Immunotoxins and cancer therapy

In the past decade,an increased amount of clinicallyloriented research involving immunotoxins has been published.Immunotoxins are a group of artificially-made cytotoxic molecules targeting cancer cells.These moleculescomposed of a targeting moiety,such as a ligand or an antibody,linked to toxin moiety,which is a toxin with eithertruncated or deleted cell-binding domain that prevents it from binding to normal cells.Immunotoxins can bedivided into two categories:chemically conjugated immunotoxins and recombinant ones.The immunotoxins of thefirst category have shown limited efficacy in clinical trials in patients with hematologic malignancies and solidtumors.Within the last few years,single-chain immunotoxins provide enhanced therapeutic efficacy overconjugated forms and result in improved antitumor activity.In this review,we briefly illustrate the design of theimmunotoxins and their applications in clinical trials.Cellular & Molecular Immunology.2005;2(2):106-112.     

Designing immunotoxins for cancer therapy

Immunotoxins are the rapeutic agents with a high degree of specificity and unique mechanism of action. An immunotoxin is achimeric protein consisting of a targeting moiety linked to a toxin. The targeting moiety selectively binds to a tumor cell and targets it for death via the attached toxin. Generally, immunotoxins are specifically potent against cancer cells in vitro and in animal models of human malignancies. However, immunotoxins can be limited clinically by immunogenicity, toxicity, and instability. In this review, weofferwaysto overcome these limitations to create “ideal immunotoxins” for cancer therapy. These include producing single chain targeting/toxin fusion proteins of fully human origin that are extracellularly stable but once internalized, can be cleaved by intracellular proteases to free the toxin and facilitate its translocation to the cytosol.     

Immunotoxins in cancer therapy.

Immunotoxins are composed of a protein toxin connected to a binding ligand such as an antibody or growth factor. These molecules bind to surface antigens (which internalize) and kill cells by catalytic inhibition of protein synthesis within the cell cytosol. Immunotoxins have recently been tested clinically in hematologic malignancies and solid tumors and have demonstrated potent clinical efficacy in patients with malignant diseases that are refractory to surgery, radiation therapy and chemotherapy - the traditional modalities of cancer treatment. This therapy is thus evolving into a separate modality of cancer treatment, capable of rationally targeting cells on the basis of surface markers. Efforts are underway to obviate impediments to clinical efficacy, including immunogenicity and toxicity to normal tissues. Immunotoxins are now being developed to new antigens for the treatment of cancer.     

结直肠癌靶向治疗的研究进展

结直肠癌是临床上最常见的恶性肿瘤之一。21世纪以来,靶向药物联合传统化学药物治疗中、晚期结直肠癌是临床研究的热点,但仍存在诸多争议。表皮生长因子受体和血管内皮生长因子是目前研究得较多的结直肠癌分子靶点。靶向基因一病毒治疗已显示出令人鼓舞的初步结果;肿瘤干细胞将会是一种很有前景的肿瘤治疗策略。     

肿瘤基因治疗的策略

肿瘤的基因治疗是将目的基因导入靶细胞,使其在体内表达并发挥特定的功能,杀伤或抑制肿瘤细胞从而达到治疗的目的。近年来关于基因治疗肿瘤的研究报道很多,该文就肿瘤的基因治疗策略作一概述。     

Hormone replacement therapy in cancer survivors

Objective: Thousands of women are treated each year for cancer; many of these are already in menopause, while other younger patients will go into early menopause due to surgery, or chemotherapy, or the need for radiotherapy to the pelvic region. In most cases the oncologist and the gynaecologist would advise these women against the use of HRT. The purpose of this paper is to review biological and clinical evidences in favour and against HRT use in the different tumours and to propose an algorithm that can help choosing the treatment for the single woman. Methods: We performed a systematic literature review through April 2002 concerning: (1) biological basis of hormonal modulation of tumour growth; (2) epidemiological data on the impact of HRT on different cancers risk in healthy women; (3) safety of HRT use in cancer survivors; (4) alternatives to HRT. Results: With the exception of meningioma, breast and endometrial cancer, there is no biological evidence that HRT may increase recurrence risk. In women with previous breast and endometrial cancer HRT is potentially hazardous on a biological basis, even if published data do not show any worsening of prognosis. Conclusions: Even if a cautious approach to hormonal-dependent neoplasias is fully comprehensible and the available alternative treatment should be taken into greater consideration, the reticence to prescribe HRT in women previously treated for other non hormone-related tumours has neither a biological nor a clinical basis. An algorithm based on present knowledge is proposed.     

Targeted therapy in gastric cancer

Gastric cancer is often diagnosed at an advanced stage. Although chemotherapy prolongs survival and improves quality of life, the survival of gastric cancer patients with advanced disease is short. Thanks to recent insights into the molecular pathways involved in gastric carcinogenesis, new targeted treatment options have become available for gastric cancer patients. Trastuzumab, an antibody targeted to HER‐2, was shown to improve survival of advanced gastric cancer patients harboring HER‐2 overexpression due to gene amplification in their tumor cells, and is currently also explored in adjuvant and neoadjuvant settings. Another agent with promising results in clinical trials is ramucirumab, an antibody targeting VEGFR‐2. No clear survival benefit, however, were experienced with agents targeting EGFR (cetuximab, panitumumab), VEGF‐A (bevacizumab), or mTOR (everolimus). Drugs targeting c‐MET/HGF are currently under investigation in biomarker‐selected cohorts, with promising results in early clinical trials. This review will summarize the current status of targeted treatment options in gastric cancer.     

胃癌分子分型及免疫靶向治疗

目前曲妥珠单抗、ramucirumab是已经被FDA获批用于晚期胃癌的靶向药物.同时仍正在研究的靶点包括EGFR、PI3K蛋白激酶B/哺乳动物雷帕霉素靶点(mTOR)途径、c-MET以及免疫检查点抑制剂.本综述主要讨论晚期胃癌的分子分型和目前已经用于晚期胃癌的靶向药物,同时讨论临床试验阶段的免疫靶向药物.     

Complement inhibition in cancer therapy

For decades, complement has been recognized as an effector arm of the immune system that contributes to the destruction of tumor cells. In fact, many therapeutic strategies have been proposed that are based on the intensification of complement-mediated responses against tumors. However, recent studies have challenged this paradigm by demonstrating a tumor-promoting role for complement. Cancer cells seem to be able to establish a convenient balance between complement activation and inhibition, taking advantage of complement initiation without suffering its deleterious effects. Complement activation may support chronic inflammation, promote an immunosuppressive microenvironment, induce angiogenesis, and activate cancer-related signaling pathways. In this context, inhibition of complement activation would be a therapeutic option for treating cancer. This concept is relatively new and deserves closer attention. In this article, we summarize the mechanisms of complement activation on cancer cells, the cancer-promoting effect of complement initiation, and the rationale behind the use of complement inhibition as a therapeutic strategy against cancer.     

Targeted therapy for upper gastrointestinal tract cancer: current and future prospects

Gastric and oesophageal carcinoma remain major causes of worldwide mortality and morbidity. Despite incredible progress in understanding tumour biology, few targeted treatment options have proved effective in prolonging survival, and adjuvant therapy is largely interchangeable in these carcinomas. Through large‐scale sequencing by the Cancer Genome Atlas and the Asian Cancer Research Group, numerous potential molecular targets have been discovered. Of the approved targeted therapies for gastric and oesophageal cancer, pathologists play a role in patient selection for the majority of them. Trastuzumab has been approved as a first‐line therapy in conjunction with standard treatment in adenocarcinomas with either 3+ HER2/neu expression by immunohistochemistry or ERBB2 amplification by FISH. PD‐L1 immunohistochemistry showing a combined positive score of 1 or greater qualifies patients for third‐line pembrolizumab therapy, and identification of microsatellite instability‐high carcinomas may qualify patients for second‐line pembrolizumab. Ramucirumab, targeting VEGFR2, has also been approved for second‐line therapy in gastric carcinoma. Non‐surgical therapy for gastrointestinal stromal tumours relies mainly upon tyrosine kinase inhibitors, while new targeted therapy options for neuroendocrine neoplasms have recently emerged. Potential future options for targeted therapy in all these malignancies are being investigated in clinical trials, as this review will discuss.     

Redox-responsive polyanhydride micelles for cancer therapy

Biodegradable polyanhydrides possess unique features like those that they can predominantly undergo surface erosion, and the payloads can be released by a steady speed. However, there is little work that has been published to describe the polyanhydride micelles with redox-responsiveness as a nanocarrier for drug delivery. In this study, we develop one type of new amphiphilic polyanhydride copolymer containing disulfide bonds between the hydrophilic and hydrophobic segments. The copolymer can self-assemble into stable micelles with well-defined core–shell structure and a uniform size distribution with an average diameter of 69 nm. The disassembly behaviors of the micelles triggered by glutathione are evaluated from the changes of the micellar size, morphology and molecular weight. An approximate zero-order in vitro drug release mode with a fast speed can be achieved in a reducing and acid environment similar with that of tumor cells. In vitro cytotoxicity analysis demonstrate that the Cur-loaded micelles are of great efficiency in inhibiting the growth of cancer cells due to the rapidly intracellular delivery of therapeutic agent. Both the qualitative and quantitative results of the antitumor activity in 4T1 tumor-bearing BALB/c mice reveal that the redox-responsive micelles have a more significant therapeutic effect to artificial solid tumor compared to the redox-insensitive micelles. This study provides a new insight into the biomedical application of polyanhydrides in drug delivery.     

Strategies for cancer gene therapy using adenoviral vectors

Modification of tumor cells using gene transfer either to enhance host immunity or to act directly on tumor cells is being intensively studied in animal models. Remarkable results have yielded to approved clinical protocols in the treatment of cancer patients using this approach. Several methods of gene delivery have been developed. This article is particularly devoted to the interest of the use of adenoviral vectors in the different strategies of cancer gene therapy.Abbreviations CSF Colony-stimulating factor - IL Interleukin - pfu plaque forming units     

哺乳动物雷帕霉素靶蛋白抑制剂联合其它抗肿瘤药物治疗肿瘤的研究进展

哺乳动物雷帕霉素靶蛋白（mTOR）是P13K／Akt／mTOR信号通路下游的重要效应蛋白,其底物主要控制与细胞生长和增殖密切相关的蛋白质的合成。mTOR在多种恶性肿瘤中表达异常,是肿瘤靶向治疗的新靶点。临床前研究和Ⅰ、Ⅱ期临床实验表明,以雷帕霉素及其衍生物为代表的mTOR抑制剂和其它传统抗肿瘤药物的联合应用取得了良好的的抗肿瘤效果,为肿瘤的靶向治疗提供了新的方向。     

用于肿瘤联合治疗的基因和化疗药物纳米共载体系的研究进展

化学药物治疗（化疗）或基因治疗单独使用治疗肿瘤均具有较多缺陷,而将两者联合应用能协同治疗肿瘤,克服单一疗法的不足.纳米载体既能包载化疗药物又能递送基因,其用于肿瘤的联合治疗,可减少化疗药物的剂量,增加药物在靶器官的分布量,减轻毒副作用,从而提高抗肿瘤效果;同时保护携带基因的稳定性和完整性,一定程度上提高基因的转染效率,以达到减轻毒副作用及提高疗效的协同目的.基因和化疗药物纳米共载体系用于肿瘤的联合治疗是近年来肿瘤治疗的研究热点.就基因和化疗药物纳米共载体系的类型及负载基因类型,特别是纳米共载体系用于肿瘤联合治疗的研究进行总结和展望.     

Targeting cancer stem cells by melatonin: Effective therapy for cancer treatment

Melatonin is a physiological hormone produced by the pineal gland. In recent decades, enormous investigations showed that melatonin can prompt apoptosis in cancer cells and inhibit tumor metastasis and angiogenesis in variety of malignancies such as ovarian, melanoma, colon, and breast cancer; therefore, its possible therapeutic usage in cancer treatment was confirmed. CSCs, which has received much attention from researchers in past decades, are major challenges in the treatment of cancer. Because CSCs are resistant to chemotherapeutic drugs and cause recurrence of cancer and also have the ability to be regenerated; they can cause serious problems in the treatment of various cancers. For these reasons, the researchers are trying to find a solution to destroy these cells within the tumor mass. In recent years, the effect of melatonin on CSCs has been investigated in some cancers. Given the importance of CSCs in the process of cancer treatment, this article reviewed the studies conducted on the effect of melatonin on CSCs as a solution to the problems caused by CSCs in the treatment of various cancers.     

Targeted therapy in prostate cancer

The therapeutic approach to advanced prostate cancer has seen greater changes in the last 7 years than it did in the preceding 70. Although only one of the newly approved agents that improve overall survival is a targeted agent, it is a validation of the method of pathway analysis and drug design in delivering novel, clinically usable agents. As our knowledge of the molecular circuitry of tumour invasion, metastases and treatment resistance has become more refined, the number of new, potentially useful, targets has grown exponentially. This is reflected in the vast array of diverse targeted agents that are currently being evaluated in human trials. In this review, we briefly describe some of the key pathways that are involved in the evolution of the prostate cancer 'lethal phenotype', and review the clinical activity of some of the newly approved targeted therapies or those in advanced phases of clinical development.     

膀胱癌干细胞标志物及相关信号通路:抗体靶向治疗思路

背景:膀胱癌是泌尿系统中最常见的恶性肿瘤之一,严重威胁患者的生命健康.膀胱癌干细胞的不断深入研究为膀胱癌治愈提供了新的治疗方向,近年来对膀胱癌干细胞重要标志物和信号通路的研究为膀胱癌靶向治疗提供了有力依据.目的:综述近年来国内外对膀胱癌干细胞主要标志物和信号通路的研究进展.方法:计算机检索中国期刊全文数据库(CNKI)...     

Targeted therapy in melanoma: the era of personalized medicine

Malignant melanoma is the most aggressive of all cutaneous tumours, with over 76, 000 new cases and 9700 deaths estimated for 2014 in the United States.¹ In Canada, both the incidence and mortality of melanoma are increasing, with a risk of developing melanoma being 1 in 59 for men and 1 in 73 for women.² The incidence of melanoma is higher in Australia, with a risk of 1 in 14 for males and 1 in 23 for females to age 85 reported for 2009.³ Although early melanoma can be managed surgically, until recently there have been few advances in the treatment of advanced melanoma. However, with the introduction of molecular targeted therapies, the landscape of melanoma treatment has changed dramatically in the past five years, resulting in improved survival rates for patients with metastatic disease. In this review, we will discuss the molecular basis and implementation for some of these novel treatments with particular emphasis on BRAF and BRAF inhibitors.     

基于纳米材料与纳米技术的肿瘤靶向治疗

结合多学科的力量、特别是借助新技术的发展对肿瘤进行有效治疗,是目前肿瘤治疗研究方面的一个重要趋势。本文在肿瘤靶向治疗的定义和对主要几类方法说明的基础上,重点介绍和分析纳米材料和纳米技术的被动靶向、场致靶向和分子靶向等方面的最新研究进展,并讨论存在的一些问题和今后可能的努力方向。     

Co-delivery of all-trans-retinoic acid and doxorubicin for cancer therapy with synergistic inhibition of cancer stem cells

Combination treatment through simultaneous delivery of two or more drugs with nanoparticles has been demonstrated to be an elegant and efficient approach for cancer therapy. Herein, we employ a combination therapy for eliminating both the bulk tumor cells and the rare cancer stem cells (CSCs) that have a high self-renewal capacity and play a critical role in cancer treatment failure. All-trans-retinoic acid (ATRA), a powerful differentiation agent of cancer stem cells and the clinically widely used chemotherapy agent doxorubicin (DOX) are simultaneously encapsulated in the same nanoparticle by a single emulsion method. It is demonstrated that ATRA and DOX simultaneous delivery-based therapy can efficiently deliver the drugs to both non-CSCs and CSCs to differentiate and kill the cancer cells. Differentiation of CSCs into non-CSCs can reduce their self-renewal capacity and increase their sensitivity to chemotherapy; with the combined therapy, a significantly improved anti-cancer effect is demonstrated. Administration of this combinational drug delivery system can markedly augment the enrichment of drugs both in tumor tissues and cancer stem cells, prodigiously enhancing the suppression of tumor growth while reduce the incidence of CSC in a synergistic manner.