乳铁蛋白抗肿瘤作用及机制研究进展

乳铁蛋白（lactoferrin,LF）主要存在于哺乳动物的乳汁中,也分布在其他分泌液（泪液、精液、胆汁、关节液、唾液、胰液、鼻腔分泌液、羊水等）中。乳铁蛋白具有多种生物学活性,如抗氧化,抗真菌活性、抗病毒活性,抗微生物活性等,近年来研究表明,乳铁蛋白还具有抗肿瘤作用[1]。     

青蒿素及其衍生物对肿瘤的放疗增敏作用

青蒿素及其衍生物是一类高效、速效、低毒的抗疟疾药物.近年来研究发现,青蒿素类药物不仅可以抗疟疾,还具有免疫抑制、抗病毒及抗肿瘤等多方面的药理作用.大量研究证实,青蒿素及其衍生物对鼻咽癌、宫颈癌、肺癌和脑胶质瘤等肿瘤有放疗增敏作用,其作用机制与Weel蛋白下调、Cyclin B1蛋白上调、G2-M期阻滞和细胞凋亡有关.     

铁蛋白为肿瘤诊治提供新的视角

铁既是生命所必须,又与肿瘤的发生、发展密切相关。铁在氧化态和还原态之间循环导致自由基形成,由此产 生包括肿瘤形成在内的有害作用。异常铁代谢增加肿瘤发病风险,促进肿瘤的生长。铁蛋白是一种由肝脏合成的糖蛋白, 在铁的平衡中起至关重要的作用。铁蛋白通过将铁摄入并贮存,避免了细胞内高浓度游离铁对细胞的毒性作用。血清铁蛋 白是反映体内铁储备的主要指标,大多数肿瘤患者中铁蛋白的表达增加。铁蛋白通过参与抗氧化损伤、血管生成、免疫抑制、 促进细胞增殖等促进肿瘤的发生、发展。高表达铁蛋白的患者生存期短,提示其可作为评估肿瘤预后的指标。下调铁蛋白 的表达不仅能够抑制肿瘤增殖,还能增加化疗药物的敏感性,提示其在抗肿瘤治疗中的潜在前景。许多新发现让我们重新 认识铁蛋白,但是仍需要更深入的研究来继续揭示铁蛋白的新功能。本文拟通过阐述铁蛋白促进肿瘤增殖机制的最新研究 及其与肿瘤预后的相关性,对铁蛋白在抗肿瘤治疗中的临床意义以及进一步应用进行综述。     

青蒿素类药物抗肿瘤作用机制的研究进展

青蒿素类药物是治疗疟疾的主要药物,其衍生物有青蒿琥酯、蒿甲醚和二氢青蒿素等,主要的作用机制是通过铁离子介导的细胞损伤。近年来研究发现,青蒿素类药物还具有更广泛的药理作用,它可以通过阻滞细胞周期、诱导细胞凋亡、抗血管生成、调节肿瘤相关基因的表达以及损伤细胞线粒体等机制从而发挥抗肿瘤作用,其抗肿瘤作用日愈受到人们的重视。     

青蒿素及其衍生物抗肿瘤作用及其分子机制

青蒿素及其衍生物是治疗疟疾的首选药,近年来大量体内外研究显示青蒿素及其衍生物具有良好的抗肿瘤活性,其抗肿瘤机制主要包括氧化损伤反应、抑制肿瘤细胞增殖以及抗新生血管生成等。青蒿素类药物不良反应小、成本较低,对多药耐药细胞有效,对放化疗具有增效作用,可能成为具有临床应用价值的抗癌新药。     

氨基酸载体抗肿瘤活性研究进展

摘 要：氨基酸是构成生物体蛋白质并同生命活动有关的最基本物质,氨基酸载体具有良好的生物相容性和亲和性,将氨基酸引入抗肿瘤药物分子中,可提高对肿瘤细胞的选择性,增加药物的溶解性,降低对正常细胞的毒性。随着对其构效关系及作用机制的不断研究,氨基酸类衍生物在抗肿瘤药物中的应用前景广阔。全文总结氨基酸类化合物衍生化后抗肿瘤作用的研究进展及应用,为抗肿瘤药物的研发提供参考。     

澳洲茄碱的抗肿瘤活性及其机制研究进展

澳洲茄碱（SS）是一种天然来源的生物活性小分子化合物,已经被证实具有抗菌、抗炎和抗肿瘤等功效。在抗肿瘤作用方面,SS可以通过多种机制在不同类型肿瘤中有效发挥抗肿瘤作用,其作用机制包括诱导肿瘤细胞凋亡、阻滞肿瘤细胞周期、诱导肿瘤细胞铁死亡、调控肿瘤相关非编码RNA、调节免疫和炎症反应、削弱肿瘤细胞的侵袭和转移能力、抑制糖酵解进程和肿瘤干细胞的产生等,涵盖了肺癌、肝癌、胃癌、乳腺癌、胆管癌、膀胱癌、胰腺癌、白血病、骨肉瘤等多种癌症类型。阐明SS在不同类型肿瘤中的抗肿瘤活性及其作用机制,为促进SS抗肿瘤作用机制的进一步研究和开发更有效安全的抗肿瘤药物提供了重要的理论基础。     

维生素E聚乙二醇琥珀酸酯在抗肿瘤研究中的进展

摘 要：维生素E聚乙二醇琥珀酸酯（TPGS）长期以来一直作为药物载体在临床应用,近年来研究发现,TPGS除了作为药物载体,有提高抗肿瘤药物疗效的作用,同时还可以逆转耐药。由于其作为一个维生素的衍生物,目前的研究主要集中在其作为辅料的研究上,而其作为潜在的抗肿瘤的活性目前研究较少。此外,其作用机制尚有待于深入研究。全文对TPGS抗肿瘤的研究进展进行综述。     

盐霉素抗肿瘤作用及其衍生物研究进展

肿瘤细胞中离子稳态的改变是影响肿瘤起始与进展的重要原因，为此人们将离子载体作为抗肿瘤药物进行研发。盐霉素是一种聚醚类离子载体抗生素，能够与钾离子、钠离子以非共价形式结合，协助离子跨膜转运，因而被用于防治鸡球虫病和促进反刍动物生长。新近研究发现，盐霉素具有杀伤多种肿瘤细胞尤其是特异杀伤肿瘤干细胞的作用，其可通过干预离子稳态、抑制肿瘤细胞相关信号通路和直接抑制其结合靶蛋白等发挥抗肿瘤作用，是潜在的新型抗肿瘤药物。然而，水溶性低、健康组织毒性、血液循环时间短等特点，限制了盐霉素的临床应用。新型衍生物或其靶向传递系统的开发，可有效提高盐霉素抗肿瘤作用及其安全性。现将盐霉素抗肿瘤应用、机制及其新药研究进展进行综述。     

紫草素及其衍生物的抗肿瘤作用

紫草为传统的中药,紫草的化学 成份复杂,具有广泛的药理作用,抗肿瘤 作用是其中之一。天然紫草素类化合物 由于抗瘤作用弱,仍未用于临床。为了减 少它们的毒副反应和增强抗肿瘤作用,人 们半合成了许多紫草素类衍生物。实验 证明,天然紫草素类化合物及其衍生物具 有不同程度的细胞毒作用和抗肿瘤作用。 初步的作用机制研究表明,紫草素类化合 物及其衍生物能诱导肿瘤细胞凋亡,激活 促细胞分裂原激活蛋白激酶(mitogen acti vatedproteinkinase,MAPK),抑制蛋白酪 氨酸激酶和DNA拓扑异构酶I的活性,从 而影响肿瘤细胞的代谢、增殖、分化、信号 传递、基因表达等过程,阻碍肿瘤细胞的 生长。     

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.