a number of tumors and cancer cells. In most cancers, the expression patterns of Kv1.3 and Kv1.5 are remodeled, and in some cases, a correlation has been established between protein abundance and grade of tumor malignancy. The list of cancers evaluated is constantly growing, indicating that these proteins may be future targets for treatment. The aim of this review is to provide an updated overview of Kv1.3 and Kv1.5 channels during cancer development. Unlike Kv1.5, Kv1.3 is characterized by a very selective and potent pharmacology, which could lead to specific pharmacological targeting. Because potassium channels may play a pivotal role in tumor cell proliferation, these proteins should be taken into account when designing new cancer treatment strategies. 相似文献