天然植物活性成分通过下调P-糖蛋白逆转肿瘤多药耐药的研究进展

多药耐药（multidrug resistance, MDR）是临床上肿瘤患者复发及化疗失败的主要因素，其发生机制较为复杂，目前研究最为深入的机制之一为肿瘤细胞膜上P-糖蛋白（P-glycoprotein, P-gp）过表达所致。大多数化疗药物为P-gp的底物，肿瘤细胞会通过P-gp介导的主动转运将化疗药物转运到胞外，使细胞内有效药物浓度降低，从而产生耐药性，导致临床疗效下降。P-gp的逆转剂可通过下调P-gp表达和转运活性，减少化疗药物从胞内泵出，增强肿瘤细胞对化疗药物的敏感性，从而提高治疗效果。本文将对可逆转P-gp介导的MDR的天然植物活性成分及其调控机制进行总结，为临床及相关研究提供参考。     

使用化疗药物外渗的护理要点

化疗药物是对各种病原微生物、恶性肿瘤所致疾病的治疗药物,化疗药物作用在肿瘤细胞生长繁殖的不同环节上抑制或杀死肿瘤细胞从而达到治疗的目的。安全使用化疗药物,避免化疗药物外渗是使用化疗药物的重要护理措施。     

灰树花β多糖协同化疗药物抗肿瘤作用及其分子机理初探

目的探讨灰树花β多糖在抗肿瘤细胞中的作用和协同化疗药物增加其杀伤肿瘤细胞的作用。另外通过对p53和M DM 2的研究,发现了两者协同作用的分子机理。方法用CCK-8方法测定了灰树花β多糖协同化疗药物处理HCT 116后的细胞存活率(cell surv iva l rate,CSR);用PCR的方法测定了p53、M DM 2基因的表达。结果(1)灰树花β多糖对肿瘤细胞的直接杀伤作用高于灵芝多糖。(2)灰树花β多糖协同化疗药物增强其对肿瘤细胞的杀伤作用。(3)灰树花β多糖协同化疗药物的分子机理和抑制抑癌基因p53的拮抗物M DM 2基因的表达相关。结论灰树花β多糖具有直接杀伤肿瘤作用和化学药物协同抗肿瘤作用。     

以bcl—2基因为靶标的反义治疗克服肿瘤化疗耐药

化疗耐药是肿瘤治疗中的难题,研究耐药机制和寻求克服途径成为当今肿瘤防治的重点。ｂｃｌ－２是一个重要的细胞凋亡抑制基因,在许多肿瘤上超量表达。临床和分子生物学证明,ｂｃｌ－２超量表达与化疗耐药有关。应用反度药物抑制ｂｃｌ－２基因表达,肿瘤细胞能恢复对化疗药物治疗的敏感性。ｂｃｌ－２反义药物与传统化疗药物协同使用有望成为解决肿瘤化疗耐药的新突破口。     

肿瘤多药耐药及其逆转研究现状

所谓多药耐药是指肿瘤细胞接触一种化疗药物后 ,不但对该药产生耐药性 ,而且对其他结构和作用机制不同的多种药物产生耐药性 ,即有交叉耐药性。多药耐药主要有两种类型 :(1)内在性多药耐药 :是指肿瘤细胞固有的对化疗药物不敏感 ;(2)获得性多药耐药 :是指肿瘤开始对化疗药物敏感 ,但经过几个疗程化疗后 ,肿瘤细胞不仅对该药产生耐药 ,而且对结构和作用机理不同的药物也产生耐药。1肿瘤的多药耐药机制1.1转运蛋白的过度表达 :(1)P-糖蛋白 (Permeability- glyco protein,P- gp,P170)是由MDR-1基因编码的 ,分子量为170KD的跨膜糖蛋白 (故又…     

中药逆转卵巢癌多药耐药的研究进展

多药耐药（muhidrug resistance，MDR）指肿瘤细胞对一种抗肿瘤药产生耐药性后，对结构与作用机制不同的抗肿瘤药产生交叉耐药的现象。这种现象可以是先天的，也可以是化疗诱导产生的。目前认为其共同的生物学基础是MDR1基因产物P2糖蛋白（P2gP）过量表达，与肿瘤内药物结合或直接从细胞膜上排除抗肿瘤药物，从而降低药物对肿瘤细胞的毒性所致。MDR是目前化疗的主要障碍，是肿瘤细胞产生耐药的重要原因。     

某些抗肿瘤药物的多药耐药性机制

肿瘤细胞的多药耐药性(MDR)是阻碍化疗药物达到理想治疗效果的主要原因之一。本文通过分析所选化疗药物产生MDR的机制表明，糖蛋白的表达、谷胱甘肽作用的改变、拓扑异构酶Ⅰ和Ⅱ表达的降低均与产生MDR有关。文章同时还介绍了化疗增敏剂的应用现状、副作用及今后相关领域的研究重点等问题。     

宫颈癌Hela多药耐药细胞株的建立

宫颈癌是女性常见恶性肿瘤之一,目前治疗方案以手术和放化疗为主。肿瘤细胞对化疗药物产生的多药耐药是肿瘤化疗失败的主要原因。所谓肿瘤多药耐药(MDR)是指肿瘤细胞长期接触了1种化疗药物后,不仅对该药物     

肿瘤多药耐药逆转剂Tariquidar的开发

目前化疗失败的主要原因是肿瘤细胞产生了对化疗药物的多药耐药性,因而开发抗肿瘤细胞多药耐药性的药物成为化疗的辅助治疗手段。本文就英国Xenova生物公司研制的此类药物Tariquidar的情况作简单介绍。     

荧光法评价单个肿瘤细胞的多药耐药性

Pgp是人多药耐药基因(MDR1)编码的分子量为170ku的膜糖蛋白,通过阻止药物在细胞内蓄积达到细胞毒作用水平而介导肿瘤细胞产生耐药。Pgp表达增高是肿瘤细胞对化疗药物天然耐药和获得性耐药的重要机理之一。ATP驱动的药物外排泵的底物包括一些内源性分子,如激素和许多结构不...     

Effect of cell differentiation and passage number on the expression of efflux proteins in wild type and vinblastine-induced Caco-2 cell lines.

The mRNA level expression of MDR1, MRP1-6, BCRP and CYP3A4 was determined by quantitative PCR in wild type (Caco-2WT) and vinblastine-treated (Caco-2VBL) Caco-2 cells at different passage levels (32-53). Differentiation increased the mRNA levels of MDR1, BCRP and all the MRPs except MRP4. Corresponding mRNA levels were observed in Caco-2WT and Caco-2VBL, except that the expression of MRD1 was higher in Caco-2VBL than in Caco-2WT cells. CYP3A4 was barely detected in either cell line. MDR1 functionality was studied using rhodamine123 and verapamil as a substrate-inhibitor pair. Corresponding to the observed differences in mRNA levels, MDR1 activity was higher in the Caco-2VBL cells. In Caco-2WT, MDR1 functionality was elevated at low passage numbers (32-35) compared to higher ones (49-53). Verapamil inhibited MDR1 efflux except at higher passage Caco-2WT cells, where no MDR1 activity could be observed. The results support the use of Caco-2VBL cells in MDR1 screening. The functional expression is higher than in Caco-2WT and remains consistent across the studied passages without major differences in mRNA levels of other efflux proteins. As both the passage number and the level of cell differentiation affect the expression profile of efflux proteins, short-term cell growth protocols should be evaluated accordingly.     

Overexpression of glutathione S-transferase A1-1 in ECV 304 cells protects against busulfan mediated G2-arrest and induces tissue factor expression

1. The antineoplastic drug busulfan is frequently used in preconditioning regimens for bone marrow transplantation. Pharmacokinetics vary tremendously between patients due to extensive metabolism in the liver via conjugation to glutathione catalysed by glutathione S-transferase (GST) A1-1. Since elevated busulfan plasma levels have been reported to be a risk factor for developing veno-occlusive disease (VOD), metabolism of busulfan may play a pivotal role in the induction of VOD. 2. Therefore, we developed a cell model to investigate the influence of busulfan metabolism on its biological effects. GSTA1-1 cDNA was transfected into the cell line ECV 304 and protein expression was demonstrated by Western blotting. Enzymatic activity could be detected by formation of tetrahydrothiophene. Additionally, effects of busulfan treatment on cell cycle and expression of tissue factor have been investigated. 3. A busulfan-induced G2-arrest was reduced in GSTA1-1-transfected cells, which consequently displayed a significantly higher activity of cdc2 kinase (24.1+/-1.5 AU mg(-1) protein) after busulfan treatment compared to controls (14.7+/-2.3 AU mg(-1) protein; P<0.01). Elevated basal expression of tissue factor in GSTA1-1-transfected ECV 304 cells could be 4 fold increased by busulfan treatment. 4. These data demonstrate that ECV 304 cells transfected with GSTA1-1 provide a valuable tool to assess busulfan metabolism in vitro. Furthermore, overexpression of GSTA1-1 leads to a partial protection against cell cycle effects of busulfan and affects tissue factor expression.     

Interactions between drugs and sulforaphane modulate the drug metabolism enzymatic system

BackgroundSulforaphane (SFN) is a potent chemopreventive agent, which is widely consumed in diet or as a diet supplement. It modulates the enzymes of II and III metabolism phase. In this paper, the influence of SFN and three commonly consumed drugs: furosemide, verapamil and ketoprofen on II and III metabolisms phase enzymes was studied. We have also investigated if the interactions between SFN and the drugs occur resulting in enzymatic system disturbances.MethodsThe Caco-2 cells were incubated with SFN and drugs separately or in a mixture simultaneously or subsequently. The impact of the compounds on the cell viability and NADPH:quinine reductase (QR) activity was determined. The expression of glutathione-S-transferase (GST) isoenzymes GSTA3, GSTM1, P-glycoprotein (PgP) and multidrug resistance protein 1 (MRP1) genes was measured by qPCR method. Since these enzymes are regulated by Nrf2 pathway, the localization of Nrf2 (Nuclear erythroid 2-related factor) after exposure to the mixtures of SFN and the drugs was evaluated by confocal microscopy.ResultsSFN was shown to interact antagonistically with the studied drugs. At most cases an increase in enzymatic activity and expression was observed. The most significant changes were observed in case of enzymes regulated by Nrf2: QR, GSTA1 and GSTA3 and also MRP1. PgP was shown to be not altered by the studied compounds.CocnclusionThe interaction between SFN and furosemide, verapamil and ketoprofen modify the activity of enzymatic system involved in drug metabolism and transport. This may lead to drug effectiveness alteration and also to multidrug resistance (MDR) development.