大剂量三苯氧胺在肿瘤领域中的应用

三苯氧胺（TAM）是一种非甾体类抗雌激素药物，适用于各期乳腺癌的内分泌治疗。近年来随着对TAM实验与临床的深入研究，发现大剂量的三苯氧胺（简称HD-TAM）在组织中的浓度为血清中的10～60倍，浓度最高的组织为肝和肺，此外在胰腺、胰腺肿瘤、乳腺癌及其转移组织中的浓度也较高。     

三苯氧胺的雌激素效应

三苯氧胺的雌激素效应上海医科大学妇产科医院张绍芬，黄敏丽三苯氧胺（ＴＡＭ），经典理论认为是一种雌激素拮抗剂。自１９６７年以来，由于其副作用小及患者耐受性好而广泛应用于治疗乳腺癌、子宫内膜癌及子宫内膜异位症。但近年来，有关ＴＡＭ的致癌作用及诱发子宫内膜...     

三苯氧胺对MCF-7人乳腺癌细胞系周期动力学影响

本实验观察了三苯氧胺对雌激素受体阳性MCF-7人乳腺癌细胞系指数生长期影响,同时,应用流式细胞计(Flow Cytometry FCM)分析了三苯氧胺对细胞周期动力学作用。结果表明,三苯氧胺对MCF-7细胞生长具有显著抑制作用。其主要抑制机理为阻止细胞自G~0/G~1期向S期转化。三苯氧胺对MCF-7细胞的这种作用具有时间及剂量的依赖性。     

三苯氧胺治疗乳腺癌30例临床分析

目的观察乳腺癌患者术后服用三苯氧胺后发生的不良反应.方法30例乳腺癌患者术后服用三苯氧胺(TAM)3～5年,随访5年,记录服药过程中的不良反应.结果发生子宫内膜癌2例,卵巢囊肿1例,18例月经量减少,周期紊乱,1例原子宫肌瘤明显缩小.结论乳腺癌患者术后服用三苯氧胺每日20mg,服用时间2年,宜与孕激素合用,服药期间应进行子宫内膜B超监测及宫腔镜检查.     

三苯氧胺预防乳腺癌可能弊大于利

在英国出现有关三苯氧胺(Tamoxifen)能大幅度地增高子宫内膜癌和某些心血管疾病危险性的新报道之后,两家主要的慈善机构极力主张妇女不要退出检验三苯氧胺对乳腺癌作用的试验。这种恐惧与乳腺癌已超过肺癌(英国最常见的疾病类型)的消息是同时出现的。美国一项大规模的有关三苯氧胺的保护性作用研究,即乳腺癌预防试验(BCPT-P-1),在1998年被提前停止了,因为研究显示,尽管三苯氧胺可使发生乳腺癌的高危险性机会降低49％,但它能引起健康妇女发生乳腺癌。此外,该报道还断定,这种治疗具有增高患子宫内膜癌危险性的可能性,该     

依西美坦替代三苯氧胺能提高无疾病生存率

2004-03-11发表于新英格兰医学杂志的一项国际性Ⅲ期多中心随机对照研究表明绝经后激素受体阳性的早期乳腺癌患者应用2年三苯氧胺后转为口服依西美坦,其局部复发和远处转移的机率会下降32%(NEnglJMed,2004,350:1081-1092)。这项研究由国际乳腺协作组发起,涉及全世界37个国家20个协作组4742名乳腺癌术后患者。入组标准为病理证实为乳腺癌,肿瘤已完全切除的激素受体阳性的绝经后妇女,已口服三苯氧胺2年不超过3年。乳腺癌患者随机分为两组,1组2362人转为口服依西美坦25mg/d,另1组2380人继续口服三苯氧胺20mg/d,两组患者治疗总时间均为5年。平…     

三苯氧胺对二甲基苯蒽诱发的大鼠乳腺癌的影响

应用ＤＭＢＡ诱发的雌性ＳＤ大鼠乳腺癌模型，初步探讨了大鼠乳腺受致癌剂作用后，三苯氧胺对乳腺癌发生的影响。结果显示：三苯氧胺使恶性肿瘤出现的平均潜伏期明显延长，恶性肿瘤的发生率明显降低。     

耐三苯氧胺大鼠乳腺癌细胞株的生物学特性

目的：建立耐ＴＡＭ的大鼠乳腺癌细胞株，有助于阐明其耐药性机制。方法：应用改良的Ｈｕｇ双层琼脂方法，对ＳＨＺ－８８细胞进行克隆培养，筛选出耐受ＴＡＭ的大鼠乳腺癌细胞。结果：该细胞株对ＴＡＭ的敏感性比原代细胞降低１０倍，但对Ｅ２的反应性无改变。结论：该细胞株的建立有助于研究耐药乳腺癌细胞的生物学行为，并可用于筛选抗耐药乳腺癌药物。     

腺性膀胱炎组织中MAPK信号传导作用的相关研究

目的:研究腺性膀胱炎病变中促分裂原活化蛋白激酶(MAPK)p42/44和p38的含量水平,探讨其可能的发生机制。方法:应用Westernblot法检测腺性膀胱炎、膀胱普通炎症、膀胱移行细胞癌和正常膀胱组织中p42/44和p38MAPK的含量,并进行比较分析。结果:腺性膀胱炎与膀胱癌组织中p42/44的水平显著高于正常膀胱组织(P<0.01),膀胱普通炎性组织p42/44蛋白水平只轻度增高,但其组织p38水平最高(P<0.01)。膀胱癌组织的p38最低,与腺性膀胱炎比较有显著性差异(P<0.05),与正常膀胱组织比较无差异。结论:腺性膀胱炎的p42/44和p38MAPK信号传导通路不同的激活或抑制可能是细胞增殖、转化和恶性变的重要机制。     

哺乳动物的促分裂原活化蛋白激酶信号途径

促分裂原活化蛋白激酶(MAPK)是一类表达于所有真核细胞的丝氨酸／苏氨酸激酶，能够被诸如细胞因子、生长因子、神经递质、激素、细胞应急以及细胞粘附等各种刺激因素激活。MAPK途径的基本组合包括MAPK、MAPK激酶(MKK)和MAPK激酶激酶(MKKK)三种保守的成分，由此建立一个连续的激活途径。哺乳动物的MAPK可以大致归纳为5类：ERK1／2(MAPK^erkl/2)、P38(MAPK^p38)、JNK(MAPK^jnk)、ERK3／4(MAPK^erk34)和ERK5(MAPK^erk5)。MAPK家族在各种细胞活动中具有重要作用，如增殖、分化、发育、转化及凋亡等。文章讨论了哺乳动物MAPK的功能和调节。     

MAPK反义寡核苷酸对K562细胞系的增殖抑制作用

目的 :探讨MAPK在慢性髓细胞白血病 (CML)信号转导中的作用及其作用机制 .方法 :用脂质体转染法将MAPKASO导入K5 6 2细胞中 ,通过集落形成、DNA合成、蛋白质含量和MAPK活性的变化检测MAPKASO对K5 6 2细胞的作用 .结果 :MAPKASO可明显抑制细胞集落形成、DNA合成、蛋白质含量和MAPK活性 ,其抑制率分别为 4 6 .1% ,5 7.1% ,4 3.2 %和 6 2 .0 % ,与对照组比较有显著差异 (P <0 .0 5 ) .结论 :MAPK在CML信号转导中起重要作用 ,极有可能成为CML治疗的新靶点     

Effect of cigarette smoke extract on lipopolysaccha- ride-activated mitogen-activated protein kinase signal transduction pathway in cultured cells

Background  Lipopolysaccharide (LPS) forms outer membrane of the wall of Gram-negative cells. LPS can directly cause damage to epithelia of respiratory tract and is the major factor responsible for the chronic inflammation of respiratory passage. The mitogen-activated protein kinase (MAPK) signal transduction pathway of the airway epithelia is intimately associated with the action of LPS. The chronic inflammation of respiratory tract and smoking are interrelated and entwined in the development and progression of chronic lung diseases. This study was designed to examine the effects of cigarette smoke extract (CSE) and LPS on MAPK signal transduction pathway in order to further understand the roles CSE and LPS play in chronic lung inflammation.
Methods  Cultured primary human epithelial cells of airway were divided into four groups according to the stimulants used: blank control group, LPS-stimulation group, CSE-stimulation group and CSE plus LPS group. Western blotting was employed for the detection of phosphorylation level of extracellular-signal-regulated-kinase (ERK_1/2), p38 MAPK and c-Jun N-terminal kinase (JNK). The expression of cytokines of MAPK transduction pathway (granulocyte-macrophage colony stimulating factor (GM-CSF) and mRNA of IL-8) in the primary epithelial cells of respiratory tract was also determined.
Results  Western blotting revealed that the phosphorylation levels of ERK_1/2, p38 MAPK and JNK were low and 2 hours after the LPS stimulation, the phosphorylation of ERK_1/2, p38 MAPK and JNK were all increased. There was a significant difference in the phosphorylation between the LPS-stimulation group and blank control group (P<0.05); no significant difference was found between CSE-stimulation group and blank control group (P>0.05); there was a significant difference between CSE + LPS group and blank control group and between CSE + LPS group and LPS group (P<0.05). The phosphorylation of CSE-LPS group was higher than that of blank control group but lower than that of LPS group. In blank control group, the expression of IL-8 and GM-CSF mRNA was low in the epithelial cells of airway and the release of IL-8 and GM-CSF was also at a low level. One hour after LPS stimulation, the level of IL-8 mRNA increased (P<0.05) and reached a peak after 2 hours. On the other hand, GM-CSF mRNA level increased 2 hours after the stimulation (P<0.05) and reached the highest level 4 hours after the stimulation. Two hours after LPS stimulation, IL-8 and GM-CSF protein level began to rise (P<0.05), and the level was the highest 8 hours after the stimulation (P<0.01). Stimulation with CSE alone had no effect on the release of IL-8 and GM-CSF and expression of IL-8 mRNA (P>0.05), but pre-treatment with CSE could delay the LPS-induced release of IL-8 and GM-CSF and the expression of IL-8 mRNA and its peak was lower.
Conclusions  LPS stimulation can significantly increase the phosphorylation of ERK_1/2, p38 MAPK and JNK in the epithelial cells of airway and activate the MAPK transduction pathway, thereby can activate the downstream signal transduction pathway, and can ultimately result in the release of cytokines by the epithelial cells of airway. CSE can partially abolish the LPS-induced activation of MAPK signal transduction pathway and the expression of cytokines of the pathway, which might contribute to the development and progression of the inflammatory reactions in COPD patients.

     

Involvement of the p38 mitogen-activated protein kinase signal transduction pathway in burns-induced lung injury

Acute lung injury (ALl) is a leading complicationin extensively burned patients, especially those with inhalation injury. It can cause hypoxia resulting in injury of remote organs and dysfunction.     

MAPKs在细菌所致细胞凋亡中的作用

MAPK家族是与细胞生长、分化、凋亡等密切相关的信号转导途径中的关键物质，它在介导细胞凋亡过程中起着重要的作用。近年研究发现MAPK途径在调控细菌诱导细胞凋亡的过程中发挥了极为重要的作用。探讨细菌诱导细胞凋亡的发生发展过程与MAPK信号途径中各成员间的关系，有助于从分子水平上更好地阐明病原微生物的致病机制，可能为开发新型抗感染药物提供新的靶点。     

Modulating protein kinase D1 signal transduction

Protein kinase C （PKC） consists of a family of serine/threonine kinases that are identified by the presence of two copies of the C1 domain, which form the diacylglycerol （DAG）-binding module. According to their enzymatic activities PKCs are sub-divided into conventional isozymes （PKCα, β and γ; calcium, phospholipid and DAG-activated kinases）, novel isozymes （PKCδ, ε, η, μ and θ; calcium-insensitive, phospholipid-dependent and DAG-dependent）, and atypical isozymes （PKCζ and λ; calcium-insensitive and DAG-insensitive enzymes）. Human protein kinase Cμ and its mouse homolog, protein kinase D1 （PKD1）, which has been under intense investigation in recent years, is a DAG-dependent, Ca^2＋-independent serine/threonine protein kinase as a novel PKC isoform. Recently PKDs were classified as a novel subgroup of the calcium/calmodulin-dependent protein kinase （CAMK） family, based on sequence similarities of the kinase domain; the catal~ctic domain of PKD1 has the highest homology to CAMK. PKD1 has three main pathways for activation. One is DAG-phospholipase C （PLC）-PKC-dependent activation of PKD1. In this model, PKD 1 not only acts as a direct DAG target but also lies downstream of PKCs to regulate biological processes in cells.     

磷酸化p38 MAPK在皮肤鳞状细胞癌中的表达及意义

目的探讨磷酸化p38丝裂原活化蛋白激酶（p-p38 MAPK）在皮肤鳞状细胞癌（SCC）中的表达及意义。方法采用免疫组化SP法检测60例皮肤SCC中p-p38 MAPK的表达。结果p-p38 MAPK的表达主要定位于胞核,在皮肤SCC的阳性表达率明显高于正常皮肤。p-p38 MAPK的表达与年龄、性别无关,与病理分级、肿瘤大小、淋巴结转移有关。结论p38丝裂原活化蛋白激酶的过表达可能与皮肤SCC的发生发展有关。     

蛋白激酶C对肥大细胞活化信号转导的影响

目的 :观察蛋白激酶 C (PKC)对肥大细胞 RBL - 2 H 3活化时酪氨酸磷酸化及 c- fos和 c- jun表达等信号转导的影响。方法 :采用流式细胞术和酶联免疫吸附试验测定活化的 RBL - 2 H 3细胞在佛波酯 (PMA)作用后 ,酪氨酸磷酸化和组胺浓度的改变 ;用 RT- PCR观察 PKC对 RBL - 2 H3细胞 c- fos和 c- jun基因 m RNA表达的影响。结果 :致敏 RBL - 2 H3细胞 ,在 PMA作用 48h后 ,抗原活化时磷酸化酪氨酸的平均荧光强度和组胺浓度分别为 (2 .79± 0 .0 7) %和 (6 0 .75± 1.38) nm ol/L ,都明显低于对照组的 (4 .47± 0 .0 3) %和 (10 4.47± 1.31) nm ol/L (P<0 .0 5 ) ;c- fos和 c- jun m RNA的表达量分别减少 91%和 82 %。结论 :PKC的活化可调节肥大细胞酪氨酸蛋白激酶活性 ,上调 c- fos和 c- jun m RNA的表达     

p38蛋白激酶不同亚型在RAW264.7细胞中的定位

目的 探讨p38的4种亚型在细胞中的分布以及对外界刺激的反应。方法 应用激光共聚焦显微镜对RAW264.7单核细胞内的4种亚型进行定位观察。结果 p38(、p38(在未受刺激的静息细胞内的荧光强度呈弥散性分布,受脂多糖（LPS）刺激后,细胞核荧光强度明显增强,细胞浆荧光强度降低,提示LPS诱导p38(和p38(磷酸化活化后移位入细胞核。p38(在静息和受LPS刺激后的细胞中均呈散在、弥漫性地分布,提示p38(刺激后无移位现象。静息时,p38(弥散地分布于细胞,刺激后细胞核膜部荧光强度增高,提示受刺激后p38(移位于核膜周围。结论 p38不同亚型在细胞受LPS刺激后移位表现不同,可能与它们在组织和细胞分布的特异性及作用途径有关。