与肿瘤的抗血管生成治疗相关的生物标志物

抗血管生成药物的抗肿瘤机制与化疗药物不同,细胞毒药物的生物标志物对抗血管生成药物来说未必适用,因此寻找和选择有关的生物标志物对于抗血管生成治疗来说十分必要。目前一些与血管生成相关的蛋白质、内皮细胞、微血管密度等已在抗肿瘤血管生成的研究中越来越受到重视。本文将围绕以上这些与抗血管生成治疗相关的生物标志物的检测手段,以及它们在剂量指示、早期临床受益、耐药性出现和二线治疗选择等方面的应用进行综述。     

Anti-angiogenic therapy as a cancer treatment paradigm

The inhibition of angiogenesis is an emerging therapeutic strategy for cancer treatment. In contrast to conventional therapies, anti-angiogenic therapies primarily target tumor-associated endothelial cells which serve as a lifeline for tumor growth, progression and metastasis. By blocking the supply of essential nutrients and the removal of metabolites, anti-angiogenic therapies aim to delay both primary and metastastic tumor growth while overcoming the inherent cytotoxicities of classical chemotherapies. Indeed, tumor-related angiogenesis is a multi-step process initiated by a cascade of proangiogenic factors secreted from both the tumor and host tissues. These intricate processes involve a close interaction of tumor and associated endothelial cells as well as an intimate communication between proliferating endothelial cells, stromal cells and extracellular matrix components. Inhibition of these proangiogenic mechanisms has become a major challenge for the development of anti-cancer treatment modalities. In this regard, anti-angiogenic therapies embody a potentially powerful adjunct to traditional cancer therapies. In this review, we provide an overview of traditional anti-cancer drugs and discuss the fundamentals of anti-angiogenic therapies. While presenting the salient features of the anti-angiogenic agents targeting the individual phases of angiogenesis, we highlight the potential for specific agent development as novel anti-angiogenic therapeutics. Finally, we present and summarize emerging angiogenesis inhibitors.     

Cancer anti-angiogenic therapy

Tumor angiogenesis affords new targets for cancer therapy, since inhibition of angiogenesis suppresses tumor growth by cutting out the supply of oxygen and nutrients. Anti-angiogenic therapy is thought to be free of the severe side effects that are usually seen with cytotoxic anticancer drugs. Furthermore, anti-angiogenic therapy is thought not only to eradicate primary tumor tissues, but also to suppress tumor metastases. However, it is uncertain whether this therapy causes tumor regression because it inhibits only angiogenic events. Recently, a novel anti-angiogenic therapy called anti-neovascular therapy (ANET) has become notable. This therapy inflicts indirect lethal damage on tumor cells by damaging newly formed blood vessels using anti-cancer drugs targeting the angiogenic vasculature, since cytotoxic anti-cancer drugs cause damage to proliferating neovascular endothelial cells as well as tumor cells. Moreover, neovascular endothelial cells would not be expected to acquire drug-resistance. Traditional chemotherapy, which directly targets tumor cells, has potential problems such as low specificity and severe side effects. On the contrary, in ANET, severe side effects may be suppressed, since traditional anti-cancer agents are delivered to the neovessels by DDS technology. Besides the usage of DDS technology, anti-neovascular scheduling of chemotherapy, or metronomic-dosing chemotherapy, has also been attempted in which anti-cancer drugs are administered on a schedule to damage neovessels. In this review, we describe traditional anti-angiogenic therapy and ANET. We also discuss anti-angiogenic cancer photodynamic therapy (PDT), since PDT is clinically applied to treat age-related macular degeneration (AMD), in which uncontrolled angiogenesis occurs.     

Strategies on the development of small molecule anticancer drugs for targeted therapy

The main challenges currently encountered in chemotherapy are the lack of tumor selectivity and drug resistance. The design of novel cytostatic drugs has become the state-of-the-art technology in terms of targeted tumor therapy. This review illustrates the mechanisms and the advantages of representative chemotherapeutic agents, and presents an updated summary of the various drug design strategies developed by modern medicinal chemists during the most recent tumor targeting research which include rational design for overcoming drug resistance, the combi-targeting strategy, the prodrug approach, and tumor specific transporter based drug design. The concept of transporter related tumor targeting strategies for small molecule anticancer drug design discussed in this review may be amenable to predictable drug discovery for targeted therapy.     

Targeting tumor stroma and exploiting mature tumor vasculature to improve anti-cancer drug delivery.

The identification of a critical role of tumour stroma in the regulation of tumour interstitial fluid pressure and the simultaneous discovery of the impact of anti-angiogenic drugs on tumour hemodynamics have provided new potential for improving tumour delivery of anti-cancer drugs. Here, we review the most recent studies investigating how tumour-associated fibroblasts and macrophages as well as the extracellular matrix itself may be targeted to facilitate delivery of both low-molecular weight drugs and macromolecules. In addition, we summarize the current understanding of the use of vasoactive compounds, radiotherapy and vascular-disrupting agents as potential adjuvants to maximize tumour delivery of anti-cancer drugs. The impact of these strategies on the diffusive and convective modes of drug transport is discussed in the light of Fick's and Starling's laws. Finally, we discuss how transcytosis through caveolae may also be exploited to optimize the selective delivery of conventional chemotherapy to the subendothelial tumour cell compartment.     

Inhibition of Tumor Growth and Metastasis by Targeting Tumor-Associated Angiogenesis with Antagonists to the Receptors of Vascular Endothelial Growth Factor

Angiogenesis, the formation of new blood vessels, is essential for both tumor growth and metastasis. Recent advances in our understanding of the molecular mechanisms underlying the angiogenesis process and its regulation have led to the discovery of a variety of pharmaceutical agents with anti-angiogenic activity. The potential application of these angiogenesis inhibitors is currently under intense clinical and pre-clinical investigation. Compelling evidence suggests that vascular endothelial growth factor (VEGF) and its receptors play critical roles in tumor-associated angiogenesis, and that they represent good targets for therapeutic intervention. This has been demonstrated in a variety of animal tumor models in which disabling the function of VEGF and its receptors was shown to inhibit both tumor growth and metastasis. We have produced a panel of antibodies directed against the VEGF receptor 2, KDR/Flk-1. These antibodies potently block VEGF/KDR/Flk-1 interaction, and inhibit VEGF-stimulated activation of the receptor and proliferation of human endothelial cells. Further, the antibodies significantly inhibited tumor-associated angiogenesis in several animal models. Antagonists of VEGF and/or its receptors may offer higher specificity towards tumors with reduced side effects, and may be less likely to elicit drug resistance compared to conventional therapy. Anti-angiogenesis therapy represents a novel strategy for the treatment of cancer and other human disorders where pathological angiogenesis is involved.     

Tumor angiogenesis: a potential target in cancer control by phytochemicals

It is now well established that angiogenesis is an obligatory event for the growth and progression of solid tumors beyond the size limit (approximately 2 mm diameter) imposed by simple diffusion for the nutrient supply. Human tumors can remain dormant for years owing to a balance between cell proliferation and apoptosis. Several hypotheses have been articulated regarding the critical importance of tumor angiogenesis in the development and metastatic spread of tumors, and how preventive/therapeutic inhibition of angiogenesis might be exploited as a novel means of controlling cancer growth. Anti-angiogenic therapy is suggested as one of the most promising approaches to control cancer, as endothelial cells are generally non-transformed cells and are less prone to acquire drug resistance. Tumor vasculature could be an important prognostic marker, and an independent predictor of pathologic stages and malignant potential of cancer. This review is focused on recent developments and comprehensive mechanistic aspects of phytochemicals related to an interplay of angiogenic promoters and inhibitors, and associated signaling in both tumor as well as endothelial cells. Since, vascular endothelial cells constitute the first line exposure to the blood-borne agents, it is plausible that anti-angiogenic activity of phytochemicals could be associated with lowering the risk of cancer by preventing the growth and metastasis of tumor.     

Angiogenesis in glioblastoma multiforme: navigating the maze

Blood vessel formation is a fundamental process that occurs during both normal and pathologic periods of tissue growth. In aggressive malignancies such as glioblastoma multiforme (GBM), vascularization is often excessive and facilitates tumor progression. In an attempt to maintain tumors in a state of quiescence, multiple anti-angiogenic agents have been developed. Although several angiogenesis inhibitors have produced enhanced clinical benefits in GBM, many of these pharmacologic agents result in transitory initial response phases followed by evasive tumor resistance. Thus, a significant need exists for the discovery of novel and effective anti-angiogenic therapies. The development of new molecular-targeted therapeutic strategies is often complicated by the complexity of angiogenic signal transduction. Due to the labyrinthine nature of these signaling pathways, increased production of other angiogenic factors may compensate for the inhibition of key vascular targets like vascular endothelial growth factor (VEGF). Such compensatory mechanisms facilitate vascularization and allow tumor growth to proceed even in the presence of anti-angiogenic agents. This review presents the challenges of targeting the intricate vascular network of GBM and discusses the clinical implications for recent advancements in targeted anti-angiogenic drug therapy.     

Tumor vasculature directed drug targeting: applying new technologies and knowledge to the development of clinically relevant therapies

Recognition of the dependence of solid tumor growth on the formation of new blood vessels has ignited an enormous research effort aimed at the development of new therapeutic strategies for cancer. Besides direct application of drugs inhibiting endothelial cell function during angiogenesis, tumor vasculature directed drug-targeting strategies have been investigated for this purpose. In animal models of disease, proof of principle regarding the potential of selective interference with tumor blood flow as a powerful tumor therapy has been generated to its full extent. The challenge for the coming years will be to develop these strategies into clinically applicable ones. New insights into the molecular mechanisms prevailing in the endothelium during angiogenesis and into the mechanism(s) of action of drugs with anti-angiogenic activities, as well as new techniques to identify useful tumor endothelium specific target epitopes have in recent years been exploited to meet this challenge. This review summarizes vasculature directed therapeutic strategies proven to be successful in pre-clinical models and new (drug targeting) technologies enabling the development of more effective therapeutics for the treatment of cancer.     

Integrins as novel drug targets for overcoming innate drug resistance

Acquired drug resistance continues to be one of the major obstacles hindering the successful treatment of many forms of cancer. Compounds utilized as antagonists of these cytoprotective mechanisms have, for the most part, proven to be ineffective at overcoming clinical resistance to cytotoxic drugs. Recently, the tumor cell microenvironment has been found to have a significant bearing on the survival of tumor cells following exposure to a wide variety of anti-neoplastic agents, prior to the acquisition of known drug resistance mechanisms. Specifically, interactions between cell surface integrins and extracellular matrix components have been shown to be responsible for this phenomenon of innate drug resistance, which we have termed Cell Adhesion Mediated Drug Resistance, or CAM-DR. Following its discovery using a multiple myeloma cell line model, evidence for CAM-DR has been found in a multitude of other human tumor cell types. In contrast to many other drug resistance mechanisms, integrin-mediated cell signaling is capable of protecting against death induced by an extremely wide variety of structurally and functionally diverse agents from traditional DNA damaging agents to the promising novel kinase inhibitor STI-571. This review examines the role of integrins in regard to their ability to protect tumor cells from drug- and radiation-induced apoptosis through numerous intracellular mechanisms. Current and future antagonists of specific integrin heterodimers may have the potential to sensitize tumor cells when used in combination with standard chemotherapy regimens. Specific signal transduction pathways initiated by integrin ligation will also be discussed as potential bridge points for inhibiting cell survival during cytotoxic drug exposure.     

New indications for established drugs: combined tumor-stroma-targeted cancer therapy with PPARgamma agonists, COX-2 inhibitors, mTOR antagonists and metronomic chemotherapy

In search of new strategies for the treatment of cancer, the interaction between tumor and stroma attracts more and more attention. Disruption of stroma functions, e.g. angiogenesis, has evolved into a promising target for cancer therapies. Since stromal cells are genetically stable, stroma-targeted therapies seem to be less susceptible to the development of drug resistance. Several well-established drugs, which had initially been developed for other indications, also exhibit antitumor activity. Among those, PPARgamma agonists, COX-2 inhibitors, and mTOR antagonists are the most remarkable examples. Current research data and clinical experience suggest that these drugs target stroma functions in cancer, in particular angiogenesis, but immunological mechanisms and direct antitumor effects seem to participate as well. In addition to these drugs, frequent administration of low-dose chemotherapeutics, referred to as metronomic chemotherapy, reveals profound anti-angiogenic effects. In the meantime, a multitude of preclinical and clinical studies have been undertaken, which demonstrate the efficacy of these drugs in cancer therapy. Combinatorial use of these agents has been suggested to be superior in terms of antitumor efficacy and prevention of drug resistance. The toxicity of these therapies is surprisingly low compared with conventional high-dose chemotherapy regimens. Patients with advanced disease, often heavily pretreated and presenting multiple drug resistance, could particularly profit from such tumor-stroma-targeted therapies. However, larger randomized clinical trials are required for further evaluation and optimization of this concept.     

Polymeric nanoparticles for cancer therapy

Cancer is an ever-increasing menace that needs to be curbed soon. Though chemotherapy is successful to some extent, the main drawbacks of chemotherapy is the limited accessibility of drugs to the tumor tissues requiring high doses, their intolerable toxicity, development of multiple drug resistance and their non-specific targeting. Nanoparticles (NPs), an evolution of nanotechnology, have the potential to successfully address these problems related to drug delivery and retention and are considered potential candidates to carry drugs to the desired site of therapeutic action. In this review, we give an overview of the use of clinically applicable NPs mainly for cancer therapy. We also focus on the different types of nanoscale polymer carriers used for the delivery of chemotherapeutic agents and the mechanisms that facilitate their targeted delivery to tumor cells.     

Polymeric nanoparticles for cancer therapy

Cancer is an ever-increasing menace that needs to be curbed soon. Though chemotherapy is successful to some extent, the main drawbacks of chemotherapy is the limited accessibility of drugs to the tumor tissues requiring high doses, their intolerable toxicity, development of multiple drug resistance and their non-specific targeting. Nanoparticles (NPs), an evolution of nanotechnology, have the potential to successfully address these problems related to drug delivery and retention and are considered potential candidates to carry drugs to the desired site of therapeutic action. In this review, we give an overview of the use of clinically applicable NPs mainly for cancer therapy. We also focus on the different types of nanoscale polymer carriers used for the delivery of chemotherapeutic agents and the mechanisms that facilitate their targeted delivery to tumor cells.     

Emerging role of apelin as a therapeutic target in cancer: a patent review

Since tumors cannot grow or spread without forming new blood vessels, inhibiting angiogenesis is an excellent approach for the treatment of cancer. Further, inhibitors of angiogenesis have mild side effects since they act on endothelial cells, which eliminate the possibility of developing resistance or tolerance in tumor cells, unlike that seen with chemotherapy drugs. The anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab acts by preventing new blood vessel formation in solid tumors and is approved by FDA to treat colorectal, lung, breast, glioblastoma and kidney cancers. The registration of this drug and its ongoing success in the clinic has validated the targeting of angiogenesis as an important approach to the treatment of solid tumors. Apelin is a novel angiogenic factor and recent studies indicate that apelin promotes angiogenesis, lymphangiogenesis and tumor growth in vivo and the angiogenic potential of apelin is similar to that of VEGF. Also, apelin expression is upregulated and has been shown to be associated with clinical outcome in certain human cancers. Thus, inhibition of apelin activity might lead to a new class of anti-angiogenesis drugs which should be more efficacious than those currently on the market due to their ability to be both anti-angiogenic as well as anti-lymphangiogenic. There are very few patents on the angiogenic effects of apelin and this review article focuses on these patented claims related to inhibiting apelin signaling and sheds more light on how blocking apelin signaling might open doors to a new class of angiogenic inhibitors.     

肿瘤血管生成抑制剂的研究进展

化学疗法治疗恶性肿瘤常因耐药性使其疗效受到很大限制。抗血管生成治疗的作用靶点为肿瘤内皮细胞,因而很少产生甚至不产生耐药性。文中主要综述目前已开发的几类主要血管生成抑制剂的化学结构、作用机制、抗肿瘤活性及临床应用。     

Clinical relevance of P-glycoprotein in drug therapy

The drug efflux transporter P-glycoprotein (P-gp) is known to confer multidrug resistance in cancer chemotherapy. The P-gp is highly expressed in many types of tumor cells, as well as many normal tissues, including the apical surface of intestinal epithelial cells, and the luminal surface of capillary endothelial cells in the brain. Because of its expression and localization, it has been suggested that P-gp plays an important role in cancer chemotherapy, intestinal absorption, and brain uptake. This review addresses the significance of the role of P-gp in cancer chemotherapy, drug absorption, and brain uptake. Based on the clinical and animal studies with P-gp modulators, it has become apparent that the role of P-gp in multidrug resistance is far less important compared to other biological factors. Although P-gp is highly expressed in both intestinal epithelial cells and endothelial cells of brain capillaries and functions as an efflux transporter in both organs, the magnitude of P-gp's impact on intestinal absorption and brain uptake of drugs is quantitatively very different. From animal and clinical studies, it is evident that P-gp plays a very important role in CNS penetration of drugs, whereas the effect of P-gp on drug absorption is not as important as generally believed.     

Antiangiogenic therapy

Angiogenesis, the formation of blood vessels from preexisting ones, plays a crucial role in tumor progression. Activation of an "angiogenic switch" allows tumor cells to invade and metastasize. The growing interest in the use of antiangiogenic agents in the treatment and prevention of cancer lies in the theoretical advantages of this molecularly targeted modality of chemotherapy. Delivery of antiangiogenic agents are not complicated by having to penetrate large bulky masses but, instead, have easy access to tumoral endothelial cells. Antiangiogenic drugs may not cause cytopenias and thus will avoid many of the unwarranted toxicities of standard chemotherapeutic agents. Because they act directly on nascent endothelial cells, antiangiogenic agents may avoid tumor resistance mechanisms. If antiangiogenic agents are successful, they might be applicable to many tumor types and not be dependent on cell type or growth fraction of cells within a tumor. However, several important obstacles remain with regards to using antiangiogenic drugs in clinical trials with which we must contend in order to determine accurately the efficacy of these agents. In this article, we review the different classes of antiangiogenic agents available, ongoing clinical trials, as well as potential pitfalls and future directions in this exciting field.     

Two-domain vascular disruptive agents in cancer therapy

The two-domain vascular drug constructs are selective anti-cancer agents capable of specific targeting and subsequent elimination of endothelial cells lining tumor blood vessels. The destruction of existing vasculature within tumor tissue causes insufficient oxygenation of adjacent neoplastic cells and their necrotic death. The recognition (cognitive) domain of the vascular disruptive agents is responsible for recognizing markers specific for endothelial cells. This domain can be formed by variable regions of antibodies or by suitable ligands (such as those binding various integrin or growth factor receptors). The effector domain, in turn, can be constructed from proteins participating in blood clotting process, as well as from toxins, cytokines, radioactive isotopes or pro-apoptotic factors. This article outlines issues important for constructing such two-domain vascular disruptive agents and emphasizes the modularity of their assembly. Several pharmacokinetic and pharmacodynamic properties of these novel agents are discussed. Compared to known cytostatic substances exerting anti-angiogenic effects, such vascular disruptive agents can be much more effective as cytotoxic agents, especially in combination with proven anti-cancer drugs.     

Microtubule-targeting agents in angiogenesis: where do we stand?

Angiogenesis is a key event of tumor progression and metastasis and hence a target for cancer chemotherapy. Therapeutic strategies focused on angiogenesis include the discovery of new, targeted anti-angiogenic agents and the re-evaluation of conventional anti-cancer drugs. Here, we review the most recent studies investigating the molecular and cellular mechanisms responsible for the anti-angiogenic activity of microtubule-targeting agents (MTAs). These agents include some of the most widely used and effective antitumor drugs that are also among the most anti-angiogenic. In addition, we summarize the latest results of pre-clinical and clinical studies involving MTAs administered at low metronomic doses and in anti-angiogenic combination strategies. Finally, we discuss the future development of these agents, their clinical potential and their limitations.     

Advances in polymeric micelles for drug delivery and tumor targeting

A plethora of formulation techniques have been reported in the literature for targeting drugs to specific sites. Polymeric micelles (PMs) can be targeted to tumor sites by passive as well as active mechanisms. Some inherent properties of PMs, including size in the nanorange, stability in plasma, longevity in vivo, and pathological characteristics of tumor allow PMs to be targeted to the tumor site by a passive mechanism called the enhanced permeability and retention effect. PMs formed from an amphiphilic block copolymer are suitable for encapsulation of poorly water-soluble, hydrophobic anticancer drugs. Other characteristics of PMs such as separate functionality at the outer shell are useful for targeting the anticancer drug to tumor by active mechanisms. PMs can be conjugated with many ligands such as antibody fragments, epidermal growth factors, α₂-glycoprotein, transferrin, and folate to target micelles to cancer cells. Application of heat or ultrasound are the alternative methods to enhance drug accumulation in tumoral cells. Targeting using micelles can also be directed toward tumor angiogenesis, which is a potentially promising target for anticancer drugs. PMs have been used for the delivery of many anticancer agents in preclinical and clinical studies. This review summarizes recently available information regarding targeting of anticancer drugs to the tumor site using PMs.From the Clinical EditorThis review summarizes recent developments related to targeted anticancer drug delivery to tumor sites using polymeric micelles via active and passive mechanisms. Polymeric micelles can be conjugated with diverse ligands such as antibodies fragments, epidermal growth factors, α2-glycoprotein, transferrin, folate to target micelles to cancer cells.