Biology of Cox-2: an application in cancer therapeutics

Cyclooxygenase-2 (Cox-2) is an inducible enzyme involved in the conversion of arachidonic acid to prostaglandin and other eicosanoids. Molecular pathology studies have revealed that Cox-2 is over-expressed in cancer and stroma cells during tumor progression, and anti-cancer chemo-radiotherapies induce expression of Cox-2 in cancer cells. Elevated tumor Cox-2 is associated with increased angiogenesis, tumor invasion and promotion of tumor cell resistance to apoptosis. Several experimental and clinical studies have established potent anti-cancer activity of NSAID (Non-steroidal anti-inflammatory drugs) and other Cox-2 inhibitors such as celecoxib. Much attention is being focused on Cox-2 inhibitors as beneficial target for cancer chemotherapy. The mode of action of Cox-2 and its inhibitors remains unclear. Further clinical application needs to be investigated for comprehending Cox-2 biological functions and establishing it as an effective target in cancer therapy.     

Protein kinases as targets for cancer treatment

In various types of malignancies, conventional forms of therapy (surgery, radiation and chemotherapy) are often ineffective, as well as harmful. In the last few years, a convergence of scientific advances has enabled the identification of molecular targets and signaling pathways specific to cancer cells, resulting in therapies with enhanced selectivity and efficacy and reduced toxicity. Compound validation has relied on target validation first, although some of the most successful drugs often have effects outside of their postulated mechanism. Protein kinases represent such molecular targets; considerable research effort has been devoted to the development of targeted drugs that inhibit the action of pathogenic kinases, and clinical studies performed so far have validated the positive effects of kinase inhibitors for cancer treatment. In this review, the specificity, mechanism of action and antitumor activity of several new small-molecule inhibitors of tyrosine and serine/threonine kinases are discussed.     

Novel chemotherapeutic agents for the treatment of brain cancer

Brain cancer encompasses both primary and metastatic brain tumours and accounts for over 120,000 new patients each year. Despite aggressive therapy, the majority of patients with brain cancer have poor prognosis and have brief survival intervals. Current chemotherapy drugs, used alone or in combination, have minimal or only modest activity. Novel agents that have recently been applied to brain cancer include temozolomide, irinotecan and paclitaxel. Temozolomide is a DNA alkylating agent, irinotecan inhibits DNA topoisomerase I and paclitaxel binds to microtubules and induces polymerisation. Neoplastic angiogenesis and brain tumour invasion are also targets for therapeutic intervention with new agents such as thalidomide, suramin and marimastat. All of these agents have demonstrated activity against brain cancer in vitro. Several of the drugs, in particular temozolomide, paclitaxel and irinotecan, have entered preliminary clinical trials and have demonstrated some efficacy. However, chemotherapy for primary brain tumours remains rather non-specific and mostly ineffective. The use of chemotherapy may be more effective against selected metastatic brain tumours. Continued basic research is needed to further elucidate the genetic basis of transformation, tumour invasion and angiogenesis. It is hoped that this research will lead to new therapeutic targets for drug design and development. In addition, new strategies must be developed to overcome the problem of chemotherapy resistance.     

基于HDAC的双靶点抗肿瘤药物研究进展

多靶点作用的抗肿瘤药物比目前单靶点药物具有更好的药效,且能够降低耐药性和毒副作用。为了探索多靶点药物在肿瘤化疗中的应用前景,以组蛋白去乙酰化酶(HDAC)抑制剂为基础设计多种作用的双靶点抑制剂已经成为了研究热点,其中部分化合物抑制肿瘤细胞增殖活性比现有的上市药物更好。本文综述了基于HDAC的双靶点抑制剂的研究进展,重点介绍了作用机制、设计策略和生物活性。     

Novel chemotherapeutic agents for the treatment of brain cancer

Brain cancer encompasses both primary and metastatic brain tumours and accounts for over 120,000 new patients each year. Despite aggressive therapy, the majority of patients with brain cancer have poor prognosis and have brief survival intervals. Current chemotherapy drugs, used alone or in combination, have minimal or only modest activity. Novel agents that have recently been applied to brain cancer include temozolomide, irinotecan and paclitaxel. Temozolomide is a DNA alkylating agent, irinotecan inhibits DNA topoisomerase I and paclitaxel binds to microtubules and induces polymerisation. Neoplastic angiogenesis and brain tumour invasion are also targets for therapeutic intervention with new agents such as thalidomide, suramin and marimastat. All of these agents have demonstrated activity against brain cancer in vitro. Several of the drugs, in particular temozolomide, paclitaxel and irinotecan, have entered preliminary clinical trials and have demonstrated some efficacy. However, chemotherapy for primary brain tumours remains rather non-specific and mostly ineffective. The use of chemotherapy may be more effective against selected metastatic brain tumours. Continued basic research is needed to further elucidate the genetic basis of transformation, tumour invasion and angiogenesis. It is hoped that this research will lead to new therapeutic targets for drug design and development. In addition, new strategies must be developed to overcome the problem of chemotherapy resistance.     

Antimitotic drugs in cancer chemotherapy: Promises and pitfalls

Cancer cells usually display higher proliferation rates than normal cells. Some currently used antitumor drugs, such as vinca alkaloids and taxanes, act by targeting microtubules and inhibiting mitosis. In the last years, different mitotic regulators have been proposed as drug target candidates for antitumor therapies. In particular, inhibitors of Cdks, Chks, Aurora kinase and Polo-like kinase have been synthesized and evaluated in vitro and in animal models and some of them have reached clinical trials. However, to date, none of these inhibitors has been still approved for use in chemotherapy regimes. We will discuss here the most recent preclinical information on those new antimitotic drugs, as well as the possible molecular bases underlying their lack of clinical efficiency. Also, advances in the identification of other mitosis-related targets will be also summarized.     

Molecular targets of ovarian carcinomas with acquired resistance to platinum/taxane chemotherapy

Ovarian cancer of epithelial origin remains one of the most lethal malignancies despite response rates of more than 80% in first-line combination chemotherapy with platinum drugs and taxanes following surgery. Poor overall prognosis is mainly due to acquired resistance of the recurring tumor mass to initially used and other chemotherapeutic agents. Therefore, novel therapeutic approaches are based on concepts to prevent (improvement of tumor exposure to drugs) or circumvent drug resistance, e.g. with new drugs structurally related to the currently used cytotoxic agents, other types of cytotoxic substances, or with target-specific novel drugs interfering with signaling and apoptotic pathways. In addition, acquired molecular characteristics of drug resistant ovarian carcinoma cells can be defined by expression profiling at different stages of therapy and might be used as specific targets for tumor-suppressing drugs and prodrugs containing cytotoxic components. Revelation of mechanistic details of drug resistance also provides the basis for the development of therapies with novel or conventional antitumor drugs in combination with specific inhibitors able to re-establish chemosensitivity. In this review, we summarize novel approaches in the treatment of ovarian cancer progressed to drug resistant stages and focus on the discussion of recently reported experimental and early clinical results with potentially useful strategies to overcome or modulate acquired drug resistance.     

AIT-082, a novel purine derivative with neuroregenerative properties

Introduction: The interaction between the VEGFRs and their ligands plays an important role in tumor angiogenesis. Despite a series of problems encountered during early work on blocking growth factors, current evidence injects further vigor into researching the modulation of VEGFR activity. Emerging preclinical and clinical studies suggest that attenuating receptor activity can synergistically promote antitumor action if utilized concurrently with conventional therapies.

Areas covered: This review presents an up-to-date assessment of the potential role of modulating receptor activities in various cancers. The sentinel work on the proof of principles in various animal models, and the current translational research on these small molecule inhibitors and receptor blocking antibodies, from Phase I to Phase III trials, has been systematically examined with an emphasis on agents in earlier stages of development.

Expert opinion: Many clinical trials are ongoing, but early phase trials show promising results. Recently, there has been a huge explosion of research activity either in the development of new drugs or in the understanding its biology. Many current trials lend support to the rationale behind these therapies, which can function as adjuvants to conventional treatments. It has been argued that normalization of tumor-induced vasculature can promote better drug delivery and prevent resistance to radiotherapy. However, strategies involving the inhibition of the interaction of VEGFRs with ligands and their downstream pathways are not, in general, at a stage where it will be directly useful in clinical cancer treatment. A deeper understanding of these biologic therapies will help to improve the efficacy of conventional treatments and furthermore reduce dose-dependent cytotoxic activity.     

Optimizing drug delivery for enhancing therapeutic efficacy of recombinant human endostatin in cancer treatment

Recombinant human endostatin (rhEndostatin) is uniquely able to target neovascular endothelial cells (ECs) and has the potential for antiangiogenetic and antitumor activities. In this review, we explore experimental approaches and clinical trials focusing on drug delivery of endostatin. Continued endostatin therapy can maintain tumors in a state of dormancy, and no signs of drug-induced resistance have been observed. Prolonged delivery of endostatin may be achieved by using pumps (mini-osmotic pumps) or cell encapsulation systems. The largest benefit from rhEndostatin is expected when drug delivery of rhEndostatin is begun as early as possible. Although endostatin has shown promise in controlling tumor neovasculature, a major problem in pharmacotherapy is the side effects of constant drug administration and the limited half-life of antiangiogenic proteins. Gene therapy offers the advantages of maximizing cost effectiveness and maintaining sustained levels of antiangiogenic factors, which may enhance antitumor efficacy. Therefore, we have investigated recent advances in gene delivery of endostatin for cancer treatment. In recent years, preclinical and clinical data have demonstrated the synergistic effects of rhEndostatin combined with other therapies on inhibiting growth of malignant tumors, with minimal toxicity. rhEndostatin has not been proven to prolong the survival rate of patients challenged with cancer when used as single therapy. Thus, we suggest that the combination of rhEndostatin with chemotherapy, radiotherapy, and biotherapy (i.e., fusion protein, molecular-targeted therapy on cancers, etc.) might provide an optimal strategy for cancer treatment.     

Evading tumor evasion: Current concepts and perspectives of anti-angiogenic cancer therapy

Within three decades, anti-angiogenic therapy has rapidly evolved into an integral component of current standard anti-cancer treatment. Anti-angiogenic therapy has fulfilled a number of its earlier proposed promises. The universality of this approach is demonstrated by the broad spectrum of malignant and benign tumor entities, as well as non-neoplastic diseases, that are currently treated with anti-angiogenic agents. In contrast to tumor cell targeting therapies, the development of acquired drug resistance (e.g., via mutations in growth factor receptor signaling genes) has not been described yet for the principal target of anti-angiogenic therapy—the tumor endothelium. Moreover, the tumor endothelium has emerged as a critical target of conventional cancer therapies, such as chemotherapy and radiotherapy. The presumption that tumor growth and metastasis are angiogenesis-dependent implies that the number of potential targets of an anti-cancer therapy could be reduced to those that stimulate the angiogenesis process. Therefore, the set of endogenous angiogenesis stimulants might constitute an “Achilles heel” of cancer. Direct targeting of tumor endothelium via, e.g., endogenous angiogenesis inhibitors poses another promising but clinically less explored therapeutic strategy. Indeed, the majority of current anti-angiogenic approaches block the activity of a single or at most a few pro-angiogenic proteins secreted by tumor cells or the tumor stroma. Based on our systems biology work on the angiogenic switch, we predicted that the redundancy of angiogenic signals might limit the efficacy of anti-angiogenic monotherapies. In support of this hypothesis, emerging experimental evidence suggests that tumors may become refractory or even evade the inhibition of a single pro-angiogenic pathway via compensatory upregulation of alternative angiogenic factors. Here, we discuss current concepts and propose novel strategies to overcome tumor evasion of anti-angiogenic therapy. We believe that early detection of tumors, prediction of tumor evasive mechanisms and rational design of anti-angiogenic combinations will direct anti-angiogenic therapy towards its ultimate goal—the conversion of cancer to a dormant, chronic, manageable disease.     

Angiogenesis inhibitors. Drug selectivity and target specificity

The critical role of angiogenesis in tumor development and progression has long been appreciated. The elucidation of the mechanisms of tumor angiogenesis and the emergence of anticancer drugs targeting the tumor vasculature has been a breakthrough in the treatment of several tumors in the last few years. Several novel molecules are being developed that target different aspects of angiogenesis. This review outlines the principle of anti-angiogenic therapies, illustrates the main mechanisms and complexity of growth signals involved in tumor angiogenesis, its interactions with hypoxia, stroma and tumor microenvironment. It provides a comprehensive review of clinical results obtained with anti-angiogenic agents (VEGF/VEGFR signaling inhibitors, direct angiogenesis inhibitors, vascular disrupting agents) and finally discusses the differences of the several approaches and their limitations due to the emergence of resistance.     

塞来昔布抗肿瘤效应及其作用机制的研究进展

塞来昔布是一种特异性环氧化酶-2抑制剂,具有抗炎、镇痛和退热作用。近年来,塞来昔布的抗肿瘤作用受到广泛关注,已被应用于消化道肿瘤、乳腺癌、肺癌、肝癌、前列腺癌等的化学辅助治疗和放射治疗增敏。综述了塞来昔布的抗肿瘤效应,并总结了其作用机制,如抑制肿瘤细胞增殖、抑制肿瘤细胞侵袭和转移、抑制肿瘤新生血管生成、诱导肿瘤细胞分化、诱导肿瘤细胞凋亡、调节肿瘤免疫、逆转肿瘤细胞的多药耐药性,以期为塞来昔布的深入研究和临床肿瘤防治提供用药参考。     

Blocking the interaction of vascular endothelial growth factor receptors with their ligands and their effector signaling as a novel therapeutic target for cancer: time for a new look?

INTRODUCTION: The interaction between the VEGFRs and their ligands plays an important role in tumor angiogenesis. Despite a series of problems encountered during early work on blocking growth factors, current evidence injects further vigor into researching the modulation of VEGFR activity. Emerging preclinical and clinical studies suggest that attenuating receptor activity can synergistically promote antitumor action if utilized concurrently with conventional therapies. AREAS COVERED: This review presents an up-to-date assessment of the potential role of modulating receptor activities in various cancers. The sentinel work on the proof of principles in various animal models, and the current translational research on these small molecule inhibitors and receptor blocking antibodies, from Phase I to Phase III trials, has been systematically examined with an emphasis on agents in earlier stages of development. EXPERT OPINION: Many clinical trials are ongoing, but early phase trials show promising results. Recently, there has been a huge explosion of research activity either in the development of new drugs or in the understanding its biology. Many current trials lend support to the rationale behind these therapies, which can function as adjuvants to conventional treatments. It has been argued that normalization of tumor-induced vasculature can promote better drug delivery and prevent resistance to radiotherapy. However, strategies involving the inhibition of the interaction of VEGFRs with ligands and their downstream pathways are not, in general, at a stage where it will be directly useful in clinical cancer treatment. A deeper understanding of these biologic therapies will help to improve the efficacy of conventional treatments and furthermore reduce dose-dependent cytotoxic activity.     

Targeting angiogenesis for the treatment of prostate cancer

INTRODUCTION: While multiple therapies exist that prolong the lives of men with advanced prostate cancer, none are curative. This had led to a search to uncover novel targets for prostate cancer therapy, distinct from those of traditional hormonal approaches, chemotherapies, immunotherapies and bone-targeting approaches. The process of tumor angiogenesis is one target that is being exploited for therapeutic gain. AREAS COVERED: The most promising anti-angiogenic approaches for treatment of prostate cancer, focusing on clinical development of selected agents. These include VEGF-directed therapies, tyrosine kinase inhibitors, tumor-vascular disrupting agents, immunomodulatory drugs and miscellaneous anti-angiogenic agents. While none of these drugs have yet entered the market for the treatment of prostate cancer, several are now being tested in Phase III registrational trials. EXPERT OPINION: The development of anti-angiogenic agents for prostate cancer has met with several challenges. This includes discordance between traditional prostate-specific antigen responses and clinical responses, which have clouded clinical trial design and interpretation, potential inadequate exposure to anti-angiogenic therapies with premature discontinuation of study drugs and the development of resistance to anti-angiogenic monotherapies. These barriers will hopefully be overcome with the advent of more potent agents, the use of dual angiogenesis inhibition and the design of more informative clinical trials.     

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.     

细胞毒药物与肿瘤血管生成

细胞毒药物在传统抗肿瘤化疗中运用较多,然而由于高剂量的使用难免会引起毒副作用和耐药性。为了使细胞毒药物能安全有效地治疗肿瘤,近年来,人们研究了合理运用细胞毒药物的方法,使其作用从直接杀死肿瘤细胞转变为毒对肿瘤血管生成。本文就近十年来在该方面的研究作一综述。     

Drug resistance and apoptosis in cancer treatment: development of new apoptosis-inducing agents active in drug resistant malignancies

Modulation of multidrug resistance (MDR) has been extensively studied in vitro and in vivo. However, several clinical trials have failed to show any important benefits in terms of response to chemotherapy or the length of survival using MDR reversing agents. This may be due to the expression or co-expression of other drug resistance mechanisms in malignant cells. Several studies have shown that most, if not all, chemotherapeutic agents exert their anticancer activity by inducing apoptosis; therefore, resistance to apoptosis may be a major factor limiting the effectiveness of anticancer therapy. In the last few years, effort has been made to understand the biochemical alterations of apoptotic pathways in cancer. Many of these alterations confer a multidrug resistant phenotype to malignant cells. In this context, the new recently developed anticancer therapies based on drugs that modulate apoptosis may have importance for the treatment of tumors that are scarcely responsive to the conventional anticancer chemotherapy. In this review, we discuss the current knowledge about drug resistance, apoptosis and cancer and report the recently developed apoptosis modulating strategies that have potential therapeutic implications for the drug resistant tumors.     

Possibilities of poly(D,L-lactide-co-glycolide) in the formulation of nanomedicines against cancer

Due to a very poor specificity, many chemotherapy agents generate a low antitumor effect and important severe side effects. Poly(D,L-lactide-co-glycolide) (PLGA)-based nanomedicines are under investigation to assure a very efficient anticancer activity in chemotherapy. In this work, we analyze the major applications of this FDA-approved biodegradable polymer in the formulation of nanomedicines against cancer. Despite conventional PLGA colloids could be only used to target tumors located into the mononuclear phagocyte system (MPS), special strategies are under intensive research to enhance the accumulation of anticancer drugs into any given tumor site. These are passive targeting (through the enhanced permeability and retention effect, so-called EPR effect), drug delivery through stimuli-sensitive colloids, and ligand-mediated targeting. We further discuss unique approaches of PLGA colloids in oral chemotherapy, drug delivery to brain tumors, and multi-drug resistance of cancer cells.     

Possible effects of early treatments of hsp90 inhibitors on preventing the evolution of drug resistance to other anti-cancer drugs

Hsp90 is a chaperone that is critically important for both cancer progression and tumor survival. Hsp90 is an exciting target for anti-cancer drugs because most of the proteins that interact with Hsp90 are known to be in the cell cycle, signaling and chromatin-remodeling pathways. Recent work in fungi has shown that reduction of Hsp90 activity dramatically increases the efficacy of many fungicides. Furthermore, in studies on the evolution of drug resistance in fungi, it has been shown that high levels of Hsp90 increase the rate of the development of fungicide resistance, whereby low levels of Hsp90 decrease the rate of fungicide resistance. Similarly, in humans and mammalian models, Hsp90 inhibitors have been shown to act additively or synergistically with many other cancer therapies for killing both solid tumors and leukemias. Also, several recent studies have shown that Hsp90 inhibitors potentiate the activity of drugs in cancer cells lines that are otherwise resistant to the drug. However, during the evolution of drug resistance in cancer cells, it has not yet been determined whether early exposure to Hsp90 inhibitors slows the rate of developing resistance to other anti-cancer drugs, as would be expected from the fungal studies. In this review, we summarize the effects of the Hsp90 inhibitors geldanamycin and its derivatives with other anti-cancer drugs on killing cancer cells. We also discuss other basic science and clinical studies that need to be done to determine the optimum exposure regimens for Hsp90 inhibitor treatments to maximize its cancer-killing activities, and to minimize the evolution of resistance to other anti-cancer drugs.