Molecular pathogenesis. Its importance in targeted therapy in colorectal cancer

Colorectal cancer has the second highest mortality of all cancers in Germany. In spite of advances in surgical and chemotherapeutic treatment, efficient new therapies need to be developed. In recent years, advances have been achieved by novel targeted therapies that are specifically directed against altered signaling pathways of malignant cells. Colorectal cancers represent a heterogeneous tumor entity, and response to targeted therapies varies individually. About 15% of colorectal carcinomas are characterized by a deficient DNA mismatch repair system and microsatellite instability (MSI). These MSI cancers apparently have a decreased sensitivity to chemotherapy and frequently show evidence of a pronounced anti-tumoral immune response of the host. This immune response is likely to be mediated by a high number of tumor-specific antigens generated during MSI tumorigenesis. Interventions specifically targeting these antigens may be the basis for novel therapeutic strategies in MSI colorectal cancer and will be evaluated in clinical trials.     

乳腺癌治疗靶点及靶向治疗研究新进展

乳腺癌靶向治疗在临床实践中取得了显著的疗效,把乳腺癌的治疗推向了一个前所未有的水平。信号转导干预治疗是针对信号转导通路中发生异常的环节来干预这种不正常的信号转导,从而达到抑制肿瘤生长的目的,主要治疗药物有曲妥珠单抗、拉帕替尼、蛋白激酶C（PKC）-α抑制剂、环氧化酶2（COX-2）抑制剂。表皮生长因子受体（EGFR）靶向治疗的主要药物有吉非替尼和西妥昔单抗,其它的靶点和药物有血管内皮生长因子（VEGF）的靶向治疗（贝伐单抗）、血管生成抑制（阿瓦斯丁）、细胞凋亡（G3139和组蛋白脱乙酰基转移酶抑制剂）和热点靶蛋白（Mr70000）。本文主要讲述了乳腺癌治疗的靶点及靶向治疗研究新进展。乳腺癌分子靶向治疗的优势很多,但还不能替代传统的手术切除和化疗,靶向治疗只是术后辅助治疗的一种重要的手段。     

抗体药物与肿瘤靶向治疗

 单克隆抗体（单抗）对相应的抗原具有高度特异性，因此，单抗在疾病的诊断和治疗中有着巨大的潜力与应用价值。抗体药物临床应用最多的领域为癌症，其次为自身免疫病，以及感染性疾病、心血管疾病、器官移植排斥反应等。近年来, 抗体药物，尤其是治疗肿瘤的抗体药物研究取得了突破性进展。自1997年以来，美国FDA已先后批准了9种用于肿瘤治疗的抗体药物，包括Rituximab（Rituxan，利妥昔，1997），Trastuzumab（Herceptin，赫赛汀，1998），Gemtuzumab（Mylotarg，麦罗塔，2000），Alemtuzumab（Campath，坎帕斯，2001），Ibritumomab（Zevalin，泽娃灵，2002），Tositumomab（Bexxar，2003），Bevacizumab（Avastin，阿瓦斯汀，2004）和Cetuximab（Erbitux，爱必妥，2004），Panitumumab（Vectibix，2006）[1]。我国国家食品药品监督管理局（SFDA）近2年批准了2个用于肿瘤治疗的I类单抗新药：重组人源化抗人表皮因子受体（EGFR）抗体hR-3（泰欣生）和131I标记的metuximab（美妥昔）单抗（Licartin）（Anti-HAb18G/CD147）。抗体药物的研究与开发已成为生物技术药物领域的热点，展示出美好的发展前景。全球有超过200家公司正在研发治疗用单抗药物，超过300种产品正在研发中，其中有150种以上处于临床试验阶段。据美国制药工业协会的调查报告显示，单抗药物居所有医药生物技术产品之首，占生物技术产品的30%以上[2]。所有这些均表明，抗体工程药物时代已经来临。本文就抗体药物尤其是抗肿瘤抗体药物的特点及发展前景作一介绍。...     

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。     

病毒介导的免疫治疗癌症进展

病毒主要作为基因转染载体在免疫治疗中发挥重要作用.本文详细地介绍了病毒载体类型,病毒介导的对肿瘤细胞、宿主细胞的调节,病毒疫苗等免疫治疗癌症的研究进展,可为癌症免疫治疗的基础和临床研究提供参考.     

Molecular basis of targeted therapy in metastatic renal cancer

The introduction of targeted therapy in metastatic renal cancer patients provides a whole array of individual therapeutic options. The basis for this treatment is the inactivation of the von Hippel-Lindau tumor suppressor gene, resulting in high expression of pro-angiogenic growth factors, e.g. vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). This provides the rationale for targeting these pathways in clear cell renal cell carcinomas by small molecule inhibitors. This article gives a review on clinical trials with sunitinib, sorafenib, and temsirolimus in patients with advanced renal cell carcinoma and shows how promising treatments can emerge from an understanding of the molecular genetics and signaling pathways of tumors. However, a predictive marker, e.g. specific mutations associated with drug-resistant or responsive tumors, has not yet been identified and is paramount for the future.     

肿瘤分子靶向治疗药物及临床应用研究新进展

随着分子生物学的不断发展，人们对肿瘤发生、发展机制的了解也越来越深入。近年来，与该过程相关的一些特异性蛋白质，如生长因子受体、信号转导分子、细胞周期蛋白、细胞凋亡调节因子、血管内皮生长因子（VEGF）等被相继发现，并且都有可能成为肿瘤治疗的分子靶点，于是学者们提出了肿瘤分子靶向治疗的概念，即利用特异性分子（单克隆抗体、小分子物质）封闭或抑制这些分子靶点，从而抑制肿瘤细胞的生长、转移或诱导其凋亡。     

Antibodies for targeted cancer therapy -- technical aspects and clinical perspectives.

The efficacy of traditional anti-cancer agents comes with the price of toxicity to normal cells, which limits the success of therapy. In the past 2 decades, greater understanding of the molecular differences between malignant and normal cells has led to the development of therapies that more specifically target human tumors. These include new anti-cancer agents directed against intracellular targets associated with malignant alterations, such as increased proliferation, impaired apoptosis or angiogenesis. In addition, antibodies have been developed that are directed towards tumor-associated antigens and provide tailor-made effector functions by inhibiting cell growth, inducing apoptosis or constituting cytotoxic drug delivery systems. Since the targeted approach of anti-cancer therapies increases the exposure of malignant cells and at the same time reduces the exposure of normal tissues, it offers the promise of enhanced efficacy and lower side effects. Antibodies, immunoconjugates and liposomal drug delivery systems derived thereof are now mainstream cancer therapeutics, and by the end of 2003 17 marketed antibody-based products generated several billion in combined annual sales. This study highlights the most recent breakthroughs in antibody technology and summarizes major achievements in antibody-based cancer therapy in oncology trials.     

Folate-decorated nanogels for targeted therapy of ovarian cancer

Nanogels are comprised of swollen polymer networks and nearly 95% water and can entrap diverse chemical and biological agents for cancer therapy with very high loading capacities. Here we use diblock copolymer poly(ethylene oxide)-b-poly(methacrylic acid) (PEO-b-PMA) to form nanogels with the desired degree of cross-linking. The nanogels are further conjugated to folic acid (FA) and loaded with different types of drugs (cisplatin, doxorubicin). For the first time we demonstrate a tumor-specific delivery and superior anti-tumor effect in?vivo of an anti-cancer drug using these polyelectrolyte nanogels decorated with folate-targeting groups. This reinforces the use of nanogels for the therapy of ovarian and other cancers, where folate receptor (FR) is overexpressed.     

An introduction to molecular targeted therapy of cancer

The rapidly advancing elucidation of molecular targets in human cancers during the last decade has provided an excellent basis for the development of novel therapeutics. A huge variety of potential target structures have been identified, many of which are already being exploited for therapeutic purposes. This review introduces the reader into the concept of molecular targeted therapies, and provides some prototypic examples.     

肝癌干细胞的分子标记与靶向治疗

肿瘤干细胞假说认为只有很小一部分细胞具有引起肿瘤发生、维持肿瘤生长、保持肿瘤异质性的能力,这样的细胞叫肿瘤干细胞（cancer stem cell,CSC）。     

肺癌分子标志物在病理诊断及靶向治疗中的研究进展

肺癌是当今世界上对人类健康与生命危害最大的恶性肿瘤之一,其总体发病率在世界范围内整体呈上升趋势[1].肺癌因其不易早期发现并且对化疗和放疗常产生耐药,故病死率高.     

GPNMB与肿瘤靶向治疗

非转移性黑色素瘤糖蛋白 B(glycoprotein non-metastatic melanoma protein B,GPNMB)是一种高度糖基化的 I 型跨膜糖蛋白,定位于细胞膜或贮存于内涵体及溶酶体中.膜结合型 GPNMB 可被金属蛋白酶如 ADAM 10 裂解,释放出可溶性形式.该蛋白最初被发现于非转移性黑色...     

肿瘤分子靶向治疗药物的临床应用研究进展

恶性肿瘤严重威胁人类生命和健康,其发病率和死亡率高居不下,根据世界卫生组织国际癌症研究机构（international agency of research on cancer,IARC）报告,2008年全球癌症新发病例1 270万,死亡病例760万,已为人类健康最大杀手[1]。我国研究也表明2008年癌症居我国城乡居民疾病死亡原因首位。恶性肿瘤因难以早期发现、诊断及治疗,成为危害人们健康和影响生活质量的严重疾病,     

Drug delivery with upconversion nanoparticles for multi-functional targeted cancer cell imaging and therapy

Upconversion nanoparticles (UCNPs) with unique multi-photon excitation photoluminescence properties have recently been intensively explored as novel contrast agents for low-background biomedical imaging. In this work, we functionalize UCNPs with a polyethylene glycol (PEG) grafted amphiphilic polymer. The PEGylated UCNPs are loaded with a commonly used chemotherapy molecule, doxorubicin (DOX), by simple physical adsorption via a supramolecular chemistry approach for intracellular drug delivery. The loading and releasing of DOX from UCNPs are controlled by varying pH, with an increased drug dissociation rate in acidic environment, favorable for controlled drug release. Upconversion luminescence (UCL) imaging by a modified laser scanning confocal microscope reveals the time course of intracellular delivery of DOX by UCNPs. It is found that DOX is shuttled into cells by the UCNP nano carrier and released inside cells after endocytosis. By conjugating nanoparticles with folic acid, which targets folate receptors over expressed on various types of cancer cells, we further demonstrate targeted drug delivery and UCL cell imaging with UCNPs. Besides DOX, this non-covalent drug loading strategy can also be used for loading of photosensitizer molecules on UCNPs for potential near-infrared light induced photodynamic therapy. Our results suggest the promise of UCNPs as interesting nano carriers for multi-functional cancer therapy and imaging.     

Overcoming the immunologic response to foreign enzymes in cancer therapy

Foreign enzymes play a part in a variety of cancer treatments and have the potential for a much greater role. In most cases, repeated administration of the enzyme is required for effective therapy, however, this can be restricted by undesirable effects caused by immunogenicity. Repeated or prolonged treatment can lead to an antibody response, and this may neutralize the enzyme and prevent it from remaining in the circulation. Ultimately, this can lead to a diminished therapeutic effect and increase the risk of infusion reactions. More insidiously, there is a danger that antibodies will not only neutralize the foreign enzyme, but will crossreact with a vital component in normal tissue. Such responses can damage normal tissues and give rise to serious clinical syndromes. The aim for enzymes in cancer therapy is to allow repeated treatments without compromising safety or efficacy. This can potentially be achieved by understanding and controlling the immune response and by modifying the enzyme accordingly. A crucial requirement, and one that is particularly challenging for enzymes to achieve, is that the modifications introduced do not interfere with structure, function or stability.