肿瘤的靶向治疗

靶向治疗是针对肿瘤细胞恶性表型的分子靶点,作用于促进肿瘤生长、存活的特异性细胞受体、信号传导等通道,实现抑制肿瘤细胞生长或促进凋亡的抗肿瘤作用。新的靶向治疗药物rituximab、伊马替尼、赫赛汀和全反式维甲酸已开始用于临床治疗,本文综述这些药物的作用机制、适应证、疗效及安全性。与传统细胞毒化疗不同,肿瘤靶向治疗具有特异性抗肿瘤作用,并且毒性明显减少。肿瘤靶向治疗令人鼓舞的初步成果为其进一步发展奠定了基础,提供了典范,开创了肿瘤化疗的新领域。     

scFv-sTRAIL融合蛋白靶向诱导肿瘤细胞凋亡的研究进展

随着分子生物学技术的进步和在分子水平上对恶性肿瘤发病机制认识的不断加深,以细胞受体、表面抗原、关键基因和细胞内调控分子为靶点的分子靶向治疗已成为辅助传统治疗的合理选择。抗体导向治疗是一种新颖的分子靶向治疗手段。目前已研发多种抗体导向类抗癌药物,这类药物由特异性识别肿瘤细胞的靶向部分和杀伤肿瘤的效应部分组成,因而具有较强的靶向杀伤肿瘤细胞作用,同时可有效降低药物对局部正常组织和全身的系统性毒性作用。利用基因工程技术将人类血清可溶性肿瘤坏死因子相关凋亡诱导配体(serum-soluble TNF-related apoptosis-inducing ligand,sTRAIL)与抗肿瘤单链抗体(single chain antibody fragment,scFv)融合,构建scFv-sTRAIL融合蛋白,是一种理想的抗体导向治疗策略。通过scFv与肿瘤细胞所特有的细胞表面抗原的特异结合,加强sTRAIL在肿瘤病灶的富集,靶向诱导肿瘤细胞凋亡,从而获得增强抗体的疗效和更高的药物安全性。     

放射性药物FAK抑制剂靶向肿瘤侵袭力的作用研究

[目的]化学合成、放射性核素标记局部黏着斑激酶(FAK)抑制剂,评价新型放射性药物FAK抑制剂对恶性肿瘤组织侵袭力靶向示踪及治疗的潜在应用价值。[方法]以恶性肿瘤组织高表达FAK为靶点,利用计算机辅助药物设计方法的优势,经计算机模拟设计、化学合成新型FAK小分子抑制剂化合物,通过药物有效性筛选后,选择与FAK受体特异性结合,明显抑制肿瘤细胞增殖、侵袭能力的FAK抑制剂化合物,研究放射性核素碘标记方法,评价核素标记FAK小分子抑制剂的理化性质及体内外稳定性。[结果]对97个FAK抑制剂分子进行了3D-QSAR计算,得到FAK抑制剂的有效骨架结构,在此基础上进行不同结构修饰,设计并合成17个新型FAK小分子化合物。细胞活力实验检测发现FAK小分子抑制剂及其稳定碘标志物对恶性肿瘤细胞的毒性作用存在明显的差异。其中,对与恶性肿瘤细胞特异性结合的化合物3进行放射性核素125I标记,标记率达49%以上。应用HPLC对放射性核素标记化合物进行放化纯分析及稳定性研究发现125I标记化合物3在体外能够稳定存在。[结论 ]新型放射性药物FAK抑制剂靶向结合FAK位点,对多种恶性度较高,侵袭、转移能力较强的肿瘤靶向示踪和放射性核素靶向治疗具有潜在应用价值。     

肺癌靶向治疗的新境界:活得更长,活得更好

分子靶向治疗是21世纪肺癌治疗最具希望的治疗策略,与传统的细胞毒药物不同,分子靶向治疗可以特异性地作用于肿瘤细胞的某些特定位点,高度选择性的杀死肿瘤细胞而不杀伤或仅很少损伤正常细胞,靶向治疗药物最大的特点是安全性和耐受性极好,毒副作用轻微,临床应用具有非常大的优势。近年来靶向治疗以惊人的速度和独特的疗效引起了广大从事肿瘤治疗的广泛关注,新的靶向治疗药物Et新月异,新的治疗方案、治疗策略层出不穷,本文对近来有关晚期肺癌靶向治疗的最新研究作一综述,希望对肺癌临床研究工作者有所帮助。     

肿瘤细胞特异性适配子筛选技术及其应用的研究进展

指数富集的配基系统进化技术(systematic evolution of ligands by exponential enrichment,SELEX)应用人工合成的随机寡核苷酸文库,通过筛选、分离、富集获得能与各种配体特异结合的寡核苷酸适配子(aptamer)。适配子能特异性结合多肽、蛋白质等多种靶分子,且具有高亲和力。细胞-SELEX技术在SELEX基础上发展起来,它以活细胞为基础,可以在对肿瘤细胞分子标志物一无所知的情况下有效地筛选出肿瘤细胞特异性适配子,是一个潜在的发现肿瘤细胞新标志物的理想策略。肿瘤细胞特异性适配子作为分子探针,在肿瘤基础研究、早期诊断,以及靶向治疗方面展示了巨大的应用前景。目前已筛选出淋巴细胞白血病、肝癌等多种肿瘤细胞的适配子,这些适配子已应用在肿瘤细胞检测,肿瘤早期发现、诊断、游离肿瘤细胞的分选和富集,以及肿瘤细胞靶向药物递送等方面,并且由于适配子适用范围广泛、易于修饰等特点,显示出良好的敏感性、特异性和其他独特的优越性。适配子在肿瘤研究中受到越来越多的关注,在肿瘤检测、诊断和治疗等方面发挥重要作用。     

ADC联合疗法有望成为肺癌患者治疗的新选择

抗体药物偶联物(ADC)是一类通过特定连接头将靶标特异性单克隆抗体与高杀伤性的细胞毒性药物偶联起来的靶向生物药剂,以单克隆抗体为载体将小分子细胞毒性药物以靶向方式高效地运输至目标肿瘤细胞中。ADC药物的概念最初源自100年前Paul Ehrlich提出的“魔术子弹”概念,但直至20世纪80年代,才随着非免疫原性(尤其是人源化)单克隆抗体的研发而出现飞速进展。ADC药物结合了靶向性、选择性强的抗体和高抗肿瘤活性细胞毒性药物的优势,在保留小分子细胞毒性药物肿瘤杀伤特性的同时,选择性降低小分子细胞毒性药物的脱靶不良反应,有效提高了抗肿瘤治疗的获益风险比。因此,近年来ADC药物一直是肿瘤精准治疗领域的热门研究方向之一。     

肺癌分子靶向治疗的现状与进展

分子靶向药物是利用肿瘤细胞和正常细胞之间分子细胞生物学上的差异,采用封闭受体、抑制血管生成、阻断信号传导通路等方法作用于肿瘤细胞的特定靶点,特异性地抑制肿瘤细胞的生长,促使肿瘤细胞凋亡。分子靶向治疗比传统的化疗特异性强,不良反应小,将成为以后肿瘤治疗的新趋势。     

主动靶向磁纳米载体在肿瘤治疗中的研究进展

主动靶向磁性纳米载体作为一种新的预防、诊断和治疗肿瘤的方法为肿瘤的防治取得了开拓性的进展.可通过在磁性纳米粒子表面选择性修饰特异性介导分子构建具有靶向性结合能力的纳米粒子,实现主动靶向于肿瘤细胞的目的.目前,主动靶向磁性纳米粒子已用于肿瘤热疗、药物治疗和免疫检测等方面.     

非小细胞肺癌的分子靶向治疗

与传统细胞毒性化疗相比,分子靶向治疗能更特异性作用于肿瘤而毒性反应较轻。新的靶向治疗药物得到发展,并相继在晚期非小细胞肺癌一线、二线治疗中进行临床试验,其中有的药物显示了较好的疗效。本文对近年来关于非小细胞肺癌靶向治疗的临床试验进行回顾。     

肺癌分子靶向治疗的现状与进展

分子靶向药物是利用肿瘤细胞和正常细胞之间分子细胞生物学上的差异，采用封闭受体、抑制血管生成、阻断信号传导通路等方法作用于肿瘤细胞的特定靶点，特异性地抑制肿瘤细胞的生长，促使肿瘤细胞凋亡。分子靶向治疗比传统的化疗特异性强，不良反应小，将成为以后肿瘤治疗的新趋势。     

The medically important dematiaceous fungi and their identification

Dematiaceous fungi include a large group of organisms that are darkly pigmented (dark brown, olivaceous, or black). In most cases the pigment is melanin, and specifically, dihydroxynaphthalene melanin. The diseases produced include chromoblastomycosis, eumycotic mycetoma, and phaeohyphomycosis. Phaeohyphomycosis is a new classification for a diverse group of previously known entities grouped together on the basis of finding dematiaceous hyphal and/or yeast-like forms in tissue; tissue involvement may be superficial, cutaneous and corneal, subcutaneous, or systemic. Identification of these fungi is based mostly upon morphology. Important structures include annellides (Phaeoannellomyces, Exophiala), phialides (Phialophora, Wangiella), adelophialides (Phialemonium without collarettes, Lecythophora with collarettes), differentiation of conidiophores (Xylohypha versus Cladosporium) and conidial hilum, septation and germination (Bipolaris, Drechslera, Exserohilum). Useful laboratory tests include the 12% gelatin test (controversial), nitrate assimilation (W. dermatitidis is negative, most other species are positive), and determination of temperature maxima (especially 37 degrees C for E. jeanselmei, 40 degrees C for W. dermatitidis and B. spicifera, 42 degrees C for X. bantiana, and 45 degrees C for Dactylaria constricta var. gallopava and Scedosporium inflatum).     

Orale Langzeitbehandlung von Onychomykosen mit Ketoconazol

Zusammenfassung: An der Studie zur Wirksamkeit und Anwendungssicherheit von Ketoconazol nahmen 27 Männer im Alter von 20 bis 80 (Median: 57) Jahre, davon 18 mit Onychomykosen und 9 als KontroUen bei den Laborwertbestimmungen, teil. Während des ersten Behandlungsmonats erhielten je 9 Patienten 200 mg und 400 mg Ketoconazol täglich. Danach wurden beide Gruppen 6 Monate mit 200 mg/d weiterbehandelt. Die klinische Beurteilung sowie hämatologische, biochemische und Plasmaspiegeluntersu-chungen erfolgten mindestens monafich, mykologische Untersuchungen wurden vor Aufnahme und bei Beendigung der Therapie vorgenommen. Erne letzte klinische Unter-suchung erfolgte 1 Jahr nach Beginn der Studie. Nach 7 Monaten Behandlung wurden 23 von 30 Nägeln mit “gebessert” bis “stark gebessert” beurteilt, nach dem behandlungsfreien Intervall galt dies für 28 von 30 Nägeln. Die Plasmaspiegel waren mit 200 mg/d ausreichend und uber den Behandlungszeit-raum konstant. Dies spricht für gute orale Resorption und Abwesenheit von Enzyminduktion. Die Laborwerte zeigten im Vergleich zu den Kontrollen und den Werten vor Behandlung keine signifikanten Abweichungen, so daß myelo-, nephro- und hepatotoxische Wirkungen von 400 bzw. 200 mg/d ausgeschlossen werden können. Der Lipidhaushalt wurde nicht beeinfluat und es trat unter Therapie als Folge der Ketoconazolwirkung lediglich Lanosterin im Serum auf. Nach Beendigung der Therapie ging der Lanosteringehalt schnell zurück. Damit erweist sich Ketoconazol in den angewandten Dosen als ein gut verträgliches und zur Langzeitbehandlung von Onychomykosen geeignetes Antimykotikum. Summary: Twenty-seven males with a median age of 57 (range: 20 to 80) years took part in this study on the efficacy and safety of ketoconazole. Eighteen men suffered from onychomycosis; nine served as controls in the safety evaluation. During the first month of treatment, nine patients received 200 mg and the nine other 400 mg ketoconazole daily. Then the treatment was uniformly continued with 200 mg/d for 6 months. Clinical evaluation and haematological, biochemical and plasma level investigations were carried out at least at monthly intervals; mycological controls were performed at the start and end of therapy. A final clinical evaluation was carried out one year after the start of the study. After 7 months of treatment, moderate or definite clinical improvement was obtained in 23 out of 30 nails. After 5 more months without antimycotic treatment this was the case in 28 of 30 nails. Plasma levels obtained with 200 mg ketoconazole daily were adequate and constant during the entire treatment period. This indicates a good oral resorption as well as the absence of induction of hepatic enzymes. The laboratory values did not show significant deviations as compared with the controls or with the pretreatment values. This excludes myelo-, nephro- and hepatotoxic effects of 400 and 200 mg ketoconazole daily. The lipid metabolism was not influenced, the only difference was the occurrence of lanosterol in the serum, which is a result of the mechanism of action of ketoconazole. After the medication period the lanosterol levels subsided rapidly. In the applied doses ketoconazole is a well-tolerated and effective drug for the systemic long-term treatment of onychomycosis.     

Laboratory Techniques Alternative to In Vivo Experiments for Studying the Liberation, Penetration and Fungicidal Action of Topical Antimycotic Agents in the Skin, Including Ciclopiroxolamine

Summary: Short-term experiments on excised skin (human, pig) gave the following results: 1. In the tissue activity test with direct inoculation (D-TAT) commercial preparations of the non-azole antimycotics ciclopiroxolamine, tolnaftate and naftifine, produced higher inhibitory activity against Trichophyton mentagrophytes (standard strain) in various levels of the horny layer than were produced by the azole antimycotics econazole, miconazole, clotrimazole, oxiconazole and bifonazole. Fast drying solutions of antimycotics invariably gave higher inhibitory activities than creams. In the ultrafiltration tissue activity test (UFT- TAT) against Candida albicans (2 strains), antimycotic agents ranked in order of effectiveness as follows: ciclopiroxolamine – most of the azole antimycotics – bifonazole and naftifine. 2. In tests of fungicidal activity against T. mentagrophytes (2 strains) and Microsporum gypseum (1 strain) the first step was to inoculate the skin surface. After the horny layer had been penetrated by fungal mycelia, antimycotic agents of documented fungicidal potency, chiefly in the form of creams, were applied to the skin surface and left to act for up to 18 hours. The horny layer and epidermis were then scraped off and the concentration of viable fungi was determined. Ciclopiroxolamine cream and lotion produced by far the greatest diminution in viable fungi; creams containing oxiconazole and naftifine were moderately effective and those containing tioconazole and bifonazole produced a relatively small decrease in viable fungi. To avoid erroneous results it is important to homogenize and dilute the skin scrapings; if this is not done certain antimycotics will give misleadingly high fungal killing rates. At this early stage the scatter of results is still wide and minor differences in efficacy cannot as yet be detected with certainty. 3. From the results of various comparative tests it is evident that pig skin can be used as a substitute for human skin in the tests listed under 1. and 2. above. This discovery may make a valuable contribution towards limiting the need for experiments on living animals and trials on human beings. Zusammenfassung: In Kurzzeitversuchen an exzidierter Haut (Mensch, Schwein) wurde gefunden: 1. Im Gewebeaktivitätstest mit direkter Inokulation (D-GAT) wurde mit Handelspräparaten der Nichtazol-Antimykotika Ciclopiroxolamin, Tolnaftat und Naftifin in verschiedenen Hornschichtniveaus eine höhere Hemmaktivität gegenüber Trichophyton mentagrophytes (Standard-Stamm) erzielt als mit solchen der Azol-Antimykotika Econazol, Miconazol, Clotrimazol, Oxiconazol und Bifonazol. Rasch trocknende Lösungen von Antimykotika ergaben durchweg höhere Hemmaktivitäten als Cremes. Im Ultrafiltrations-Gewebeaktivitätstest (UFT-GAT) gegenüber Candida albicans (2 Stämme) ergab sich nach erzielter Wirksamkeit die Rangfolge Ciclopiroxolamine – Mehrzahl der Azolantimykotika – Bifonazol und Naftifin. 2. In Fungizidie-Testen gegenüber T. mentagrophytes (2 Stämme) und Microsporum gypseum (1 Stamm) wurde zunächst die Hautoberfläche inokuliert. Nach Durchdringung der Hornschicht mit Pilzmyzelien wirkten auf die Hautoberfläche bis zu 18 Stunden lang überwiegend Cremes von als fungizid publizierten Antimykotika ein. Während sich in abgeschabter Hornschicht und Epidermis der so bearbeiteten Hautoberflächen mit Ciclopiroxolamin-Creme und -Lotion die weitaus höchste Verminderung lebensfähiger Keime ergab, bewirkten Cremes mit Oxiconazol und Naftifin eine mittlere und solche mit Tioconazol und Bifonazol eine relativ niedrige Keimeliminierung. Zur Vermeidung von fehlerhaften Ergebuissen mußten Homogenisierung und Verdünnung der Hautschabsel erfolgen, anderenfalls bei mehreren Antimykotika eine zu hohe Keimabtötung vorgetäuscht worden wäre. Wegen der vorerst noch hohen Streuung der Ergebnisse können kleinere Wirksamkeitsunterschiede noch nicht sicher erfaßt werden. 3. Nach dem Ergebnis verschiedener Vergleichstests kann in den Testen zu 1. und 2. Schweinehaut als Ersatz für Haut vom Menschen dienen und dürfte damit wesentlich zur Einschränkung von Versuchen am lebenden Tier und von Prüfungen am Menschen beitragen.     

Efficiency of crude and purified fungal antigens in serodiagnosis to discriminate mycotic from other respiratory diseases

Mycotic immunodiagnosis was performed in 186 hospitalized patients with different respiratory diseases, mostly considered as tuberculosis and others with a doubtful diagnosis. Crude histoplasmin, coccidioidin, paracoccidioidin, blastomycin, candidin, aspergillin, and sporotrichin, as well as purified polysaccharide-protein complexes (PPC) of Histoplasma capsulatum, Coccidioides immitis, and Paracoccidioides brasiliensis were used as antigens. Immune tests used included skin test (ST), gel immunodiffusion (ID), counterimmunoelectrophoresis (CIE), complement fixation (CF), and ELISA. A possible association with candidosis was observed in 17% of patients with tuberculosis and diabetes; one presumptive paracoccidioidomycosis, one confirmed aspergillosis, and six cases of active histoplasmosis were determined. Candidin ST showed 29% of positive reactions with an increased frequency in patients between 31 and 55 years of age. CF test showed the highest positivity percentages with crude antigens, specially for Candida antigen (26.3%) and histoplasmin (18.2%). Cross reactions were evident with crude antigens but decreased when PPC's were used in ELISA.     

Isoconazole nitrate in the treatment of tropical dermatomycoses

Summary. A total of 54 patients with culturally proven tropical dermatomycoses, comprising 23 with various types of dermatophytoses, one with foot infection due to Trichosporon beigelii and one with foot infection due to Geotrichum candidum , two with candidoses of the groin and 27 with pityriasis versicolor, were included in a clinical trial of efficacy of 1% isoconazole cream (Travogen^R, Schering, Berlin, Germany). Five patients were not evaluable. A clinical and mycological cure was achieved in 29 cases in 3–4 weeks. In 15 (31%) of the remaining patients treatment was required for 5–6 weeks, while another three patients required treatment for 8 weeks. In two patients the disease proved to be resistant to treatment with the drug.
Zusammenfassung. Insgesamt 54 Patienten mit kulturell gesicherter Dermatomykose, (23 unterschiedliche Dermatophytosen, eine Trichosporon beigelii - und eine Geotrichum candidum -Fußinfektion, 2 Candidosen der Leistengegend und 27 Pityriasis versicolor) wurden in einer klinischen Wirksamkeits-studie mit 1% iger Isoconazol-Creme (Travogen^R, Schering, Berlin, Deutschland) behandelt. Fünf Patienten waren nicht auswertbar. Eine klinische und mykologische Heilung wurde bei 47 von 49 Patienten (96%) erreicht. Bei 29 patienten (59%) wurde die Heilung bereits nach 3–4 Wochen Behandlung erreicht. Weitere 15 Patienten (31%) benötigten 5–6 Wochen und drei Patienten 8 Wochen Behandlungsdauer. Zwei Mykosesituationen erwiesen sich als therapieresistent.     

Large-scale molecular characterization and analysis of gastric cancer

The recent effort by The Cancer Genome Atlas （TCGA） Network has revealed that gastric cancer, which is a leading cause of cancerrelated deaths worldwide with a 5-year survival rate less than 25%, is a much more heterogeneous disease than previously thought. And yet, conventional treatment approaches and clinical trials have assumed it is a single disease. Although it is well known that under the microscope, gastric cancer cells appear quite different, the current classification scheme recognizes two main categories of gastric cancer： diffuse and intestinal.     

A conceptually new treatment approach for relapsed glioblastoma: Coordinated undermining of survival paths with nine repurposed drugs (CUSP9) by the International Initiative for Accelerated Improvement of Glioblastoma Care

To improve prognosis in recurrent glioblastoma we developed a treatment protocol based on a combination of drugs not traditionally thought of as cytotoxic chemotherapy agents but that have a robust history of being well-tolerated and are already marketed and used for other non-cancer indications. Focus was on adding drugs which met these criteria: a) were pharmacologically well characterized, b) had low likelihood of adding to patient side effect burden, c) had evidence for interfering with a recognized, well-characterized growth promoting element of glioblastoma, and d) were coordinated, as an ensemble had reasonable likelihood of concerted activity against key biological features of glioblastoma growth. We found nine drugs meeting these criteria and propose adding them to continuous low dose temozolomide, a currently accepted treatment for relapsed glioblastoma, in patients with recurrent disease after primary treatment with the Stupp Protocol. The nine adjuvant drug regimen, Coordinated Undermining of Survival Paths, CUSP9, then are aprepitant, artesunate, auranofin, captopril, copper gluconate, disulfiram, ketoconazole, nelfinavir, sertraline, to be added to continuous low dose temozolomide. We discuss each drug in turn and the specific rationale for use- how each drug is expected to retard glioblastoma growth and undermine glioblastoma''s compensatory mechanisms engaged during temozolomide treatment. The risks of pharmacological interactions and why we believe this drug mix will increase both quality of life and overall survival are reviewed.     

Endometrial cancers and predisposition

As nearly 5% of all endometrial cancers occur because of a predisposition, this possibility has systematically to be explored. The hallmarks of predisposition, a young age at diagnosis, a personal or a familial history of cancer, have to be searched systematically. The identification of a predisposition in a family has a major impact on the management of the proband or his relatives. The endometrial cancer main predisposition is Lynch's syndrome. In this review, we will focus on this condition and describe its clinical manifestations, the underlying molecular mechanisms, the cancer risks and the management guidelines. We will also get onto some far less frequent other predispositions.