Introduction: The occurrence of pregnancy in women is a risky situation. Prenatal care is necessary, which is not often the case in our context. Aim: To analyze the influence of antenatal surveillance on maternal and ...Introduction: The occurrence of pregnancy in women is a risky situation. Prenatal care is necessary, which is not often the case in our context. Aim: To analyze the influence of antenatal surveillance on maternal and perinatal prognosis. Patients and Method: Preliminary longitudinal and analytical survey at the Owendo University Hospital (OHU) over 6 months. It focused on prenatal surveillance. The study population consisted of parturients who gave birth within 24 hours and we studied sociodemographic characteristics, variables related to antenatal contact, those of delivery as well as maternal and newborn outcomes. Results: 2485 deliveries were recorded and 1300 patients were retained according to the inclusion criteria. No prenatal contact (ANC0) was performed in 93 (7.15%), insufficient (ANCI) in 943 patients (72.5%), and sufficient (ANCS) in 264 patients (20.30%). Patients with low school level were significantly found when the NPC was not performed or insufficient and the same was true for the group of patients who were not employed and those who were single (p < 0.005). The caesarean section rate and perinatal mortality are high in this case. Conclusion: The quality of prenatal contact is insufficient in our context. The absence or inadequacy of the latter has a strong negative impact on maternal and perinatal morbidity and mortality.展开更多
The purpose of this paper is to investigate the reversal effect of small interfering RNA (siRNA) targeting MDRI and MDR3 genes on the resistance of MCF-7/ADR cells to adriamycin. siRNA plasmid vector targeting MDRI ...The purpose of this paper is to investigate the reversal effect of small interfering RNA (siRNA) targeting MDRI and MDR3 genes on the resistance of MCF-7/ADR cells to adriamycin. siRNA plasmid vector targeting MDRI and MDR3 genes was transfected into MCF-7/ADR cells, and then was stained with Annexin-V FITC (fluorescein isothiocyanate conjugated) to detect the early stage cell apoptosis by flow cytometry (FCM). 50 % inhibition concentration (IC50) of adriamycin for MCF-7/ADR cells was determined by MTT method. MDRI and MDR3 mRNA was assessed by RT-PCR. Treatment of MCF-7/ADR cells with the two kinds of siRNAs resulted in a reversal of adriamycin resistance of MDR to different extents. 1) The apoptosis efficiency of MDRI and MDR3 siRNA vector after transfection was (18.21 ± 1.65) % and (9.07±2.16) % respectively (P〈0.05), and there was significant differences in the apoptosis efficiency between pSuppressor Neo vector and the MDRIsiRNA or MDR3 siRNA vector (P〈0.01); 2) The reversal effect of MDRIsiRNAis higher than that of MDR3 siRNA (P〈0.05); 3 ) The expression of MDRI and MDR3 mRNA can be restrained by pSuppressor Neo MDRI and MDR3 siRNA respectively, and the reduction in the mRNA level was in a time-dependent manner (P〈0.01). MDRI and MDR3 gene silencing can enhance intracellular adriamycin accumulation in MCF-7/ADR cells, improve sensitivity of MCF-7/ADR cells to adriamycin, and induce cell apoptosis. The reversal effect of adriamycin resistance by siRNA of MDR1 was more effective than that of MDR3.展开更多
Objective: Overexpression of mdr-1 gene is associated with multidrug resistance (MDR) and aggressive characteristics of malignance. Our purposewas to detect the levels of P-gp expression in fresh untreated esophageal ...Objective: Overexpression of mdr-1 gene is associated with multidrug resistance (MDR) and aggressive characteristics of malignance. Our purposewas to detect the levels of P-gp expression in fresh untreated esophageal carcinomas, and to correlate these levels to current prognostic indicators of morphology.Methods: Reverse transcription polymerase chain reaction (RT-PCR) was used to investigate mdr-1 gene expression of 46 samples from untreated esophageal carcinoma, and compared the positive incidences among differentiated grades, TNM stages and macroscopic types.Results: All 46 samples were pathologically squamous cell carcinoma. The positive' incidences of mdr-1 gene expression were 37% (17/46) in whole group,35% (6/17), 40% (8/20), 33% (3/9), for Ⅰ,Ⅱ and Ⅲdifferentiated grades, respectively. The expression rates of 33% (6/18), 40% (5/12), and 37% (6/16), were found in Ⅱa, Ⅱ, and Ⅲ stage of TNM, respectively. In macroscopic type view, the positive incidence was 37%(3/8) in constrictive, 33% (5/15) in fungating, 40% (6/14)in marrowlike, 33% (319) in ulcerative type. There were no statistically significant differences among each category system of morphology.Conclusion: The result, high level expression of mdr-1 gene in untreated esophageal carcinoma, suggested the poor efficacy of chemotherapy for some esophageal carcinoma patients. And we should cautiously choose cases who will receive chemotherapy. Surgery is still the best treatment for carcinoma of esophagus. Besides, the data also revealed that the expression of mdr-1 gene in untreated esophageal cancer was independent of morphologic prognostic indexes, and that there were no correlation between mdr-1 gene expression and morphological indexes.展开更多
To explore the reversal effect of mifepristone on multidrug resistance (MDR) in drug-resistant human breast cancer cell line MCF7/ADR and its mechanisms. Methods: Expression of MDR1 and MDR-associated protein(MRP) mRN...To explore the reversal effect of mifepristone on multidrug resistance (MDR) in drug-resistant human breast cancer cell line MCF7/ADR and its mechanisms. Methods: Expression of MDR1 and MDR-associated protein(MRP) mRNA in MCF7/ADR cells was detected using reverse transcription- polymerase chain reaction(RT-PCR). Western blotting was used to assay the protein levels of P-glycoprotein (P-gp) and MRP. Intracellular rhodamine 123 retention and [3H]vincristine (VCR) accumulation were measured by flow cytometry and liquid scintillation counter, respectively. MTT reduction assay was used to determine the sensitivity of cells to the anticancer agent, adriamycin (ADR). Additionally, a MCF7/ADR cell xenograft model was established to assess the reversal effect of mifeprisone on MDR in MCF7/ADR cells in vivo. Results: Miferpristone dose-dependently down- regulated the expression of MDR1 and MRP mRNA in MCF7/ADR cells, accompanied by a significant decrease in the protein levels of P-gp and MRP. After exposure to 5, 10, and 20 mmol/L mifepristone, MCF7/ADR cells showed a 3.87-, 5.81-, and 7.40-fold increase in the accumulation of intracellular VCR(a known substrate of MRP), and a 2.14-, 4.39-, and 5.53-fold increase in the retention of intracellular rhodamine 123(an indicator of P-gp function), respectively. MTT analysis showed that the sensitivity of MCF7/ADR cells to ADR was enhanced by 7.23-, 13.62-, and 20.96-fold after incubation with mifepristone as above-mentioned doses for 96 h. In vivo, mifepristone effectively restored the chemosensitivity of MCF7/ADR cells to ADR. After 8 weeks of administration with ADR(2 mg穔g-1穌-1) alone or in combination with mifepristone(50 mg穔g-1穌-1), the growth inhibitory rate of xenografted tumors in nude mice was 8.08% and 37.25%, respectively. Conclusion: Mifepristone exerts potent reversal effects on MDR in MCF7/ADR cells in vitro and in vivo through down- regulation of MDR1/P-gp and MRP expression and inhibition of P-gp- and MRP-dependent drug efflux, thus increasing the sensitivity to anticancer drug.展开更多
AIM: To investigate the effect of bromocriptine (BCT) and tumor necrosis factor-α (TNF-α) on hepatocellular carcinoma (HCC) multidrug resistance (MDR) in nude mouse MDR model of liver neoplasm.METHODS: Human hepatoc...AIM: To investigate the effect of bromocriptine (BCT) and tumor necrosis factor-α (TNF-α) on hepatocellular carcinoma (HCC) multidrug resistance (MDR) in nude mouse MDR model of liver neoplasm.METHODS: Human hepatocarcinoma cell line HepG2, drug resistant hepatocarcinoma cell line HepG2/adriamycin (ADM) and hepatocarcinoma cell line transfected with TNF-α gene HepG2/ADTM/TNF were injected into the liver of nude mice via orthotopic implantation and MDR model of liver neoplasm in vivo was established (HepG2, ADM,TNF, BCT groups). Among these groups, BCT group and TNF group were treated with BCT through gastric canal. Each group was divided into control group and chemotherapy group. Size and weight of the tumor were measured.Furthermore, tumor histological character and growth of the nude mice were observed and their chemosensitivity was tested. MDR-associated genes and proteins (MRP, LRP) of implanted tumors were detected by immunohistochemistry,reverse transcriptase polymerase chain reaction, and apoptosis rate of hepatocarcinoma cells was detected by TUNEL assay.RESULTS: The nude mouse model of each cell line was inoculated successfully. The tumor growth rate and weight were significantly different among groups. After chemotherapy, abdominal cavity tumor growth inhibition rate was higher in BCT group (67%) compared to ADM and TNF groups, and similar to HepG2group (54%). MDR1 and LRPmRNA could be detected in all groups, but TNF-αwas detected only in TNF and BCT groups. Furthermore,MDR1 and LRP protein expression of tumors in TNF and BCT groups was low similar to HepG2 group. The apoptosis rate of hepatocarcinoma cells was much higher in BCT group than in other groups with TUNEL assay.CONCLUSION: BCT and TNF-α can reverse HCC MDR in nude mouse MDR1 model of liver neoplasm.展开更多
In order to investigate the effect of chitosan/pshRNA plasmid nanoparticles targeting MDR1 genes on the resistance of A2780/TS cells to paclitaxel, chitosan/pshRNA plasmid nanoparti- cles were synthesized by means of ...In order to investigate the effect of chitosan/pshRNA plasmid nanoparticles targeting MDR1 genes on the resistance of A2780/TS cells to paclitaxel, chitosan/pshRNA plasmid nanoparti- cles were synthesized by means of a complex coacervation technique and transfected into A2780/TS cells. The cells transfected with MDRl-targeted chitosan/pshRNA plasmid nanoparticles were experimental cells and the cells transfected with chitosan/pGPU6/GFP/Neo no-load plasmid nanoparticles served as negative control cells. Morphological features of the nanoparticles were observed under transmission electron microscope (TEM). MDR1 mRNA expression was assessed by RT-PCR. Half-inhibitory concentration (IC50) ofpaclitaxel for A2780/TS cells was determined by MTT method. TEM showed that the nanoparticles were round-shaped, smooth in surface and the diameters varied from 80 to 120 nm. The MDR1 mRNA in the transfected cells was significantly decreased by 17.6%, 27.8% and 52.6% on the post-transfection day 2, 4 and 7 when compared with that in A2780/TS cells control (P〈0.05). MTT assay revealed that the relative reversal efficiency was increased over time and was 29.6%, 51.2% and 61.3% respectively in the transfected cells 2, 4, 7 days after transfection and IC_50 (0.197±0.003, 0.144±0.001, 0.120±0.004) were decreased with difference being significant when compared with that in A2780/TS (0.269±0.003) cells control (P〈0.05). It was concluded that chitosan/pshRNA plasmid nanoparticles targeting MDR1 can effectively reverse the paclitaxel resistance in A2780/TS cells in a time-dependent manner.展开更多
Objective: To investigate the expression of MDR-1 P-glycoprotein(MDR-1 Pgp) in breast cancer and analyze its correlation to the biological behavior and prognosis of the disease. Methods:The expression of MDR-1 Pgp...Objective: To investigate the expression of MDR-1 P-glycoprotein(MDR-1 Pgp) in breast cancer and analyze its correlation to the biological behavior and prognosis of the disease. Methods:The expression of MDR-1 Pgp was examined in 75 cases of breast cancer patients by using three different monoclonal antibodies(JSB1, C219 and C494) with S-P immunohistochemisty. These patients were followed up for 5 years, and the correlation between MDR-1 Pgp expression, survival rate and lymph metastasis was analyzed. Results: Positive detection of MDR-1 Pgp by JSB1, C219 and C494 in 75 cases of breast cancer was 86.7%, 48% and 85.3%, respectively. MDR-1 Pgp expression was not related to ages of patients (P 〉 0.05). JSBl-detected expression of MDR-1 Pgp was related to lymph node metastasis(P〈 0.05); while C219 and C494 were not(P 〉 0.05). The patients with MDR-1 Pgp expression positively detected by either two of the three antibodies, had five-year survival rate that was significantly higher than those positively detected by all the three antibodies(P 〈 0.05). Conclusion:Three antibodies should be used simultaneously to detect MDR-1 Pgp expression in breast cancer. Positive MDR-1 Pgp expression in breast cancer detected by all the three antibodies may represent a poor prognosis; while positive MDR-1 Pgp detection by JSB1 and C494 is associated with lymph metastasis.展开更多
Objective: The purpose of the present study is to detect characteristics of primary expression of mdr 1 gene in several neoplasms which has high morbidity in clinic. Methods: 151 resected samples, which are patholog...Objective: The purpose of the present study is to detect characteristics of primary expression of mdr 1 gene in several neoplasms which has high morbidity in clinic. Methods: 151 resected samples, which are pathologically malignant and clinically untreated before operation, were obtained from Anyang Cancer Hospital. All of them were investigated with RT PCR for the expression of mdr 1 gene and correlated each other. Besides, we evaluated the advantages of RT PCR in this study. Results: The mdr 1 gene expression rate of these 151 samples, including cancers of stomach and gastric cardia (n=51), esophagus (n=46), colorectum (n=16), breast (n=15), thyroid (n=10), lung (n=9), uterine cervix (n=4), was 33.3%, 37%, 31.3%, 13.2%, 40%, 55%, 0%, respectively. Conclusion: Compared with other methods, RT PCR for studying mdr 1 gene expression had certain advantages in simplicity, reliability, and accuracy. Overexpression of mdr 1 gene in these neoplasms suggested that cases should be distinguished before treatment according to MDR of tumor and to choose effective drugs for individual cancer patient.展开更多
Purpose: The drug resistance pattern in tuberculosis (TB) is still under investigated. We analyzed the clinical data from the patients with smear positive TB and applied the model to predict the patients with smear-po...Purpose: The drug resistance pattern in tuberculosis (TB) is still under investigated. We analyzed the clinical data from the patients with smear positive TB and applied the model to predict the patients with smear-positive TB. Materials and Methods: Medical records information of 6977 cases was included from 11,950 inpatients from January 2009 to November 2013. The cases data were divided into a training set, test set and prediction set. Logistic regression analysis was applied to the training set data to establish a prediction classification model, the effect of which was then evaluated using the test set by receiver operating characteristic (ROC) analysis. The model was then applied to the prediction set to identify incidence of snMDR-TB. Results: Sixteen factors which correlate with MDR-TB-including frequency of hospitalization, province of origin, anti-TB drugs, and complications, were identified from the comparison between SP-TB and spMDR-TB. The area under the ROC curve (AUC) of the prediction model was 0.752 (sensitivity = 61.3%, specificity = 83.3%). The percentage of all inpatients with snMDR-TB (snMDR-TB/Total) was 28.7% ± 0.02%, while that of all SN-PTB with snMDR-TB (snMDR-TB/SN-PTB) was 26.5% ± 0.03%. The ratio of snMDR-TB to MDR-TB (snMDR-TB/MDR-TB) was 2.09 ± 0.33. Conclusion: snMDR-TB as an important source of MDR-TB is a significant hidden problem for MDR-TB control and can be identified by the prediction model. A kind of vicious circle with a certain delay effect exists between snMDR-TB and MDR-TB. To better control MDR-TB, it is necessary to pay greater attention to snMDR-TB, conduct further research and develop targeted therapeutic strategies.展开更多
Acinetobacter baumannii has greatly increased its degree of resistance to become multidrug resistant (MDR) over the past 30 years and is on the red line of the most widely replicated bacteria according to World Health...Acinetobacter baumannii has greatly increased its degree of resistance to become multidrug resistant (MDR) over the past 30 years and is on the red line of the most widely replicated bacteria according to World Health Organization (WHO). The efflux pumps are the main cause for the increasing antibiotic resistance of A. baumannii originated from nosocomial infection. The progressive resistance of A. baumannii even on the recent drugs (tigecycline and fosfomycin) reduces to very effective antibiotic scale. With attention focused on MDR and pan-drug-resistant (PDR) in A. baumannii multiple works on efflux pumps chemical inhibitor (NMP, PAβN, omeprazole, verapamil, reserpine, CCCP) are still in progress. Certain inhibitors from plants (Biricodar and timcodar, Falvone, Mahonia, Dalea versicolor, Lycopus europaeus, and Rosmarinus officinalis) have the capability to have such compounds according to their very significant synergistic effect with antibiotics. In this review we focused on the growth of antibiotic resistance to explain the mechanism of efflux pumps into these different super families and a comprehensive understanding of the extrusion, regulation and physiology role of drug efflux pumps in the essential development of anti-resistivity drugs. We recapitulated the evolution of the work carried out in these fields during the last years and in the course of elaboration, with the aim of increasing the chances of decreasing bacterial resistivity to antibiotics.展开更多
TPGS approved by FDA can be used as a P-gp inhibitor to effectively reverse multi-drug resistance(MDR)and as an anticancer agent for synergistic antitumor effects.However,the comparatively high critical micelle concen...TPGS approved by FDA can be used as a P-gp inhibitor to effectively reverse multi-drug resistance(MDR)and as an anticancer agent for synergistic antitumor effects.However,the comparatively high critical micelle concentration(CMC),low drug loading(DL)and poor tumor target limit its further clinical application.To overcome these drawbacks,the pH-sensitive star-shaped TPGS copolymers were successfully constructed via using pentaerythritol as the initial materials,ortho esters as the pH-triggered linkages and TPGS active-ester as the terminated MDR material.The amphiphilic star-shaped TPGS copolymers could self-assemble into free and doxorubicin(DOX)-loaded micelles at neutral aqueous solutions.The micelles exhibited the lower CMC(8.2×10^(−5) mg/ml),higher DL(10.8%)and long-term storage and circulation stability,and showed enhanced cellular uptake,apoptosis,cytotoxicity,and growth inhibition for in vitro MCF-7/ADR and/or MCF-7/ADR multicellular spheroids and in vivo MCF-7/ADR tumors via efficiently targeted drug release at tumoral intracellular pH(5.0),MDR reversal of TPGS,and synergistic effect of DOX and TPGS.Therefore,the pH-sensitive micelles self-assembled from star-shaped TPGS copolymers with ortho ester linkages are potentially useful to clinically transform for enhanced MDR cancer treatment.展开更多
Objective: To further validate a knockdown approach for circumventing the multidrug resistance gene (MDR1), we used small interfering RNA(siRNA) targeting MDR1 gene to inhibit the expression of MDR1 gene and P-gl...Objective: To further validate a knockdown approach for circumventing the multidrug resistance gene (MDR1), we used small interfering RNA(siRNA) targeting MDR1 gene to inhibit the expression of MDR1 gene and P-glycoprotein(P-gp) in vivo. Methods: Ascite tumor xenografts were established by implanting human ovarian carcinoma cells SKOV3/AR intraperitoneally into the nude mice. The mice were randomized into the following three treatment groups with each group six mice respectively: Taxol, Taxol with lipofectamine and Taxol with siRNA/MDR1- lipofectamine intraperitoneal injection. The tumor growth rate and the ascite growth rate of mice were investigated. The expressions of MDR1 gene and P-gp in mice were determined by reverse transcription-polymerase chain reaction(RT-PCR) and immunohistochemistry respctively. Results: The growth of tumors and ascites in mice treated with Taxol and siRNA/MDR1- lipofectamine was significantly inhibited compared with those in mice of other groups. After 28 days' treatment, the average tumor weight and ascite volume decreased by 43.6% and 29.7% in the group treated with Taxol and siRNA/MDRl-lipofectamine compared with these treated with Taxol alone (P〈0.001). The expressions of MDR1 gene and P-gp in the group treated with Taxol and siRNA/MDRl-lipofectamine were also decreased compared with those in the group treated with Taxol alone (P〈0.001). Conclusion: Small interfering RNA targeting-MDR1 can effectively and specifically suppress the expression of MDRl(P-glycoprotein) and inhibit ovarian cancer growth in vivo.展开更多
Objective: To investigate the effects of neoadjuvant chemotherapy on the expression of drug resistance genes, multidrug resistance-1 (MDR1) and multidrug resistance-associated protein (MRP), in patients with primary b...Objective: To investigate the effects of neoadjuvant chemotherapy on the expression of drug resistance genes, multidrug resistance-1 (MDR1) and multidrug resistance-associated protein (MRP), in patients with primary breast cancer. Methods: MDR1 and MRP expression were detected by semi-quantitative RT-PCR in 20 patients with primary breast cancer, before and after chemotherapy. Results: Before chemotherapy, MDR1 and MRP expression can be detected in 15 cases (75%) and 18 cases (90%) respectively. After chemotherapy, expression of MDR1 is not significantly different from that before chemotherapy, but expression of MRP is significantly different from that before chemotherapy. Conclusion: Expression of drug resistance gene MRP, but not MDR1, is enhanced in patients with primary breast cancer submitted to neoadjuvant chemotherapy.展开更多
Several related substances were detected at trace level in (2R)-2,3-dihydro-2-methyl-6-nitro-2-[[4-[4-[4-(trifluoromethoxy)phenoxy]-1-piperidinyl] phenoxy] methyl]imidazo[2, 1-b]oxazole drug substance by a newly devel...Several related substances were detected at trace level in (2R)-2,3-dihydro-2-methyl-6-nitro-2-[[4-[4-[4-(trifluoromethoxy)phenoxy]-1-piperidinyl] phenoxy] methyl]imidazo[2, 1-b]oxazole drug substance by a newly developed high-performance liquid chromatography method. All related substances were characterized rapidly but some impurities were found to be intermediates. Proposed structures were further confirmed by characterization using NMR, FT-IR, and HRMS techniques. Based on the spectroscopic data;unknown related sub-stances were characterized as 1-(Methylsulfonyl)-4-[4-(trifluoromethoxy) phenoxy]piperidine;4-{4-[4-(Tri-fluoromethoxy)-phenoxy]piperidin-1-yl}phenol and 4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}phenyl methane sulfonate;4-Bromophenyl methane sulfonate, Ethyl 3,6-dihydro-1(2H)-pyridine carboxylate, (2S)-3-(4-Bromophenoxy)-2-hydroxy-2-methylpropyl methane sulfonate, (2S)-3-(4-Bromophenoxy)-2-methylpropane-1,2-diyldimethane-sulfonate, (2S)-2-Methyl-3-(4-{4-[4-(trifluoromethoxy) phenoxy]-piperidin-1-yl} phenoxy)-propane-1,2-diyldimethane sulfonate, (S)-3-(4-Bromophenoxy)-2-methyl-propane-1,2-diol and corresponding Enantiomer, (2R)-2-[(4-Bromo-phenoxy)methyl]-2-methyloxirane and (2R)-2-[(4-bromophenoxy)methyl]-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole. A possible mechanism for the formation of these related substances is also proposed.展开更多
文摘Introduction: The occurrence of pregnancy in women is a risky situation. Prenatal care is necessary, which is not often the case in our context. Aim: To analyze the influence of antenatal surveillance on maternal and perinatal prognosis. Patients and Method: Preliminary longitudinal and analytical survey at the Owendo University Hospital (OHU) over 6 months. It focused on prenatal surveillance. The study population consisted of parturients who gave birth within 24 hours and we studied sociodemographic characteristics, variables related to antenatal contact, those of delivery as well as maternal and newborn outcomes. Results: 2485 deliveries were recorded and 1300 patients were retained according to the inclusion criteria. No prenatal contact (ANC0) was performed in 93 (7.15%), insufficient (ANCI) in 943 patients (72.5%), and sufficient (ANCS) in 264 patients (20.30%). Patients with low school level were significantly found when the NPC was not performed or insufficient and the same was true for the group of patients who were not employed and those who were single (p < 0.005). The caesarean section rate and perinatal mortality are high in this case. Conclusion: The quality of prenatal contact is insufficient in our context. The absence or inadequacy of the latter has a strong negative impact on maternal and perinatal morbidity and mortality.
文摘The purpose of this paper is to investigate the reversal effect of small interfering RNA (siRNA) targeting MDRI and MDR3 genes on the resistance of MCF-7/ADR cells to adriamycin. siRNA plasmid vector targeting MDRI and MDR3 genes was transfected into MCF-7/ADR cells, and then was stained with Annexin-V FITC (fluorescein isothiocyanate conjugated) to detect the early stage cell apoptosis by flow cytometry (FCM). 50 % inhibition concentration (IC50) of adriamycin for MCF-7/ADR cells was determined by MTT method. MDRI and MDR3 mRNA was assessed by RT-PCR. Treatment of MCF-7/ADR cells with the two kinds of siRNAs resulted in a reversal of adriamycin resistance of MDR to different extents. 1) The apoptosis efficiency of MDRI and MDR3 siRNA vector after transfection was (18.21 ± 1.65) % and (9.07±2.16) % respectively (P〈0.05), and there was significant differences in the apoptosis efficiency between pSuppressor Neo vector and the MDRIsiRNA or MDR3 siRNA vector (P〈0.01); 2) The reversal effect of MDRIsiRNAis higher than that of MDR3 siRNA (P〈0.05); 3 ) The expression of MDRI and MDR3 mRNA can be restrained by pSuppressor Neo MDRI and MDR3 siRNA respectively, and the reduction in the mRNA level was in a time-dependent manner (P〈0.01). MDRI and MDR3 gene silencing can enhance intracellular adriamycin accumulation in MCF-7/ADR cells, improve sensitivity of MCF-7/ADR cells to adriamycin, and induce cell apoptosis. The reversal effect of adriamycin resistance by siRNA of MDR1 was more effective than that of MDR3.
文摘Objective: Overexpression of mdr-1 gene is associated with multidrug resistance (MDR) and aggressive characteristics of malignance. Our purposewas to detect the levels of P-gp expression in fresh untreated esophageal carcinomas, and to correlate these levels to current prognostic indicators of morphology.Methods: Reverse transcription polymerase chain reaction (RT-PCR) was used to investigate mdr-1 gene expression of 46 samples from untreated esophageal carcinoma, and compared the positive incidences among differentiated grades, TNM stages and macroscopic types.Results: All 46 samples were pathologically squamous cell carcinoma. The positive' incidences of mdr-1 gene expression were 37% (17/46) in whole group,35% (6/17), 40% (8/20), 33% (3/9), for Ⅰ,Ⅱ and Ⅲdifferentiated grades, respectively. The expression rates of 33% (6/18), 40% (5/12), and 37% (6/16), were found in Ⅱa, Ⅱ, and Ⅲ stage of TNM, respectively. In macroscopic type view, the positive incidence was 37%(3/8) in constrictive, 33% (5/15) in fungating, 40% (6/14)in marrowlike, 33% (319) in ulcerative type. There were no statistically significant differences among each category system of morphology.Conclusion: The result, high level expression of mdr-1 gene in untreated esophageal carcinoma, suggested the poor efficacy of chemotherapy for some esophageal carcinoma patients. And we should cautiously choose cases who will receive chemotherapy. Surgery is still the best treatment for carcinoma of esophagus. Besides, the data also revealed that the expression of mdr-1 gene in untreated esophageal cancer was independent of morphologic prognostic indexes, and that there were no correlation between mdr-1 gene expression and morphological indexes.
文摘To explore the reversal effect of mifepristone on multidrug resistance (MDR) in drug-resistant human breast cancer cell line MCF7/ADR and its mechanisms. Methods: Expression of MDR1 and MDR-associated protein(MRP) mRNA in MCF7/ADR cells was detected using reverse transcription- polymerase chain reaction(RT-PCR). Western blotting was used to assay the protein levels of P-glycoprotein (P-gp) and MRP. Intracellular rhodamine 123 retention and [3H]vincristine (VCR) accumulation were measured by flow cytometry and liquid scintillation counter, respectively. MTT reduction assay was used to determine the sensitivity of cells to the anticancer agent, adriamycin (ADR). Additionally, a MCF7/ADR cell xenograft model was established to assess the reversal effect of mifeprisone on MDR in MCF7/ADR cells in vivo. Results: Miferpristone dose-dependently down- regulated the expression of MDR1 and MRP mRNA in MCF7/ADR cells, accompanied by a significant decrease in the protein levels of P-gp and MRP. After exposure to 5, 10, and 20 mmol/L mifepristone, MCF7/ADR cells showed a 3.87-, 5.81-, and 7.40-fold increase in the accumulation of intracellular VCR(a known substrate of MRP), and a 2.14-, 4.39-, and 5.53-fold increase in the retention of intracellular rhodamine 123(an indicator of P-gp function), respectively. MTT analysis showed that the sensitivity of MCF7/ADR cells to ADR was enhanced by 7.23-, 13.62-, and 20.96-fold after incubation with mifepristone as above-mentioned doses for 96 h. In vivo, mifepristone effectively restored the chemosensitivity of MCF7/ADR cells to ADR. After 8 weeks of administration with ADR(2 mg穔g-1穌-1) alone or in combination with mifepristone(50 mg穔g-1穌-1), the growth inhibitory rate of xenografted tumors in nude mice was 8.08% and 37.25%, respectively. Conclusion: Mifepristone exerts potent reversal effects on MDR in MCF7/ADR cells in vitro and in vivo through down- regulation of MDR1/P-gp and MRP expression and inhibition of P-gp- and MRP-dependent drug efflux, thus increasing the sensitivity to anticancer drug.
基金Supported by the Clinical Key Program Point Subject Foundation of Ministry of Public Health, No. 2001-2003
文摘AIM: To investigate the effect of bromocriptine (BCT) and tumor necrosis factor-α (TNF-α) on hepatocellular carcinoma (HCC) multidrug resistance (MDR) in nude mouse MDR model of liver neoplasm.METHODS: Human hepatocarcinoma cell line HepG2, drug resistant hepatocarcinoma cell line HepG2/adriamycin (ADM) and hepatocarcinoma cell line transfected with TNF-α gene HepG2/ADTM/TNF were injected into the liver of nude mice via orthotopic implantation and MDR model of liver neoplasm in vivo was established (HepG2, ADM,TNF, BCT groups). Among these groups, BCT group and TNF group were treated with BCT through gastric canal. Each group was divided into control group and chemotherapy group. Size and weight of the tumor were measured.Furthermore, tumor histological character and growth of the nude mice were observed and their chemosensitivity was tested. MDR-associated genes and proteins (MRP, LRP) of implanted tumors were detected by immunohistochemistry,reverse transcriptase polymerase chain reaction, and apoptosis rate of hepatocarcinoma cells was detected by TUNEL assay.RESULTS: The nude mouse model of each cell line was inoculated successfully. The tumor growth rate and weight were significantly different among groups. After chemotherapy, abdominal cavity tumor growth inhibition rate was higher in BCT group (67%) compared to ADM and TNF groups, and similar to HepG2group (54%). MDR1 and LRPmRNA could be detected in all groups, but TNF-αwas detected only in TNF and BCT groups. Furthermore,MDR1 and LRP protein expression of tumors in TNF and BCT groups was low similar to HepG2 group. The apoptosis rate of hepatocarcinoma cells was much higher in BCT group than in other groups with TUNEL assay.CONCLUSION: BCT and TNF-α can reverse HCC MDR in nude mouse MDR1 model of liver neoplasm.
基金supported by grants from Scientific Research Foundation of Hubei health department (No.JX2B17)a grant from Key Technologies R&D Programme of Hubei Province (No.2007AA301C20)
文摘In order to investigate the effect of chitosan/pshRNA plasmid nanoparticles targeting MDR1 genes on the resistance of A2780/TS cells to paclitaxel, chitosan/pshRNA plasmid nanoparti- cles were synthesized by means of a complex coacervation technique and transfected into A2780/TS cells. The cells transfected with MDRl-targeted chitosan/pshRNA plasmid nanoparticles were experimental cells and the cells transfected with chitosan/pGPU6/GFP/Neo no-load plasmid nanoparticles served as negative control cells. Morphological features of the nanoparticles were observed under transmission electron microscope (TEM). MDR1 mRNA expression was assessed by RT-PCR. Half-inhibitory concentration (IC50) ofpaclitaxel for A2780/TS cells was determined by MTT method. TEM showed that the nanoparticles were round-shaped, smooth in surface and the diameters varied from 80 to 120 nm. The MDR1 mRNA in the transfected cells was significantly decreased by 17.6%, 27.8% and 52.6% on the post-transfection day 2, 4 and 7 when compared with that in A2780/TS cells control (P〈0.05). MTT assay revealed that the relative reversal efficiency was increased over time and was 29.6%, 51.2% and 61.3% respectively in the transfected cells 2, 4, 7 days after transfection and IC_50 (0.197±0.003, 0.144±0.001, 0.120±0.004) were decreased with difference being significant when compared with that in A2780/TS (0.269±0.003) cells control (P〈0.05). It was concluded that chitosan/pshRNA plasmid nanoparticles targeting MDR1 can effectively reverse the paclitaxel resistance in A2780/TS cells in a time-dependent manner.
基金This work was supported by the Science Development Foundation of the Nanjing Medical University(2006NMUZ023)The research in Dr. W. Zhang's laboratory was supported by funding from the National Research Council of Canada and a Canadian Research Program spon- sored by CIHR, HSFC, ASC and Pfizer(PG-04-0248)
文摘Objective: To investigate the expression of MDR-1 P-glycoprotein(MDR-1 Pgp) in breast cancer and analyze its correlation to the biological behavior and prognosis of the disease. Methods:The expression of MDR-1 Pgp was examined in 75 cases of breast cancer patients by using three different monoclonal antibodies(JSB1, C219 and C494) with S-P immunohistochemisty. These patients were followed up for 5 years, and the correlation between MDR-1 Pgp expression, survival rate and lymph metastasis was analyzed. Results: Positive detection of MDR-1 Pgp by JSB1, C219 and C494 in 75 cases of breast cancer was 86.7%, 48% and 85.3%, respectively. MDR-1 Pgp expression was not related to ages of patients (P 〉 0.05). JSBl-detected expression of MDR-1 Pgp was related to lymph node metastasis(P〈 0.05); while C219 and C494 were not(P 〉 0.05). The patients with MDR-1 Pgp expression positively detected by either two of the three antibodies, had five-year survival rate that was significantly higher than those positively detected by all the three antibodies(P 〈 0.05). Conclusion:Three antibodies should be used simultaneously to detect MDR-1 Pgp expression in breast cancer. Positive MDR-1 Pgp expression in breast cancer detected by all the three antibodies may represent a poor prognosis; while positive MDR-1 Pgp detection by JSB1 and C494 is associated with lymph metastasis.
文摘Objective: The purpose of the present study is to detect characteristics of primary expression of mdr 1 gene in several neoplasms which has high morbidity in clinic. Methods: 151 resected samples, which are pathologically malignant and clinically untreated before operation, were obtained from Anyang Cancer Hospital. All of them were investigated with RT PCR for the expression of mdr 1 gene and correlated each other. Besides, we evaluated the advantages of RT PCR in this study. Results: The mdr 1 gene expression rate of these 151 samples, including cancers of stomach and gastric cardia (n=51), esophagus (n=46), colorectum (n=16), breast (n=15), thyroid (n=10), lung (n=9), uterine cervix (n=4), was 33.3%, 37%, 31.3%, 13.2%, 40%, 55%, 0%, respectively. Conclusion: Compared with other methods, RT PCR for studying mdr 1 gene expression had certain advantages in simplicity, reliability, and accuracy. Overexpression of mdr 1 gene in these neoplasms suggested that cases should be distinguished before treatment according to MDR of tumor and to choose effective drugs for individual cancer patient.
文摘Purpose: The drug resistance pattern in tuberculosis (TB) is still under investigated. We analyzed the clinical data from the patients with smear positive TB and applied the model to predict the patients with smear-positive TB. Materials and Methods: Medical records information of 6977 cases was included from 11,950 inpatients from January 2009 to November 2013. The cases data were divided into a training set, test set and prediction set. Logistic regression analysis was applied to the training set data to establish a prediction classification model, the effect of which was then evaluated using the test set by receiver operating characteristic (ROC) analysis. The model was then applied to the prediction set to identify incidence of snMDR-TB. Results: Sixteen factors which correlate with MDR-TB-including frequency of hospitalization, province of origin, anti-TB drugs, and complications, were identified from the comparison between SP-TB and spMDR-TB. The area under the ROC curve (AUC) of the prediction model was 0.752 (sensitivity = 61.3%, specificity = 83.3%). The percentage of all inpatients with snMDR-TB (snMDR-TB/Total) was 28.7% ± 0.02%, while that of all SN-PTB with snMDR-TB (snMDR-TB/SN-PTB) was 26.5% ± 0.03%. The ratio of snMDR-TB to MDR-TB (snMDR-TB/MDR-TB) was 2.09 ± 0.33. Conclusion: snMDR-TB as an important source of MDR-TB is a significant hidden problem for MDR-TB control and can be identified by the prediction model. A kind of vicious circle with a certain delay effect exists between snMDR-TB and MDR-TB. To better control MDR-TB, it is necessary to pay greater attention to snMDR-TB, conduct further research and develop targeted therapeutic strategies.
文摘Acinetobacter baumannii has greatly increased its degree of resistance to become multidrug resistant (MDR) over the past 30 years and is on the red line of the most widely replicated bacteria according to World Health Organization (WHO). The efflux pumps are the main cause for the increasing antibiotic resistance of A. baumannii originated from nosocomial infection. The progressive resistance of A. baumannii even on the recent drugs (tigecycline and fosfomycin) reduces to very effective antibiotic scale. With attention focused on MDR and pan-drug-resistant (PDR) in A. baumannii multiple works on efflux pumps chemical inhibitor (NMP, PAβN, omeprazole, verapamil, reserpine, CCCP) are still in progress. Certain inhibitors from plants (Biricodar and timcodar, Falvone, Mahonia, Dalea versicolor, Lycopus europaeus, and Rosmarinus officinalis) have the capability to have such compounds according to their very significant synergistic effect with antibiotics. In this review we focused on the growth of antibiotic resistance to explain the mechanism of efflux pumps into these different super families and a comprehensive understanding of the extrusion, regulation and physiology role of drug efflux pumps in the essential development of anti-resistivity drugs. We recapitulated the evolution of the work carried out in these fields during the last years and in the course of elaboration, with the aim of increasing the chances of decreasing bacterial resistivity to antibiotics.
基金This work is financially supported by the National Natural Science Foundation of China(No.51803001)the Research Foundation of Education Department of Anhui Province of China(No.KJ2018ZD003 and KJ2018A0006)the Academic and Technology Introduction Project of Anhui University(AU02303203).
文摘TPGS approved by FDA can be used as a P-gp inhibitor to effectively reverse multi-drug resistance(MDR)and as an anticancer agent for synergistic antitumor effects.However,the comparatively high critical micelle concentration(CMC),low drug loading(DL)and poor tumor target limit its further clinical application.To overcome these drawbacks,the pH-sensitive star-shaped TPGS copolymers were successfully constructed via using pentaerythritol as the initial materials,ortho esters as the pH-triggered linkages and TPGS active-ester as the terminated MDR material.The amphiphilic star-shaped TPGS copolymers could self-assemble into free and doxorubicin(DOX)-loaded micelles at neutral aqueous solutions.The micelles exhibited the lower CMC(8.2×10^(−5) mg/ml),higher DL(10.8%)and long-term storage and circulation stability,and showed enhanced cellular uptake,apoptosis,cytotoxicity,and growth inhibition for in vitro MCF-7/ADR and/or MCF-7/ADR multicellular spheroids and in vivo MCF-7/ADR tumors via efficiently targeted drug release at tumoral intracellular pH(5.0),MDR reversal of TPGS,and synergistic effect of DOX and TPGS.Therefore,the pH-sensitive micelles self-assembled from star-shaped TPGS copolymers with ortho ester linkages are potentially useful to clinically transform for enhanced MDR cancer treatment.
基金supported by the grant from the key project of Jiangxi Bureau of Health Science(No.200506)
文摘Objective: To further validate a knockdown approach for circumventing the multidrug resistance gene (MDR1), we used small interfering RNA(siRNA) targeting MDR1 gene to inhibit the expression of MDR1 gene and P-glycoprotein(P-gp) in vivo. Methods: Ascite tumor xenografts were established by implanting human ovarian carcinoma cells SKOV3/AR intraperitoneally into the nude mice. The mice were randomized into the following three treatment groups with each group six mice respectively: Taxol, Taxol with lipofectamine and Taxol with siRNA/MDR1- lipofectamine intraperitoneal injection. The tumor growth rate and the ascite growth rate of mice were investigated. The expressions of MDR1 gene and P-gp in mice were determined by reverse transcription-polymerase chain reaction(RT-PCR) and immunohistochemistry respctively. Results: The growth of tumors and ascites in mice treated with Taxol and siRNA/MDR1- lipofectamine was significantly inhibited compared with those in mice of other groups. After 28 days' treatment, the average tumor weight and ascite volume decreased by 43.6% and 29.7% in the group treated with Taxol and siRNA/MDRl-lipofectamine compared with these treated with Taxol alone (P〈0.001). The expressions of MDR1 gene and P-gp in the group treated with Taxol and siRNA/MDRl-lipofectamine were also decreased compared with those in the group treated with Taxol alone (P〈0.001). Conclusion: Small interfering RNA targeting-MDR1 can effectively and specifically suppress the expression of MDRl(P-glycoprotein) and inhibit ovarian cancer growth in vivo.
文摘Objective: To investigate the effects of neoadjuvant chemotherapy on the expression of drug resistance genes, multidrug resistance-1 (MDR1) and multidrug resistance-associated protein (MRP), in patients with primary breast cancer. Methods: MDR1 and MRP expression were detected by semi-quantitative RT-PCR in 20 patients with primary breast cancer, before and after chemotherapy. Results: Before chemotherapy, MDR1 and MRP expression can be detected in 15 cases (75%) and 18 cases (90%) respectively. After chemotherapy, expression of MDR1 is not significantly different from that before chemotherapy, but expression of MRP is significantly different from that before chemotherapy. Conclusion: Expression of drug resistance gene MRP, but not MDR1, is enhanced in patients with primary breast cancer submitted to neoadjuvant chemotherapy.
文摘Several related substances were detected at trace level in (2R)-2,3-dihydro-2-methyl-6-nitro-2-[[4-[4-[4-(trifluoromethoxy)phenoxy]-1-piperidinyl] phenoxy] methyl]imidazo[2, 1-b]oxazole drug substance by a newly developed high-performance liquid chromatography method. All related substances were characterized rapidly but some impurities were found to be intermediates. Proposed structures were further confirmed by characterization using NMR, FT-IR, and HRMS techniques. Based on the spectroscopic data;unknown related sub-stances were characterized as 1-(Methylsulfonyl)-4-[4-(trifluoromethoxy) phenoxy]piperidine;4-{4-[4-(Tri-fluoromethoxy)-phenoxy]piperidin-1-yl}phenol and 4-{4-[4-(trifluoromethoxy)phenoxy]piperidin-1-yl}phenyl methane sulfonate;4-Bromophenyl methane sulfonate, Ethyl 3,6-dihydro-1(2H)-pyridine carboxylate, (2S)-3-(4-Bromophenoxy)-2-hydroxy-2-methylpropyl methane sulfonate, (2S)-3-(4-Bromophenoxy)-2-methylpropane-1,2-diyldimethane-sulfonate, (2S)-2-Methyl-3-(4-{4-[4-(trifluoromethoxy) phenoxy]-piperidin-1-yl} phenoxy)-propane-1,2-diyldimethane sulfonate, (S)-3-(4-Bromophenoxy)-2-methyl-propane-1,2-diol and corresponding Enantiomer, (2R)-2-[(4-Bromo-phenoxy)methyl]-2-methyloxirane and (2R)-2-[(4-bromophenoxy)methyl]-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole. A possible mechanism for the formation of these related substances is also proposed.