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排序方式: 共有2190条查询结果,搜索用时 15 毫秒
1.
Peter Chiba Barbara Tell Walter Jger Elisabeth Richter Manuela Hitzlera Gerhard Ecker 《Archiv der Pharmazie》1997,330(11):343-347
A series of 5-hydroxy and 5-benzyloxy analogs of the antiarrhythmic and multidrug resistance (MDR) modulating drug propafenone was synthesized and the MDR-modulating activity of the compounds was evaluated using a daunomycin efflux assay system. The key step of the synthesis is the selective reduction of the double bond in 1 without cleavage of the benzyl group thus leading to the phenol 3 . Alkylation with epichlorohydrine followed by nucleophilic epoxide ring opening gave the benzylated target compounds 5a–d . Subsequent cleavage of the benzyl group gave the 5-hydroxy analogs 6a–d . Structure activity relationship studies showed, that the 5-hydroxy derivates 6a–d fit the log P/log potency correlation line previously established for a series of propafenone analogs. In contrast, all four 5-benzyloxy analogs 5a–d showed almost identical EC50 values, independent of their log P value. 相似文献
2.
目的:研究肺癌放射导向手术中肿瘤及正常组织P糖蛋白(P-gp)、Ki-67抗原表达与放射性核素摄取比(T/NT)的关系.方法:采用免疫组化方法和显微图像分析技术,测定32例接受放射导向手术的肺癌病人P-gp和Ki-67抗原表达,分析P-gp和Ki-67的标记指数(LI)与T/NT之间的相关性.结果:P-gp和Ki-67的LI和肺癌病人T/NT之间均有相关性(r=-0.61,P=0.0002; r=0.75,P=0.0001).结论:Ki-67的LI越高(肿瘤增殖越旺盛),T/NT值越高;P-gp阳性的肿瘤,T/NT值较低. 相似文献
3.
Vera S. Donnenberg Gilbert J. Burckart Albert D. Donnenberg 《Clinical and Applied Immunology Reviews》2003,4(1):15-30
P-glycoprotein (P-gp), a member of the adenosine triphosphate (ATP)-binding cassette (ABC) family of transporter molecules, is responsible for maintaining low intracellular concentrations of a variety of extracellular compounds and xenobiotics, and for transport of various intracellular molecules. Many drugs are P-gp substrates and intracellular concentrations of these agents may be critical for drug action. Experience in oncology indicates that repeated exposure to P-gp substrate cytotoxic drugs leads to the selection of drug-resistant tumor cells that overexpress P-gp. Since immunosuppressive agents such as cyclosporine, tacrolimus, sirolimus and corticosteroids are substrates for P-gp and since T-cells also express P-gp, it is conceivable that an analogous mechanism exits for therapy-resistant graft rejection. As will be discussed in this article, P-gp may interfere with the response to immunosuppressive therapy through several distinct mechanisms, and as such may represent an attractive therapeutic target. 相似文献
4.
卵巢癌中蛋白激酶C的表达及其临床意义 总被引:2,自引:0,他引:2
目的 探讨上皮性卵巢癌组织蛋白激酶C (proteinkinaseC ,PKC)的表达和化疗耐药的关系 ,以及与P -糖蛋白 (P -gp)的相关性。方法 用免疫组化S -P法检测 35例卵巢上皮性肿瘤组织、 2 0例卵巢良性肿瘤组织和 2 0例正常卵巢组织中PKC和P -gp的表达 ,并进行相关临床因素分析。结果 ①PKC、P -gp在卵巢恶性肿瘤中的表达明显高于在良性及正常组织中的表达 ;并且PKC和P -gp的表达有相关性 (P <0 0 5 ) ;②卵巢癌PKC的表达与临床病理因素无直接关系 ;③恶性肿瘤中 ,初治和复发的PKC表达阳性率分别为 34 8%和 75 % ;④化疗对PKC表达阳性和阴性卵巢癌患者的有效率分别为 2 3 5 %、 6 6 7% (P <0 0 5 ) ;⑤PKC表达阴性患者的预后优于阳性者 (P =0 0 39)。结论 PKC表达与卵巢癌组织化疗耐药明显相关 ,可能在P -gp介导的卵巢癌多药耐药中起重要作用。 相似文献
5.
The volume-activated chloride current in human endothelial cells depends on intracellular ATP 总被引:6,自引:0,他引:6
Masahiro Oike Guy Droogmans Bernd Nilius 《Pflügers Archiv : European journal of physiology》1994,427(1-2):184-186
We have studied the effect of intracellular ATP on volume-activated Cl–-currents in endothelial cells from human umbilical veins by means of the whole-cell patch clamp technique. The run-down of this current in ruptured patches during repetitive applications of hypotonic solutions (HTS) could be significantly reduced if the cells were internally perfused with a pipette solution that contained 4 mmol/l ATP. This run-down was much less pronounced if currents were recorded using nystatin-perforated patches. The amplitude of the current was drastically reduced and its activation became slower if the cells were superfused with a glucose-free medium with 1 mmol/l KCN. Adding 4 mmol/l ATPS, a poorly hydrolyzable ATP-analogue, to the patch pipette prevented run-down of the current during repetitive activations by HTS, even if the cells were superfused with glucose-free solution with 1 mmol/l KCN. It is concluded that activation of the mechanosensitive Cl– conductance in human endothelial cells requires the presence of intracellular ATP, but not its hydrolysis. 相似文献
6.
Tsukamoto F Shiba E Taguchi T Sugimoto T Watanabe T Kim SJ Tanji Y Kimoto Y Izukura M Takai SI 《Breast cancer (Tokyo, Japan)》1997,4(4):259-263
Overexpression of P-glycoprotein (Pgp) in tumors is one of the major mechanisms which mediates the multidrug resistance (MDR)
phenotype. To evaluate the prognostic significance of Pgp in breast cancer, Pgp expression was examined in paraffin-embedded
tissue sections of 94 breast cancer specimens by immunohistochemistry. Tissue specimens were obtained by mastectomy without
preoperative chemotherapy. UIC2 monoclonal antibody which recognizes an extracellular epitope of human Pgp was employed. Of
the 94 breast cancer specimens, 35 (37.2%) were positive for Pgp expression. Pgp expression had no correlation with menopausal
or hormone receptor status, axillary lymph node involvement or tumor size. However, a significant correlation was observed
between Pgp expression and disease relapse (p = 0.0322). Pgp-positive patients showed a significantly shorter disease-free survival period than Pgp-negative patients by
the Kaplan-Meier method (p = 0.0433). These results suggest that immunohistochemical detection of Pgp in breast cancer tissue may have prognostic value
after radical operation. 相似文献
7.
Toru Watanabe Noriko Kokubu Steven B Charnick Mikihiko Naito Takashi Tsuruo Dalia Cohen 《British journal of pharmacology》1997,122(2):241-248
- P-glycoprotein, a 170–180 kDa membrane glycoprotein that mediates multidrug resistance, hydrolyses ATP to efflux a broad spectrum of hydrophobic agents. In this study, we analysed the effects of three MDR reversing agents, verapamil, cyclosporin A and [3′-keto-Bmt]-[Val*]-cyclosporin (PSC 833), on the adenosine triphosphatase (ATPase) activity of human P-glycoprotein.
- P-glycoprotein was immunoprecipitated with a monoclonal antibody (MRK-16) and the P-glycoprotein-MRK-16-Protein A-Sepharose complexes obtained were subjected to a coupled enzyme ATPase assay.
- While verapamil activated the ATPase, the cyclosporin derivatives inhibited both the substrate-stimulated and the basal P-glycoprotein ATPase. No significant difference was observed between PSC 833 and cyclosporin A on the inhibition of basal P-glycoprotein ATPase activity. PSC 833 was more potent than cyclosporin A for the substrate-stimulated activity.
- Kinetic analysis indicated a competitive inhibition of verapamil-stimulated ATPase by PSC 833.
- The binding of 8-azido-[α-32P]-ATP to P-glycoprotein was not altered by the cyclosporin derivatives, verapamil, vinblastine and doxorubicin, suggesting that the modulation by these agents of P-glycoprotein ATPase cannot be attributed to an effect on ATP binding to P-glycoprotein.
- The interaction of the cyclosporin derivatives with ATPase of P-glycoprotein might present an alternative and/or additional mechanism of action for the modulation of P-glycoprotein function.
8.
J. Arly Nelson Anuradha Dutt Luetta H. Allen David A. Wright 《Cancer chemotherapy and pharmacology》1995,37(1-2):187-189
The hypothesis that P-glycoprotein (P-gp) mediates the renal secretion of organic cations was tested by functional expression of mRNAs in theXenopus laevis oocyte system. Efflux of 2-deoxytubercidin (dTub), a substrate for the renal organic cation transporter (OCT) but not for P-gp, was enhanced by injection of renal mRNA but not by injection of mRNA from P-gp-overexpressing cells (MDCK cells transduced with the cDNA for humanMDR1). The functional capacity of the MDCK-MDR mRNA was established by its ability to reduce, the steady-state uptake of a classical P-gp substrate, vinblastine. Thus, these data indicate OCT and P-gp to be distinct entities. TheXenopus oocyte system provides a functional approach to further characterize the OCT.Work supported by NIH Grant RO1DK41606 from the Institute for Digestive Diseases and Kidney, and NIH Cancer Center Core Grant, CA 16672 from the National Cancer Institute 相似文献
9.
目的:探讨骨肉瘤保肢治疗中肿瘤大小、临床分期、手术方式、术前、术后化疗以及肿瘤多药耐药基因(mdr)表达产物P糖蛋白(P-170)对术后生存时间的影响。方法:统计分析近7年47例骨肉瘤保肢术患者的病理、临床资料及生存时间,并用链菌素生物素标记法(LSAB)免疫组织化学法回顾性检测肿瘤标本中P-170糖蛋白。结果:临床分期为ⅡB期患者1~5年生存率分别是974%,760%,463%,389%和340%;ⅡA期患者相应的生存率为100%,800%,800%,800%和800%;ⅠB期患者相应的生存率皆为100%;各临床分期间的生存率有统计学差异(P<01)。术前有化疗的患者1~5年生存率分别是975%,845%,674%,571%和530%;术前无化疗的患者相应的生存率分别为857%,429%和0%;两组生存率有统计学意义(P<001)。术后有化疗的患者1~5年生存率分别是971%,942%,727%,616%和572%;术后无化疗的患者相应的生存率分别是90%,200%和0%;差异有统计学意义(P<001)。P-糖蛋白阳性组1~5年生存率分别是974%,733%,471%,359%和307%;P-糖蛋白阴性组的相应值皆为100%,差异有统计学意义(P<001)。此外,在不同保肢术式中人工关节置换术患者1~5年生存率最高,分别是967%,930%,700%,631%和520%,差异有统计学意义(P<001)。结论:肿瘤临床分期、肿瘤大小、保肢术式、术前、术后化疗及P-17 相似文献
10.
P-Glycoprotein on astrocyte foot processes of unfixed isolated human brain capillaries 总被引:8,自引:0,他引:8
Sites of immunoreactive P-glycoprotein associated with human brain microvasculature were identified by labeling of unfixed isolated human brain capillaries, allowing visualization of the three-dimensional capillary structure by confocal microscopy. Capillaries isolated from human autopsy brain were dual-labeled with the MRK16 mouse monoclonal antibody (against human P-glycoprotein) and rabbit polyclonal antisera against the human brain microvascular glucose transporter (GLUT1), or glial fibrillary acidic protein (GFAP) on astrocyte foot processes. MRK16 and GLUT1 dual-labeling showed no signal overlap, identical to the staining pattern observed for dual-labeling with anti-GFAP and anti-GLUT1 antibodies: both GFAP and MRK16 labeling were discrete, discontinuous, and not co-localized with continuous GLUT1 labeling of capillary endothelium. In contrast, complete overlap of MRK16 and GFAP labeling demonstrated P-glycoprotein localization on astrocyte foot process remnants at the abluminal face of the brain microvasculature. 相似文献