受体介导肿瘤主动靶向的研究进展

肿瘤细胞表面过度表达一系列受体，能与特异性的配体或抗体结合并诱导细胞内化。以这些受体作为靶点，使药物与特异性配体或抗体结合即可将药物主动靶向肿瘤细胞。本文综述目前在临床和实验研究中用于肿瘤主动靶向的几种受体，包括酪氨酸激酶受体、叶酸受体、激素受体、脂蛋白受体、转铁蛋白受体等。通过了解这些受体及其在肿瘤主动靶向方面的作用，有助于我们对抗肿瘤药物和新型抗肿瘤药物载体的研究。     

受体介导肿瘤主动靶向的研究进展

肿瘤细胞表面过度表达一系列受体,能与特异性的配体或抗体结合并诱导细胞内化。以这些受体作为靶点,使药物与特异性配体或抗体结合即可将药物主动靶向肿瘤细胞。本文综述目前在临床和实验研究中用于肿瘤主动靶向的几种受体,包括酪氨酸激酶受体、叶酸受体、激素受体、脂蛋白受体、转铁蛋白受体等。通过了解这些受体及其在肿瘤主动靶向方面的作用,有助于我们对抗肿瘤药物和新型抗肿瘤药物载体的研究。     

叶酸受体介导的靶向给药系统研究进展

叶酸受体在多种肿瘤细胞表面过度表达,能与特异性的配体结合并将药物靶向运输到特定的肿瘤细胞。本文介绍了叶酸受体介导的靶向给药系统的作用机制和几种常见的药物载体系统。     

配体靶向药物传递系统的研究进展

利用肿瘤细胞表面过度表达的某些生物大分子受体能够与其配体特异性结合的特点,用配体与药物结合,形成配体靶向药物递送系统。配体发挥导向物作用,将药物靶向递送到肿瘤细胞(或组织),实现主动靶向释药,提高药物的选择性,从而增加药效。文中介绍了以维生素(叶酸、维生素B12,维生素A)、蛋白质(转铁蛋白、低密度脂蛋白)、多糖(半乳糖、甘露糖、透明质酸)、整合素等生物大分子为配体的靶向药物递送系统研究进展。     

短肽在靶向药物递送系统中的研究进展

近年来研究发现许多肿瘤细胞表面高表达一些肽类受体，这些肽类受体与相应的配体亲和性高，能以配体-受体方式特异性结合。以小片段活性肽作为导向物形成复合物而发展的靶向药物递送系统，能够将药物定向转运到靶细胞内，显示了良好的研究价值和应用前景。如蛙皮素/胃泌素释放肽受体介导的靶向药物递送系统、生长抑素受体介导的靶向药物递送系统、十肽SynB₃受体介导的靶向药物递送系统、黄体酮释放激素受体介导的靶向药物递送系统及其他肽类受体介导的靶向药物递送系统，其中短肽作为靶向基团与阿霉素、吡咯阿霉素、甲氨蝶呤、顺铂和喜树碱等结合形成高效的复合物，用于表达有相应受体的肿瘤，获得靶向治疗的研究非常有意义。     

叶酸纳米给药系统抗肿瘤作用研究进展

叶酸受体(folate receptor,FR)在多种肿瘤细胞表面高度表达,而在正常细胞表面不表达或低表达,能与特定的叶酸(folic acid,FA)高度特性结合,是肿瘤特异性药物递送的有效靶点。本文对叶酸受体、叶酸及其配体、叶酸纳米制剂内吞作用机制及叶酸纳米制剂抗肿瘤作用进行了综述。     

CD44介导的肿瘤靶向给药技术研究进展

CD44分子是广泛表达于细胞表面的一类跨膜单链糖蛋白,许多肿瘤细胞高表达了CD44。以CD44为作用受体靶点,将其特异性配体与药物以不同作用方式相结合,可以将药物主动靶向到肿瘤细胞。本文介绍了CD44分子及其受体介导的肿瘤靶向给药,重点关注不同载体的给药技术及其效果评价。     

以受体为靶点的药物筛选模型的建立和应用

我国的新药研制工作面临着十分严峻的竞争和挑战。在创制新药的研究中寻找和发现具有生物活性的先导化合物是至关重要的环节之一,而对大量化合物进行活性筛选则是发现先导化合物的主要手段和途径。近年来,我们应用以受体为靶点的药物筛选模型筛选新药技术,已取得了一定的经验。所谓受体配体结合技术,就是利用从器官中分离出细胞膜受体或重组受体技术制备的受体作为筛选模型,利用受体和配体结合的高度特异性以及放射性核素测量的高灵敏度的特点,用放射性核素标记配体（＊L）,在一定的条件下,使其与受体（R）结合,形成受体——配体复合物（R·＊L）,通过测量R＊L的放射性,达到了解受体的结合活性的目的,使用这种技术测定标记配体的类似物和受体的亲和力,来比较一系列的化合物与受体结合的亲和力。由于受体配体结合分析操作快速,简便,药品用量少,可作为药物构效关系研究的工具。通过大量类似活性药物结构的化合物研究,不难总结出构效关系,明确定位出药物活性的分子部位,指导化学合成,研制安全有效的新型特异性药品提供可靠的评价手段。我们利用这种技术已建立了二十六种受体配体结合技术模型,并在这些模型上分别筛选到了有价值的亲和力大小和功能活性的新化合物参数,从而大大加快了先导化合物发现的进程。     

G蛋白偶联受体的结合在镇痛中的作用[英]

体内组织特异性G蛋白偶联受体（GPCR）对于镇痛药物的发展非常重要，μ-和δ-阿片受体就属于此类。Daniels等的研究表明，同时作用于这两种受体的二价配体有与吗啡相似的镇痛效果，且无副作用。δ-阿片受体与μ-阿片受体激动剂耐受性和依赖性的形成有关，因而研究者提出同时调节两种受体的二价配体可能改善止痛药物的副作用，同时也可为研究受体的协同作用提供有力的工具。     

配体-受体系统介导的药物靶向性研究进展

配体-受体系统介导的药物靶向性研究在过去10年中得到了很大的发展。配体介导的主动靶向能够将药物定向运送到血管腔隙、细胞表面和细胞内。使用的配体包括抗体、蛋白质、肽、脂蛋白、糖类以及其他内源性分子。文章介绍了药物靶向研究中使用的多种配体-受体系统，包括运铁蛋白受体、脂蛋白受体、细胞因子受体、凝集素受体、清道夫受体和叶酸受体。     

Kinin receptors as targets for cancer therapy

INTRODUCTION: Biological fluids of cancer patients contain increased levels of kinins. Activation of kinin B1 and B2 receptors expressed on cancer cells produce an increase in cell proliferation, migration of tumor cells and release of MMPs, which are cellular and molecular events of primary importance for tumor growth. The effects of kinins on tumor cells may be amplified by stimulation of kinin receptors expressed on other cells, within the tumor microenvironment, which may in turn increase tumor growth. AREAS COVERED: This review provides a comprehensive discourse on kinins and their receptors in human neoplasia. Concepts that view kinin receptors as targets for human cancer are explored, whilst the molecular basis by which the new dimerized kinin receptor antagonists produce arrest of cell proliferation and apoptosis of cancer cells is also examined. Finally, the role of kinin receptor antagonists as therapeutic tools against human neoplasia is analyzed. EXPERT OPINION: At the present time the available potent, dimerized kinin peptide antagonists, are either specific for B1 or B2 receptors, or are effective on both receptor types. The novel approach of using kinin receptor antagonists either alone or in combination therapy will play a definitive role in the treatment of cancer.     

Effects of peripheral-type benzodiazepine receptor ligands on Ehrlich tumor cell proliferation

Peripheral-type benzodiazepine receptors have been found throughout the body, and particularly, in high numbers, in neoplastic tissues such as the ovary, liver, colon, breast, prostate and brain cancer. Peripheral-type benzodiazepine receptor expression has been associated with tumor malignity, and its subcellular localization is important to define its function in tumor cells. We investigated the presence of peripheral-type benzodiazepine receptors in Ehrlich tumor cells, and the in vitro effects of peripheral-type benzodiazepine receptors ligands on tumor cell proliferation. Our results demonstrate the presence of peripheral-type benzodiazepine receptor in the nucleus of Ehrlich tumor cells (85.53+/-12.60%). They also show that diazepam and Ro5-4864 (peripheral-type benzodiazepine receptor agonists) but not clonazepam (a molecule with low affinity for the peripheral-type benzodiazepine receptor) decreased the percentage of tumor cells in G0-G1 phases and increased that of cells in S-G2-M phases. The effects of those agonists were prevented by PK11195 (a peripheral-type benzodiazepine receptor antagonist) that did not produce effects by itself. Altogether, these data suggest that the presence of peripheral-type benzodiazepine receptor within the nucleus of Ehrlich tumor cells is associated with tumor malignity and proliferation capacity.     

Dopamine and serotonin regulate tumor behavior by affecting angiogenesis

The biogenic amines dopamine and serotonin are neurotransmitters and hormones, which are mainly produced in the central nervous system and in the gastro-intestinal tract. They execute local and systemic functions such as intestinal motility and tissue repair. Dopamine and serotonin are primarily stored in and transported by platelets. This review focuses on the recently recognized role of dopamine and serotonin in the regulation of tumor behavior by affecting angiogenesis and tumor cell proliferation. Preclinical studies demonstrate that dopamine inhibits tumor growth via activation of dopamine receptor D2 on endothelial and tumor cells. Serotonin stimulates tumor growth via activation of serotonin receptor 2B on endothelial cells and serotonin receptors on tumor cells. Drugs that stimulate dopamine receptor D2 or inhibit serotonin receptors are available and therefore clinical intervention studies for cancer patients are within reach.     

Kinin receptors as targets for cancer therapy

Introduction: Biological fluids of cancer patients contain increased levels of kinins. Activation of kinin B₁ and B₂ receptors expressed on cancer cells produce an increase in cell proliferation, migration of tumor cells and release of MMPs, which are cellular and molecular events of primary importance for tumor growth. The effects of kinins on tumor cells may be amplified by stimulation of kinin receptors expressed on other cells, within the tumor microenvironment, which may in turn increase tumor growth.

Areas covered: This review provides a comprehensive discourse on kinins and their receptors in human neoplasia. Concepts that view kinin receptors as targets for human cancer are explored, whilst the molecular basis by which the new dimerized kinin receptor antagonists produce arrest of cell proliferation and apoptosis of cancer cells is also examined. Finally, the role of kinin receptor antagonists as therapeutic tools against human neoplasia is analyzed.

Expert opinion: At the present time the available potent, dimerized kinin peptide antagonists, are either specific for B₁ or B₂ receptors, or are effective on both receptor types. The novel approach of using kinin receptor antagonists either alone or in combination therapy will play a definitive role in the treatment of cancer.     

The NK-1 receptor: a new target in cancer therapy

After binding to the specific neurokinin-1 (NK-1) receptor, the peptide substance P (SP), which is widely distributed in both the central and peripheral nervous systems, induces tumor cell proliferation, angiogenesis, and migration of the tumor cells for invasion and metastasis. However, after binding to NK-1 receptors, NK-1 receptor antagonists inhibit the three above mechanisms. In fact, the antiproliferative action exerted by NK-1 receptor antagonists is because they induce cancer cells to die by apoptosis, whereas SP exerts an antiapoptotic effect. Moreover, it is known that NK-1 receptors are overexpressed in tumors and that tumor cells express several isoforms of the NK-1 receptor. All these data suggest that the SP/NK-1 receptor system could play an important role in the development of cancer; that SP may be a universal mitogen in NK-1 receptor-expressing tumor cells, and that NK-1 receptor antagonists could offer a promising therapeutic strategy for the treatment of human cancer, since they act as broad-spectrum antitumor agents. In sum, the NK-1 receptor may be a new and promising target in the treatment of human cancer.     

Opposing effect of IFNgamma and IFNalpha on expression of NKG2 receptors: negative regulation of IFNgamma on NK cells

The effector functions of natural killer (NK) cells are regulated by integrated signals across an array of stimulatory and inhibitory receptors interacting with target cell surface ligands. The regulatory effect of interferon-alpha (IFNalpha) and interferon-gamma (IFNgamma) on expression of the family of NKG2 receptors, stimulatory NKG2D receptor and inhibitory NKG2A receptor, and cytolysis of the target tumor cells (MICA+ and HLA-E+) were studied. Results show that IFNgamma and IFNalpha influence NK cell function differently. Interferon-alpha stimulates expression of stimulatory NKG2D receptors and inhibits the expression of inhibitory NKG2A receptors on NK cells. Contrary to the stimulatory effect of IFNalpha, IFNgamma inhibits cytolysis by NK cells of tumor cells expressing MICA or HLA-E cell surface proteins. Blocking NKG2D or NKG2A receptor activity with monoclonal antibodies partly attenuates the inhibitory effect of IFNgamma while promoting the effects of IFNalpha on NK cytolysis. These results show for the first time that IFNgamma negatively regulates NK cells through NKG2 receptors, and that the balance between stimulatory and inhibitory signals through the NKG2 family of receptors may be controlled by two opposing interferons. Modulating the balance between stimulatory and inhibitory signals through cell surface receptors on NK cells may open a new approach to NK cell-based biotherapy for cancer and infectious diseases.     

Therapeutic targeting of CD95 and the TRAIL death receptors

The death receptors CD95, TRAILR1 and TRAILR2 induce cell death in many types of tumor cells. Activation of these receptors has received considerable interest due to its potential use in cancer therapy. In particular the observation that most primary cells are not or only barely TRAIL-sensitive resulted in the development of targeted therapy concepts that base on activation of the TRAIL death receptors by recombinant TRAIL or agonistic antibodies. Indeed, a variety of preclinical studies and several phase I and II clinical trials show that activation of TRAIL death receptors effectively induces apoptosis in cancer cells in vivo without therapy-limiting toxicity on normal cells. Primary tumor cells are often sparsely sensitive for TRAIL death receptor-mediated apoptosis or acquire resistance during therapy. Sensitization/resensitization of tumor cells by chemotherapeutic drugs or radiation can therefore be necessary for TRAIL-based therapies, but this involves the danger of triggering side effects related to the breakage of apoptosis resistance of non-transformed cells. Thus, there is a foreseeable need to develop optimized combination therapies or to locally restrict TRAIL receptor activation to fully exploit the antitumoral potential of TRAIL death receptors in the clinic. Although the high sensitivity of hepatocytes for CD95-mediated apoptosis prohibits therapies resulting in systemic activation of CD95, several studies have shown that this limitation can be overcome by ex vivo treatment regimes or by CD95 activating agonists with cell type-specific activity. This patent review is focused on the death receptor agonists currently under consideration in clinical trials, but also addresses the hurdles that have to be cleared to broaden and to improve the applicability of the currently used clinical concepts related to death receptor activation.     

Investigation of cancer cell lines for peptide receptor-targeted drug development

Many tumors highly express specific populations of G-protein-coupled receptors (GPCRs) that could be utilized for receptor-targeted therapy. We confirmed significant quantities of mRNAs specific for certain somatostatin (SST), vasoactive intestinal peptide (VIP), and bombesin (BN) receptors in various commercially available tumor cell lines. Very few of the tumor cell lines examined displayed the high receptor-binding affinity despite exhibiting the expression of appropriate mRNAs and proteins of the cognate receptors. However, binding assays establish that some tumor cell lines, such as pancreatic cancer CFPAC-1, prostate cancer DU-145, and pancreatic carcinoid BON, demonstrate high BN receptor binding. BON cells also demonstrate high somatostatin receptor (SSTR) affinity binding. We also found that tumor cell lines, such as BON and host cells expressing SST receptor subtypes 1 or 2 (CHO-R1 or CHO-R2), underwent a decrease in cell surface receptor density in multiple passages. BON and CHO-R2 cells also rapidly internalize a significant proportion of cell surface ligand–receptor complexes. The tumor cells CFPAC-1, DU-145, and BON with high receptor binding could be useful for peptide drug studies. BON cells were further applied to test SST/BN analogs and cytotoxic conjugates. Furthermore, the in vivo antitumor assay showed that the cytotoxic conjugate CPT-SST targeting all SSTR subtypes displayed a potent tumor-suppressive ability to BON tumors expressing multiple SSTR subtypes.     

Regulators of chemokine receptor activity as promising anticancer therapeutics

Chemokines are a family of small proteins inducing directed cell migration via specific chemokine receptors, which play important roles in a variety of biological and pathological processes. Their respective ligands act as proinflammatory mediators that primarily control leukocyte migration into selected tissues and upregulation of adhesion receptors, and also have a role in pathological conditions that require neovascularization. Therapeutic strategies based on modulation of chemokine receptor pathways were reported to be promising clinical strategies in the treatment of inflammatory diseases and viral infections. Recent studies have been also demonstrated that chemokines and chemokine receptors are produced by many different cell types, including tumor cells. Overexpression of many chemokine and chemokine receptors in tumor cells suggests that they are crucial regulators of the levels of tumor infiltrating leukocytes implicated in the tumorigenesis of multiple human cancers. In the tumor microenvironment they control a variety of biological activities, such as production and deposition of collagen, activation of matrix-digesting enzymes, stimulation of cell growth, inhibition of apoptosis and promotion of neo-angiogenesis and metastasis. In this review we elucidate key aspects of chemokine signaling as well as clinically relevant strategies to modulation of chemokine receptor activity in the treatment of cancer with emphasis on small-molecule agents. We also elucidate various research strategies which were found to be useful in the design of chemokine receptor targeted therapeutics.     

NK-1 receptor antagonists: a new generation of anticancer drugs

After binding to the neurokinin-1 (NK-1) receptor, substance P (SP) induces tumor cell proliferation, angiogenesis, and the migration of tumor cells for invasion and metastasis. After binding to NK-1 receptors, NK-1 receptor antagonists inhibit tumor cell proliferation, angiogenesis and the migration of tumor cells. These antagonists are broad-spectrum antitumor drugs. In addition, in the host they display beneficial effects: anxiolytic, antiemetic, neuroprotector, nephroprotector, hepatoprotector, antiinflammatory and analgesic. In combination therapy with classic cytostatics, NK-1 receptor antagonists have synergic effects and minimize the side-effects of these classic drugs. Thus, NK-1 receptor antagonists could offer a new and promising generation of anticancer drugs.