Interferon-α-2a

Interferon-alpha-2a, a single interferon-alpha subtype manufactured by use of recombinant DNA technology, has immmunomodulatory, antiviral and antiproliferative properties. It is a beneficial treatment for about 30% of patients with well-compensated chronic hepatitis C. Biochemical responses [defined as normalisation of serum alanine aminotransferase (ALT) levels] are achieved in 37 to 76% of patients at the end of treatment with interferon-alpha-2a at dosages of 3 to 6MU 3 times weekly (given intramuscularly or subcutaneously) for 6 to 12 months. In contrast, evidence of disease remission is seldom observed in untreated patients. Improvements in liver histology in patients receiving interferon-alpha-2a are associated with complete biochemical responses to the drug. Virological responses (defined as an absence of hepatitis C-RNA in the serum) occur in up to 86% of patients after treatment with interferon-alpha-2a 3 to 6MU 3 times weekly for 12 months. After cessation of interferon-alpha-2a therapy, a considerable proportion of treatment responders experience disease reactivation. Rates of sustained biochemical response are generally higher after 12 months' therapy (27 to 57%) than after 6-month courses of treatment (27 to 30%). The long term efficacy of interferon-alpha-2a in patients with chronic hepatitis C is improved by the concomitant administration of ribavirin. Interferon-alpha-2a shows efficacy similar to that of interferon-alpha-2b or interferon-alpha-n1 in patients with chronic hepatitis C. During the first few days of therapy with interferon-alpha-2a (or other forms of interferon-alpha), most patients experience a transient 'influenza-like' reaction, characterised by fatigue, fever, chills and headache. These symptoms are usually alleviated by paracetamol (acetaminophen). Lethargy, mild myelosuppression, alopecia and neuropsychiatric symptoms are dose-limiting adverse effects that may occur during longer term therapy. Severe adverse effects, experienced by <2% of interferon-alpha-2a recipients, include severe depression, seizures and generalised bacterial infections. Autoimmune thyroid dysfunction develops in 3 to 12% of patients during treatment with interferon-alpha-2a. Conclusion. Interferon-alpha-2a produces sustained responses in about 30% of adults with chronic hepatitis C. Its efficacy appears to be similar to that of other interferon-alpha products. Thus, the drug remains a useful first-line treatment option for adults with well-compensated chronic hepatitis C. Further research into the optimal dosage of interferon-alpha-2a and its role in combination with other agents is likely to contribute towards future advances in the management of chronic hepatitis C.     

Interferon-α-2a

Synopsis

Interferons are intercellular signalling proteins which have antiviral, antitumour and immunomodulatory activities. Interferon-α-2a is a recombinant product which has antiproliferative effects on haemopoietic progenitor cells and haematological cell lines in vitro. These properties have led to its evaluation in the treatment of chronic myelogenous leukaemia (CML), a myeloproliferative disorder resulting from neoplastic transformation of a pluripotential haemopoietic stem cell and characterised by the presence of a chromosomal marker, the Philadelphia (Ph) chromosome, in the leukaemic cells. Clinical trials have demonstrated that interferon-α-2a (often given with or after cytoreductive chemotherapy), in common with other forms of interferon-α, can eliminate or reduce the proportion of Ph-positive cells in a number of patients with CML, as well as inducing haematological remission in the majority of cases. Higher rates of cytogenetic response were achieved in small groups of patients who had relapsed following allogeneic bone marrow transplant (BMT) and those who received low-dose cytarabine in combination with interferon-α-2a. Interferon-α-2a was superior to conventional chemotherapy [hydroxycarbamide (hydroxyurea) or busulfan] in a randomised multicentre study in 322 patients; it achieved a greater number of major cytogenetic responses (19 vs 1% of patients), a greater delay in disease progression and longer overall survival (median 72 vs 52 months). However, in another large comparative study interferon-α-2a or -2b was superior to busulfan, but not hydroxy carbamide, in prolonging survival. As with other types of interferon therapy, interferon-α-2a produces an acute influenza-like syndrome (fever, chills, myalgia, headache, arthralgia). Adverse effects during long term therapy include fatigue and anorexia (the most common events), and CNS disturbances. Serum neutralising antibodies to interferon-α-2a can usually be detected in around 20 to 25% of patients receiving the drug, but the clinical significance of this is unknown. Interferon-α therapy represents an important advance in the management of CML and is presently the only alternative to BMT (the preferred treatment option) for achieving long term complete cytogenetic remission and prolonging survival in this disease. Interferon-α-2a has been found to be effective in clinical trials and was superior to standard chemotherapy in one study. Although it appeared to be more effective than partially purified interferon-α, well-designed comparative studies are needed to demonstrate any differences in efficacy between different types of interferon-α. While only a small proportion of patients achieve long term cytogenetic remission with this agent and wider clinical experience is required, interferon-α-2a nevertheless can be considered a first-line therapy option in this disease, particularly in patients who cannot receive, or relapse following, BMT. Further research is also required to evaluate combination therapy with interferon-α and other agents.

Pharmacology

Interferon-α-2a is a recombinant interferon-α. These cytokines have direct antiproliferative effects on normal and chronic myelogenous leukaemia (CML) progenitor cells and haematological cell lines (CML, acute myelogenous leukaemia, Burkitt’s lymphoma, acute lymphocytic lymphoma, multiple myeloma) in vitro, and inhibit growth of experimental transplanted tumours in vivo. They also have immunomodulatory effects, including activation of monocytes and macrophages, induction of cell surface antigen expression, enhancement of natural killer cell and cytotoxic T-lymphocyte activity, and modulation of cytokine synthesis. Other effects include alteration of autonomic function and lipid metabolism. Postulated mechanisms for the apparent selective activity of interferon-α in CML include modulation of the bone marrow environment to allow restoration of normal control mechanisms and enhancement of immune recognition.

Therapeutic Use

Clinical trials have demonstrated that interferon-α-2a can eliminate or reduce the numbers of Philadelphia (Ph)-positive cells in a proportion of patients with CML, and induces haematological remission in the majority of cases, in common with other forms of interferon-α. In many studies, interferon-α-2a was administered with or following hydroxy carbamide (hydroxyurea) or, less commonly, busulfan. No studies have formally compared different interferon-a subtypes, but comparison with a historical control group suggested that interferon-α-2a produced cytogenetic response more rapidly, and in a higher proportion of patients, than partially purified interferon-α. In preliminary studies, higher rates of cytogenetic response were achieved in patients who had relapsed following allogeneic BMT and in patients who received interferon-α-2a in combination with cytarabine. Interferon-α-2a was compared with conventional chemotherapy (hydroxycarbamide or busulfan) in 2 randomised multicentre studies, in 322 and 513 Ph-positive patients with chronic phase CML. In the first study, interferon-α-2a ≥9 MU/day induced significantly more major cytogenetic responses (elimination of Ph-positive cells or a 67 to 99% decrease in the proportion of these cells) than conventional chemotherapy (19 vs 1% of patients on intent-to-treat analysis). It also produced a greater delay in disease progression (median >72 vs 45 months) and longer overall survival (median 72 vs 52 months). The second study included a higher proportion of high-risk patients and used a lower interferon dosage; interferon-α-2a (68% of patients) or 2b (32% of patients) 5 MU/m²/day produced a relatively low cytogenetic response rate (5% complete responses). It was significantly superior to busulfan but not hydroxycarbamide in terms of survival (5-year survival rates 59 vs 32 vs 44% of patients). Minimal residual disease (persistence of small numbers of Ph-positive cells) can be detected with more sensitive assay methods, such as polymerase chain reaction assay, in most patients who are shown to be in complete cytogenetic remission by conventional cytogenetic tests following interferon-α therapy. It is not clear whether this has any impact on survival.

Tolerability

As with other types of interferon-α, interferon-α-2a produces an influenza-like syndrome, consisting of fever, chills, myalgia, headache, arthralgia and sweating within 4 to 8 hours of administration, although tolerance to many of these effects tends to develop during long term therapy. Long term adverse effects of interferon-α therapy include fatigue and anorexia (the dose-limiting toxicities), CNS disorders, including changes in behaviour, cognition, mood, memory and personality, and disturbed lipid metabolism. Induction of autoimmune reactions, with possible exacerbation or induction of diseases associated with MHC class I or II antigens (e.g. psoriasis, systemic lupus erythematosus and autoimmune thyroid disease), has also been reported. A similar pattern of events has been reported with interferon-α-2a. Serum neutralising antibodies to interferon-α-2a can usually be detected in around 20 to 25% of patients receiving the drug, depending on route and duration of therapy, type of disease and assay technique, but their clinical significance is unknown. Preliminary data suggest that seroconversion may be more common in patients receiving interferon-α-2a than in those receiving interferon-α-2b or the lymphoblastoid interferon-α-Nl.

Dosage and Administration

The optimal dosage and duration of interferon-α-2a therapy for the treatment of CML is yet to be established, and depends on individual patient factors. The manufacturer’s recommended starting dosage in adults with CML is 3MU/day, given by subcutaneous or intramuscular injection, and escalated to 6 MU/day on day 4, and to 9 MU/day on day 7. This can be reduced to a 3 times weekly schedule once response has been achieved. The efficacy, tolerability and optimum dosage of interferon-α-2a in children has not been established. Contraindications to interferon-α-2a therapy include severe renal or hepatic dysfunction, epilepsy, impaired CNS function, severe pre-existing cardiac disease or history of cardiac illness, and recent or current treatment with immunosuppressive agents other than short term ‘steroid withdrawal’. Interferon-α-2a can induce effects on the CNS and may impair performance of certain tasks, such as driving and operating machinery, and may interact with centrally-acting drugs. Periodic neuropsychiatric and haematological monitoring is recommended during treatment. Interferon-α-2a may also potentiate neurotoxic, haematotoxic or cardiotoxic effects of previously or concurrently administered drugs and may affect oxidative metabolism of some drugs.     

白细胞间介素-2

1976年Morgan等报告,在致分裂原刺激的淋巴细胞培养上清(Condtional Me-dium,C M)中存在一种因子,能维持激活后T细胞在体外长期生长。该因子后被称为T细胞生长因子(T Cell GrowthFactor,TCGF)。除此之外,人们还报道CM中还存在其他活性,如对胸腺细胞的合作刺激作用;T细胞刺激因子等。1979年在第二次国际淋巴因子会议上,认为上述活性都是由T辅助细胞释放的一种因子介导的,为统一命名,提出了白细胞间介素-2     

宁夏枸杞根际土壤链霉菌Ⅱ-2-2-2的基因组测序和次级代谢产物分析

目的 分析链霉菌Ⅱ-2-2-2基因序列,挖掘潜在次级代谢能力生物合成基因簇。方法 采用IlluminaHiSeq+PacBio测序技术获得链霉菌Ⅱ-2-2-2的基因组草图序列,经antiSMASH(v6.0.1)平台分析次级代谢产物合成基因簇,采用高效液相色谱-四极杆-飞行时间质谱技术对发酵液进行网络化分析。结果 自宁夏枸杞须根附近的土壤中分离得到一株菌株Ⅱ-2-2-2,经鉴定其与缺乏研究的Streptomycesacrimycini CSSP430 16S rRNA基因序列的相似度达99.64%。其基因组草图序列4 409 970 bp,G+C含量占66.43%,3974个蛋白质编码基因,10个rRNA操纵子和72个tRNA。Anti SMASH分析基因序列至少包含5条次级代谢产物合成基因簇,可能编码线性含唑肽类、核糖体合成和翻译后修饰的肽、非核糖体肽、聚酮类和萜类化合物。获得82个正负模式的离子,并将二级碎片离子在全球天然产物交互分子网络平台进行聚类分析和数据库搜索,发现了24个化学结构。结论 链霉菌Ⅱ-2-2-2具有丰富的次级代谢能力并可能成为研究和开发新抗生素的重要资源。     

2-巯基乙醇及其生物学意义

2-巯基乙醇(2-ME)是一种硫醇类(thiols)的化合物.七十代初叶,Click等曾首次报告它在体外对淋巴样细胞的抗体合成作用.尔后,2-ME被广泛地用于免疫学等生物医学的研究中.近年来,各国学者的进一步研究证明,在离体细胞培养时,2-ME能够非特异性的刺激活化多克隆细胞,从而为生物学研究中体外细胞的培养,以及对抗体生成细胞活化作用等的研究提供了一种新而有用的模型及分子探针.因     

胰高血糖素样肽-2

胰高血糖素样肽GLP 1和GLP 2由小肠和大肠的内分泌细胞产生并分泌。GLP 2通过对胃的动力作用和营养吸收作用保持小肠粘膜上皮的完整 ,对小肠损伤修复等均有重要的调节作用 ,GLP 2在循环中二肽肽酶Ⅳ (DPIV)的作用下氨基末段迅速裂解失去活性 ,并通过肾脏清除。利用这些肽对营养吸收和能量平衡及在糖尿病动物模型和小肠疾病的作用 ,可供临床应用并治疗人类的疾病     

环氧合酶-2与肿瘤

环氧合酶 (COX)是一种膜结合蛋白 ,具有双重酶的功能 ,是 PGs(前列腺素类 )生物合成的限速酶。目前发现它有两个亚型 ,即 COX- 1和 COX- 2。近 4、5年来 ,欧美、日本等国科学家通过对 COX- 2的广泛研究 ,发现 COX- 2在肿瘤发生、发展、分化、转移及预后等方面可能有重要作用 ,并开发了 COX- 2特异性抑制剂应用于抗肿瘤研究 ,取得了初步成效。但国内在此方面尚未见文献报导 ,本篇就国外此项研究的现状进行综述 ,旨在使国人了解此项研究的进展 ,推动该项研究在国内的开展 ,为人类征服癌症 ,提供新的手段。     

人类环加氧酶-2的cDNA

作者通过RT-PCR和引物延伸PCR得到了全长的人类环加氧酶-2(hcox-2)的cDNA,所推测的hcox-2多肽氨基酸顺序与hcox-1蛋白的氨基酸顺序有61％同源,而与鸡、鼠cox-2基因所编码的多肽分别有81％和88％同源。作者又将hcox-1、hcox-2cDNA的 DRFs亚克隆在真核表达载体pcDNA中,所得到的相应mRNA在~(35)S-甲硫氨酸兔网织红细胞裂解物中进行翻译,合成了70kD的多肽。然后分别把hcox-1和hcox-2 cDNA转染到COS细胞中,它们都表达了环加氧酶活性。这些资料表明hcox-2cDNA能够产生有酶活性的环加氧酶。作者进一步     

环氧化酶-2及其研究进展

环氧化酶有两种同工酶,环氧化酶-2(COX-2)是受细胞内外相应刺激如细胞多糖、细胞因子作用合成的诱导型酶。COX-2在基因结构、表达调控、编码蛋白、定位分布上均与COX-1不完全相同。COX-2是炎症过程中一个重要的诱导酶,在肿瘤的形成与发展过程中也有一定作用。     

大鼠不同发育阶段β-防御素-2基因

目的:探讨大鼠β-防御素-2基因在肺组织表达的发育调控。方法:根据Genbank大鼠β-防御素-2的cDNA序列,设计一对特异引物。采用RT-PCR技术在大鼠不同发育阶段的肺组织总RNA中,扩增其特异cDNA片段,并进行DNA序列测定。借助Genbank中BLAST程序,将从该cDNA序列推导的氨基酸序列与人的hBD-2和大鼠的rBD-1做相似性分析。结果:从足月胎鼠、出生8h和4d以及成年大鼠相同重量肺组织所提取的总RNA中,均扩增出一条密度相同、长度约为220bp的cDNA片段。在所推导氨基酸序列中与hBD-2氨基酸相同率为48.6%(17/35),与rBD-1氨基酸残基的相同率为31%(11/35)。其成熟分子链长35个氨基酸残基,含β-防御素共有的且排列次序相同的6个典型的半胱氨酸和其它保守氨基酸残基。结论:本实验表明不同发育阶段大鼠肺组织均表达β-防御素-2mRNA,提示该分子可能是肺组织天然抵抗微生物感染的一个重要分子基础。     

环氧合酶-2研究的新进展

环氧合酶 2 (COX 2 )为一种诱导酶 ,在正常组织中很少表达 ,当细胞受到炎症等刺激时可高表达。COX 2的高表达除参与炎症、疼痛的调节外 ,还与肿瘤、老年性痴呆等疾病密切相关 ,同时 ,COX 2也与某些组织的正常生理功能有关。     

牛白细胞介素-2研究近况

分子生物学技术已经使我们能够获得大量纯的活性牛白细胞介素2(IL-2)。经分析其分子量约为15.5kd,但从淋巴细胞培养液中制备的牛IL-2分子量变化较大,这种异质性归于糖化程度的不同。低温条件或在溶液中加入BSA 可延长保存牛IL-2的活性,过高或过低的pH 环境、高浓度脲以及胰酶的处理都可降低或丧失牛IL-2活性。这些特性和人鼠IL-2相似。对重组牛IL-2产品分析表明由135个氨基酸组成,与人鼠IL-2的同源性为69%和50%,这些同源序列被其它序列所隔开。牛IL-2可以支持牛羊淋巴细胞但对人淋巴细胞的反应性较弱。然而绵羊、豚鼠和人IL-2都能维持牛淋巴细胞。     

白细胞介素-2可望治疗癌症

<正> 美国国立癌症研究所Rosenberg S于1985年12月5日在《新英格兰医学杂志》报道用基因重组白细胞介素-2(IL-2)临床治疗癌症病人的初步而有希望的结果,在报界等产生巨大反响,其盛况不亚于当年首次用基因重组技术生产干扰素。他给25例常规治疗无效的转移性癌症,施用过继免疫疗法和IL-2。取病人白细胞,在体外用IL-2处理,继将这类“淋巴因子激活的杀伤细胞”回输给病人。有11例病人的肿瘤消失     

聚乙二醇干扰素α-2a与干扰素α-2b治疗慢性丙型肝炎疗效分析

丙型肝炎病毒(HCV)感染可导致肝脏炎症坏死和纤维化,抗病毒治疗是丙型肝炎治疗的根本疗法。我们对慢性丙型肝炎(CHC)患者分别采用聚乙二醇干扰素α-2a(PEG-IFNα-2a)和干扰素α-2b(IFNα-2b)治疗,并对两种干扰素的临床疗效进行对比分析。1资料与方法1.1病例选择43例CHC患者为20     

环氧化酶-2与肿瘤研究进展

环氧化酶(Cyclooxygenase,COX)又称前列腺素合成酶(Prostag Landin Synthase。PG synthase)。是花生四烯酸(Arachidonic Acid，AA)合成各种内源性前列腺素(PGs)过程中的限速酶。其催化产生的PGs参与机体的多种生理及病理过程。如发热、炎症、出凝血机制等。目前已知COX至少具有两种亚型。即COX-1及COX-2。COX-1为结构型(Constitutive)。被认为是“看家基因”，在大多数正常细胞中呈稳定的表达。合成生理性PGs以维持胃粘膜完整性。     

白细胞介素-2受体蛋白

成熟T淋巴细胞对抗原刺激的增殖应答受淋巴因子白细胞介素-2(IL-2)的调控。由于受抗原的激活,辅助T细胞亚群产生IL-2,并诱导T细胞呈现特异性IL-2受体。激活的T细胞可表达对IL-2亲和力不相同的二类IL-2受体。约10％的受体为高亲和力[解离常数(Kd)～10pM],以介导T细胞对IL-2的生理应答,其余的受     

白细胞间介素-2的分子生物学

本文简述了白细胞间介素-2(IL-2)在分子水平的某些研究进展,如IL-2的来源、性质、互补DNA的克隆化和全部核苷酸顺序的分析,以及对IL-2多肽链一级结构氨基酸顺序的报导和cDNA在哺乳动物细胞中的表达。此外,还概略论述了IL-2的生物学作用及其分子作用机制。     

α_2-巨球蛋白与细胞免疫

α_2-巨球蛋白(Alpha-2-Macroglo-bulin,简称α_2M)是人体具有多种生物活性的糖蛋白。分子量725 000。沉降系数17～20S。血清中浓度随年龄和性别而异,波动在140～260mg/dl之间。在一定条件下     

环氧化酶-2与肺癌研究进展

环氧化酶 2在肺癌中有较高表达 ,并在肺癌的发生发展中起重要作用。环氧化酶 2可能通过促进血管的新生 ,打破机体的免疫平衡 ,参与肺癌的发生发展。