结直肠癌的单克隆抗体治疗

单克隆抗体（单抗）自1975年产生之日即被认为会引起实验和临床免疫学的革命。这些分子因能靶向有病细胞、特别是恶性细胞被冠以“魔弹”而抗癌。单抗在体外通过抗体依赖细胞介导细胞毒性（ADCC）来杀伤细胞。因而单抗的体内施用会利用危主免疫防御系统引起肿瘤细胞死亡。肿瘤相关抗原（TAA）使肿瘤细胞能被单抗选择性识别。17－1A是其中最突出TAA之一，它高度表达与上皮来源的肿瘤如结直肠和大多数其他胃肠道恶性肿瘤。针对此抗原的鼠单抗m互了1A已被广泛用作结直肠癌等患者的临床治疗尝试。恶性肿瘤隐性转移病灶及残留恶性细胞的存在…     

靶向治疗药物临床应用进展

1 概念 肿瘤的靶向治疗是提高肿瘤治疗效果的一条重要途径.靶向治疗是指某种药物在肿瘤部位有相对较高的浓度,能存留较长时间,对肿瘤靶细胞有较强的杀伤活性.靶向治疗药物应具备的条件:体内分布的特异性、靶细胞作用的特异性.单克隆抗体对相应的抗原具有高度特异性,所以单抗是目前靶向药物的发展方向[1].单抗药物研究与开发是生物技术药物(biotechnology medicines)领域的新热点,自1997年以来得到很大发展,Rituxan、Herceptin、Gefitinib、Cetuximab、Bevacizumab和Mylotarg等在美国相继批准应用于临床.     

单抗药物的肿瘤靶向治疗

肿瘤靶向治疗的基本要求是药物在肿瘤部位有相对较高的浓度,能存留较长时间,对肿瘤靶细胞有较强的杀伤活性.靶向治疗药物须兼有体内分布的特异性与对靶细胞作用的特异性.由于单克隆抗体（单抗）对相应的抗原具有高度特异性,可以针对特定的分子靶点,制备与之特异性结合的单抗.[第一段]     

肝癌TACE抵抗的预测及后续治疗研究进展

肝动脉化疗栓塞(TACE)是中期肝细胞癌(HCC)的标准治疗方案，部分患者无法在重复的TACE疗程中获益，这种状况被称为“TACE抵抗”。TACE抵抗发生的原因尚未完全阐明，TACE治疗后肿瘤缺氧环境诱导的TP53突变是其可能的机制。基于肿瘤影像学特征、肿瘤标志物、放射组学特征和基因组数据的多个预测模型被提出，旨在早期识别TACE抵抗状态。此外，血清微小RNA、蛋白质和炎症因子也是TACE抵抗潜在的预测标志物。以索拉非尼为代表的靶向治疗是TACE抵抗后首选的替代方案，靶向治疗联合免疫检查点抑制剂可以进一步改善预后；肝癌局部治疗，包括DEB-TACE、B-TACE、SBRT、TARE、¹²⁵I粒子放射治疗及HAIC也被证明在部分TACE抵抗患者中有效。本文就TACE抵抗预测模型和发生TACE抵抗的后续治疗研究进展作一综述。     

联合CPPs靶向治疗恶性肿瘤的研究进展

在恶性肿瘤的治疗过程中,人们逐渐认识到高效抗癌药物和穿膜功能的重要性.尤其是对于细胞内发挥作用的抗癌药物来说,载体的靶向和穿膜功能缺一不可.生物技术的发展使人们意识到生物大分子物质在疾病治疗中的重要作用.人们发现一种小于30个氨基酸的短肽,能够将与之相连的生物分子在体内或体外的环境下内化入细胞,称为细胞穿透肽（cell-penetrating peptides,CPPs）.CPPs和靶向的联合将为肿瘤治疗开创一个新的途径.＂靶向结合,细胞内化疗＂能够减少药物对于正常组织和细胞的毒性作用,发挥穿膜肽的高效穿透细胞膜及强大的载运功能优势,联合CPPs靶向治疗恶性肿瘤,将起到事半功倍的治疗效果.     

胃癌分子靶向治疗进展

肿瘤分子靶向治疗是指在分子生物学的基础上,以肿瘤组织或肿瘤细胞所具有的特异性（或相对特异性）的结构分子为作用靶点,使用某些能与上述靶分子发生特异性结合的药物抑制肿瘤进展转移,达到直接治疗或导向治疗目的的一类肿瘤治疗策略。目前的这些药物多为单克隆抗体或受体酪氨酸激酶的小分子抑制物。分子靶向治疗的发展也使肿瘤治疗从基于群体数据的＂循证外科（evidence-based medicine）＂阶段,逐步发展到根据肿瘤发病分子机制的个体化治疗阶段。     

分子靶向治疗药物的研究进展

随着分子生物学研究的进展,分子靶向治疗已成为除手术、放疗、化疗之外的治疗恶性肿瘤方法中的第四种模式。与传统化疗药物相比,分子靶向治疗药物具有特异性强、疗效明显、正常组织损伤少等优点。按照分子靶向药物的作用靶点以及药物的性质归为几类,主要包括以EGFR为靶点的药物、作用于HER2/cerbB2的单克隆抗体、靶向VEGF/VEGFR的药物、以白细胞CD分子为靶点的单抗以及作用于多个靶点的药物。笔者将上述药物的研究进展作一简要综述。     

肿瘤血管靶向脂质体的研究现状

肿瘤血管生成是支撑肿瘤生长和进展的重要因素,它不仅提供肿瘤生长所需要的营养成分、氧、生长因子及其他一些物质,还为肿瘤细胞的转移提供途径。利用主动靶向技术将药物输送到实体瘤的体内实验研究证明了与传统的单纯使用抗肿瘤药物相比,主动肿瘤靶向的药物输送方式可以大大提高药物疗效且降低药物的不良反应。     

肝癌的标志物

肿瘤标志物(Tumor marker)是指在癌变过程中由肿瘤细胞或宿主所产生的对该肿瘤有一定特异性的物质。由于对一定的肿瘤具有特异性,可以识别肿瘤。临床上用作肿瘤的诊断和有可能以其抗体作为载体对肿瘤进行“导向治疗”。肝癌的标志物在各种肿瘤标志物中被研究得最多,其中最具临床应用价值的首推甲胎蛋白(AFP)。AFP是一种癌胚蛋白,胚胎时期由胚胎肝、卵黄囊细胞等产生,出生后消失。当肝细胞癌变时再现。七十年代初由Abelev氏等推荐临床应用。我国经大量临床实践证实AFP对肝癌的诊断有很高的价值,并用以进行普查证实了AFP对肝癌早期诊断的     

外泌体在肾癌诊疗中的研究进展

肾癌起病隐匿,早期诊断困难,转移风险高。转移性肾癌对放、化疗不敏感,分子靶向药物治疗易发生耐药,临床上缺乏有效治疗手段。外泌体是由细胞分泌,广泛存在于体液中的细胞外囊泡,具有细胞来源特异性,在肿瘤发生、侵袭、转移、诱导耐药和肿瘤免疫逃逸等过程中有着重要作用。本文概述了外泌体的主要生物学特性,并分析了其作为肾癌诊断及预后评估的生物标志物以及治疗靶点的潜能。     

Magnetic carrier method- an expectation for antitumoral therapy

In order to enhance antineoplastic agents efficiency new therapy methods were developed one of which being magnetic targeted chemotherapy (MTC). MTC method consists in a permanent or reversible selective binding of highly magnetic particles (carriers) with drugs, antibodies et. al., followed by targeting or adhesion of these complexes to the tumor using an external magnetic field. At this early stage of targeting tumors with magnetic particles, there are reasons to be optimistic.     

Zukunft der Chemotherapie

The future development of chemotherapy is derived based upon recent advances. With regard to adjuvant therapy a trend towards standardized prediction of recurrence risk using all available prognostic markers (e.g., nomograms) is observed. Furthermore, in some tumors major progress has been made regarding the development of "molecular classifiers" defining tumor biology (predicting clinical outcome) by analysis of molecular changes.In adjuvant therapy considerable advances may be achieved by use of new chemotherapeutic agents as well as sequential, dose-dense and dose-intensified regimens. However, in metastatic disease no breakthrough can be expected at least with regard to survival suggesting that quality of life needs to be addressed with more emphasis.Using targeted drugs alone or in combination with chemotherapy advances concerning adjuvant therapy as well as metastatic disease are observed. Further targeted drugs have entered clinical development. However, clarification of the relation between detection of the target(s) and drug activity will fundamentally change current treatment concepts.     

Changes in Therapy for Solid Tumors: Potential for Overcoming Drug Resistance In Vivo with Molecular Targeting Agents

Recent advances in molecular biology have led to the development of selective molecular targeting agents for genes involved in cell proliferation, apoptosis, and angiogenesis in cancer cells. The current success of molecular targeting therapy is shown by: imatinib mesylate (STI571, Gleevec), targeted to the Bcr/Abl fusion protein derived from a translocation between chromosomes 9 and 22 in chronic myelogenous leukemia; rituximab (Rituxan), a monoclonal antibody to CD20 used in non-Hodgkins lymphoma; trastuzumab (Herceptin), a chimeric monoclonal antibody to HER-2 used in breast cancer; and gefinitib (ZD1839, Irresa), a tyrosine kinase inhibitor of the epidermal growth factor receptor used in non-small cell lung cancer. The superior therapeutic efficacy of these molecular targeting agents over traditional chemotherapy has been shown by the survival benefit achieved for patients with advanced or recurrent cancers. Although the precise molecular mechanisms by which these agents produce or enhance an antitumor effect, alone or in combination with anticancer drugs, are not known, the specific inhibition of target genes critically involved in tumor progression and metastasis by the agent is clear. However, further studies to determine which patient groups and anticancer drugs are appropriate for combination therapy with these molecular targeting agents are needed. Herein, we discuss the current status and potential for overcoming drug resistance in solid tumors and focus on the differential features of the tumor microenvironment in solid and hematologic malignancies.     

Novel approaches in the therapy of metastatic renal cell carcinoma

Renal cell carcinoma (RCC) is the most lethal of the common urologic malignancies, with approximately 40% of patients eventually dying of cancer progression. Approximately one third of patients present with metastatic disease, and up to 40% treated for localized disease have a recurrence. Recent advances in the understanding of the pathogenesis, behavior, and molecular biology of RCC have paved the way for developments that may enhance early diagnosis, better predict tumor prognosis, and improve survival for RCC patients. The recent discovery of molecular tumor markers is expected to revolutionize the staging of RCC in the future and lead to the development of new therapies based on molecular targeting. Cytokine-based immunotherapy can be considered standard therapy in the treatment of metastatic RCC today. However, new therapies such as tumor vaccines, anti-angiogenesis agents, and small molecule inhibitors are being developed to improve efficacy and treat those patients who are unable to tolerate or are resistant to systemic immunotherapy. The aim of this review is to provide an update on current therapeutic approaches and targeted molecular therapy for metastatic RCC.     

New drugs and new approaches for the treatment of metastatic urothelial cancer

The median survival of patients with metastatic bladder cancer treated with M-VAC is approximately 1 year and long-term survival occurs in a small proportion of patients. Recent efforts to improve the outcome of patients with metastatic transitional cell carcinoma have focused on identifying new drugs with single agent activity and on their incorporation into platinum-based combination regimens. Paclitaxel, docetaxel, ifosfamide and gemcitabine are among the most active new agents. A large number of phase I-II trials have evaluated these agents in two- and three-drug combination regimens. The response proportion observed with these combinations varies considerably and median survival times range from 8 to 20 months. A better understanding of the molecular biology of bladder cancer will undoubtedly influence the selection of new therapeutic modalities. Molecular targeted small molecule therapy and monoclonal antibodies have begun to dominate contemporary studies. Whether or not this approach to therapy will lead to better results must still be determined.     

Smart drugs in prostate cancer

OBJECTIVES: Growth signaling is instrumental in tumor development. Insight into signaling pathways by molecular and cellular biology has changed the development of new anticancer agents. Outside the field of urology specifically targeted drugs such as imatinib mesylate and gefitinib showed impressive anticancer activity in chronic myeloid leukemia and non-small cell lung cancer, respectively. METHODS: Literature search of PubMed documented publications and abstracts from meetings. RESULTS: Preclinical data in prostate cancer shows upregulation of a wide variety of growth factors and their receptors such as PDGF, EGF, IGF, FGF, and VEGF suggesting efficacy of agents targeting these pathways. Here the preclinical evidence and first clinical data on the use of growth signal targeting in prostate cancer is reviewed. Although some anticancer efficacy of signal transduction inhibition monotherapy was reported, combination with chemotherapy and radiotherapy seemed most promising in prostate cancer. CONCLUSION: So-called smart drugs are small molecules targeted at specific growth signaling pathways. These new drugs will dominate clinical trials in the years to come either as single-drug modality, but more likely as combination treatment.     

Photochemical internalization of tumor-targeted protein toxins

Photochemical internalization (PCI) is a method for intracellular delivery of hydrophilic macromolecular drugs with intracellular targets as well as other drugs with limited ability to penetrate cellular membranes. Such drugs enter cells by means of endocytosis and are to a large extent degraded by hydrolytic enzymes in the lysosomes unless they possess a mechanism for cytosolic translocation. PCI is based on photodynamic therapy (PDT) specifically targeting the endosomes and lysosomes of the cells, so that the drugs in these vesicles can escape into the cytosol from where they can reach their targets. The preferential retention of the photosensitizer (PS) in tumor tissue in combination with controlled light delivery makes PCI relatively selective for cancer tissue. The tumor specificity of PCI can be further increased by delivery of drugs that selectively target the tumors. Indeed, this has been shown by PCI delivery of several targeted protein toxins. Targeted protein toxins may be regarded as ideal drugs for PCI delivery, and may represent the clinical future for the PCI technology.     

Apoptosis-modulating drugs for improved cancer therapy

Resistance to cell death induction has been recognized as a hallmark of cancer. Increasing understanding of the underlying molecular events regulating different cell death mechanisms like apoptosis, endoplasmic reticulum stress, autophagy, necroptosis and others has opened new possibilities for targeted interference with these pathways. While conventional chemotherapeutic agents usually inhibit cell cycle progression, DNA replication or mitosis execution, novel agents like small molecule kinase inhibitors also target survival-related kinases and signaling pathways and contribute to overcome resistance to chemotherapy and apoptosis. Additionally, antibodies targeting cellular death receptors have been described to specifically target tumor cells only. This review briefly highlights the pathways involved in (apoptotic) cell death and summarizes the current state of development of specific modulators of cell death and how they can help to improve the tolerability of chemotherapy regimens and increase survival rates in patients with advanced cancer diseases.     

Integrating Surgery with Targeted Therapies for Renal Cell Carcinoma: Current Evidence and Ongoing Trials

Context

Surgical intervention is the primary treatment for early-stage renal cell carcinoma (RCC), but alone it has limited benefit in patients with metastatic disease. The advent of targeted agents for RCC has improved the outcome in these patients, and there is increasing interest in exploring the efficacy and safety of these agents in combination with surgery in both early and advanced disease.

Objective

This article reviews approved and emerging targeted therapies for RCC and outlines the rationale and implications for combining these therapies with surgery.

Evidence acquisition

A search of the literature, trial registries, and meeting proceedings was performed, and reports on surgery, receptor tyrosine kinase inhibitors, vascular endothelial growth factor antibodies, mammalian target of rapamycin inhibitors, and cytokine adjuvant therapy relating to RCC were critically reviewed.

Evidence synthesis

Nephrectomy has been shown to improve overall survival in patients with metastatic RCC (mRCC) treated with interferon alpha. Combining targeted therapy with surgery has the potential to improve efficacy and tolerability relative to cytokine therapy and prospective studies are underway. In the localized setting, there is some evidence of tumor downsizing with neoadjuvant targeted therapy. The tolerability and safety of targeted agents used perioperatively must be considered, particularly in the adjuvant setting where chronic therapy is required to prevent recurrence or metastasis. Novel agents with greater specificity and improved safety profiles are under development and have the potential to enhance efficacy and minimize the risk of complications.

Conclusions

For patients with mRCC, randomized controlled trials are ongoing to define the role and sequence of nephrectomy in combination with targeted therapy. Until data are available, nephrectomy remains part of the mRCC treatment algorithm for patients with good performance status and a resectable tumor. Targeted therapy to downsize large primary tumors in nonmetastatic disease is investigational, but the rate of surgically relevant down-staging and tumor shrinkage seen with the current generation of agents is limited. In patients with high-risk nonmetastatic disease, adjuvant therapy must be administered only in the context of the ongoing clinical trials since there are no data showing efficacy in this setting.