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OBJECTIVE@#To investigate the efficacy and safety of oral fludarabine in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).@*METHODS@#The patients received oral fludarabine 40 mg/(m2.d) for 5 consecutive days, each treatment lasting 4 weeks. The efficacy was assessed with National Comprehensive Cancer Network (NCCN) criteria for response.@*RESULTS@#Twenty-two patients received the treatment, a median of 4 cycles per patient. The rate of complete response (CR), partial response (PR), and overall response (OR) was 40.9% (9/22), 45.5% (10/22), and 86.4% (19/22), respectively. Among the 17 previously untreated patients, 7 (41.2%) achieved CR and 8 (47.0%) achieved PR. Two of the 5 pre-treated patients achieved CR and the other 2 achieved PR. During a median observation of 24 months, the overall survival rate was 81.8%. The main adverse reactions were myelosuppression and infection. Grade 1 to 3 granulocytopenia was found in 7 (31.8%) patients, and infection in 3 (13.6%) patients. Nonhematologic toxicity was mild. All the adverse reactions were reversible.@*CONCLUSION@#The oral fludarabine is effective, safe, and well-tolerated in the patients with CLL/ SLL.
Subject(s)
Aged , Female , Humans , Male , Middle Aged , Antineoplastic Agents , Therapeutic Uses , Leukemia, Lymphocytic, Chronic, B-Cell , Drug Therapy , Treatment Outcome , Vidarabine , Therapeutic UsesABSTRACT
OBJECTIVE@#To determine the effect of different heating Methods combined with neferine(Nef) on the proliferation and expressions of γH2AX and mdr-1/P-gp in MCF-7/Adr breast cancer cells.@*METHODS@#MTT assay was used to determine block heating, water submerged heating, medium heating, and oven heating combined with 10 μg/mL Nef on adriamycin cultured MCF-7/Adr cell proliferation. The mdr-1mRNA expression was detected by real-time quantitative PCR. γH2AX and P-gp expressions were detected by Western blot.@*RESULTS@#The absorbance values of MCF-7/Adr cells in different heating groups at 42 degree and 45 degree were significantly decreased, the mdr-1/P-gp expression was decreased, and γH2AX expression was upregulated compared with those of the 37 degree control group (all P<0.01). The absorbance values (P<0.01) and mdr-1/P-gp expression(P<0.05) were significantly lower and γH2AX expression(P<0.05) was significantly higher in the hyperthermia combined with 10 μg/mL Nef group than those of 10 μg/mL Nef group and hyperthermia group in MCF-7/Adr cells. The water submerged heating group had the lowest P-gp expression and the highest γH2AX expression among different heating groups at 42 degree and 45 degree in MCF-7/Adr cells (P<0.05).@*CONCLUSION@#Hyperthermia can increase the cell toxicity of adriamycin to multidrug resistant breast cancer cells. Hyperthermia significantly damages DNA of MCF-7/Adr cells and the higher temperature, the worse effect. Multidrug resistant breast cancer cells may respond differently to the different heating methods. Combined treatment of hyperthermia with Nef can increase the sensitivity in adriamycin chemotherapy.
Subject(s)
Humans , ATP Binding Cassette Transporter, Subfamily B , ATP Binding Cassette Transporter, Subfamily B, Member 1 , Genetics , Metabolism , Antibiotics, Antineoplastic , Pharmacology , Benzylisoquinolines , Pharmacology , Breast Neoplasms , Genetics , Metabolism , Pathology , Cell Line, Tumor , Doxorubicin , Pharmacology , Drug Resistance, Multiple , Genetics , Drug Resistance, Neoplasm , Genetics , Drugs, Chinese Herbal , Pharmacology , Histones , Genetics , Metabolism , Hot Temperature , RNA, Messenger , Genetics , MetabolismABSTRACT
Multidrug resistance (MDR) plays a major obstacle to successful gastric cancer chemotherapy. The purpose of this study was to investigate the MDR reversal effect and mechanisms of hyperthermia in combination with neferine (Nef) in adriamycin (ADM) resistant human SGC7901/ADM gastric cancer cells. The MDR cells were heated at 42°C and 45°C for 30 min alone or combined with 10 μg/mL Nef. The cytotoxic effect of ADM was evaluated by MTT assay. Cellular plasma membrane lipid fluidity was detected by fluorescence polarization technique. Intracellular accumulation of ADM was monitored with high performance liquid chromatography. Mdr-1 mRNA, P-glycoprotein (P-gp), γH2AX expression and γH2AX foci formation were determined by real-time PCR, Western blot and immunocytochemical staining respectively. It was found that different heating methods induced different cytotoxic effects. Water submerged hyperthermia had the strongest cytotoxicity of ADM and Nef combined with hyperthermia had a synergistic cytotoxicity of ADM in the MDR cells. The water submerged hyperthermia increased the cell membrane fluidity. Both water submerged hyperthermia and Nef increased the intracellular accumulation of ADM. The water submerged hyperthermia and Nef down-regulated the expression of mdr-1 mRNA and P-gp. The water submerged hyperthermia could damage DNA and increase the γH2AX expression of SGC7901/ADM cells. The higher temperature was, the worse effect was. Our results show that combined treatment of hyperthermia with Nef can synergistically reverse MDR in human SGC7901/ADM gastric cancer cells.
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OBJECTIVE@#To determine the effect of neferine (Nef) combined with mdr-1shRNA on the expression of mdr/P-gp in K562/A02 cell line.@*METHODS@#MTT assay was used to observe the cell proliferation. The expression level of P-gp was determined by Western blot and the transcription of mdr-1 gene was detected by semi-quantitative RT-PCR.@*RESULTS@#After K562/A02 cells were treated by Nef or mdr-1shRNA alone or both for 24 h, the proliferation of K562/A02 cells was significantly higher in the Nef combined with mdr-1shRNA treatment group than that of Nef or mdr-1shRNA alone group (P<0.01).The expression of mdr-1/P-gp in the Nef with mdr-1 shRNA group was significantly lower than that of Nef or mdr-1shRNA alone group.@*CONCLUSION@#Nef enhances the inhibition of mdr-1shRNA expression vector on K562/A02 cell proliferation and on P-gp protein to effectively reverse multidrug resistance induced by mdr-1 gene encoding P-gp.
Subject(s)
Humans , ATP Binding Cassette Transporter, Subfamily B , ATP Binding Cassette Transporter, Subfamily B, Member 1 , Genetics , Metabolism , Benzylisoquinolines , Pharmacology , Drug Resistance, Multiple , Drug Resistance, Neoplasm , Drug Synergism , Drugs, Chinese Herbal , Pharmacology , K562 Cells , RNA, Small Interfering , Genetics , PharmacologyABSTRACT
OBJECTIVE@#To analyze the mdr-1 gene promoter methylation and histone acetylation status in both MCF-7/Adr and MCF-7 cells and to preliminarily explore the epigenetic mechanism of multidrug resistance in breast cancer.@*METHODS@#mdr-1 gene promoter methylation status of the 2 cell lines was detected by methylation-sensitive PCR. mRNA expression of DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) was detected by real-time quantitative PCR. Acetylation level of histone H3 and H4 was examined by optical density assay.@*RESULTS@#Promoter hypermethylation of mdr-1 gene was observed in MCF-7 cells whereas hypomethylation was found in MCF-7/Adr cells. Expression of DNMT1, DNMT3a, and DNMT3b mRNA in MCF-7/Adr cells significantly decreased compared with that of MCF-7 cells (P<0.05). H3 and H4 histone acetylation levels of MCF-7/Adr cells were obviously higher than those of the MCF-7 cells (P<0.01). Expression of HDAC1, HDAC2, HDAC7, and Sirtuin type 1 (SIRT1) mRNA in MCF-7/Adr cells was significantly reduced (P<0.05).@*CONCLUSION@#Hypomethylation of the promoter region of mdr-1 gene, high H3 and H4 histone acetylation, and low mRNA expression of DNMTs and HDACs may be important epigenetic factors for the development of MDR in MCF-7/ Adr cells.
Subject(s)
Female , Humans , ATP Binding Cassette Transporter, Subfamily B, Member 1 , Genetics , Acetylation , Breast Neoplasms , Pathology , Cell Line, Tumor , DNA (Cytosine-5-)-Methyltransferase 1 , DNA (Cytosine-5-)-Methyltransferases , Genetics , Metabolism , DNA Methylation , Genetics , Drug Resistance, Multiple , Genetics , Drug Resistance, Neoplasm , Genetics , Epigenesis, Genetic , Histone Deacetylases , Genetics , Metabolism , Histones , Chemistry , Promoter Regions, Genetic , Genetics , RNA, Messenger , Genetics , MetabolismABSTRACT
Objective To study the effects of neferine on the expression of glutathione S-transferase-pi in vitro and to explore the multi-drug resistance reversing mechanism of neferine.Methods 50% inhibition concentration(IC_(50)) of ADM on K562/A02 was determined by MTT method.The transcription of GST-? gene was detected by semi-quantitative RT-PCR and the expression level of GST-? was determined by Western blot after neferine treatment.Results Neferine remarkably enhanced chemosensitivity to ADM of K562/A02 cells.After neferine treatment in day 1,day 3 and day 5,the relative efficiency of K562/A02 to ADM was 9.6%,41.4% and 10.7%,respectively.Semi-quantitative RT-PCR showed that mRNA transcription of GST-? gene was significantly reduced(P
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Background and Purpose:Recent studies have shown that survivin is an anti-apoptosis gene,which is involved in carcinogenesis and drug resistance of leukemia.Antisense oligodeoxynucleotide(ASODN) can be used to inhibit the expression of survivin,inducing apoptosis and enhancing the chemosensitivity of leukemic cells.This study was designed to explore the effect of survivin ASODN on the growth,apoptosis,and caspase-3 activity of leukemia cell line K562/A02 with the phenotype of drug resistance.Methods:Survivin ASOND was transfected to K562/A02 cells by liposomal reagent,The rate of inhibition,expression of survivin mRNA,apoptosis,and activity of Caspase-3 were detected by colormetric MTT,RT-PCR,flow cytometry and fluorometer,respectively.Results:Survivin ASODN could inhibite the cell proliferation in a dose and time dependent manner.Compared with controls,expression of survivin mRNA decreased by 36.2%(P
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Objective It has been known that NSAIDs can inhibit the growth of tumors through cyclooxygenase, but it is unknown that whether there are other mechanisms involved. It is essential to detect the effect of indomethacin for proliferation and apoptosis in the HCT116 and explore its anti tumor mechanism. Methods Human colon adenocarcinoma cell line HCT116 was treated with different concentration of indomethacin for 24 h and CDK 2,CDK 4, Bcl 2, Bax and p21 WAF1/CIP1 protein were detected by Western blot. Results Indomethacin down regulated the expression of CDK 2, CDK 4, Bcl 2 and up regulated the expression of p21 WAF1/CIP1 , however, the expression of Bax remained unchanged. Conclusions Inhibiting proliferation and inducing apoptosis contribute to the anti tumor activity of indomethacin by down regulating the expression of CDK 2, CDK 4, Bcl 2 and up regulating the expression of p21 WAF1/CIP1 .
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Objective To investigate the effects of neferine on the proliferation and the P-glycoprotein(P-gp) expression of refractory/relapsed acute leukemic cells and to provide experimental evidence for further clinical use. Methods MTT and immunocytochemistry SABC methods were used respectively to observe the alteration of the proliferation and the expression of P-gp in refractory/relapsed acute leukemic cells after treating with neferine. Results The inhibition ratio on acute leukemic cells of neferine adding adriamycin(ADM) group was significantly higher than that of ADM group (P0.05). Conclusion [WTBZ]Neferine can inhibit the proliferation of refractory/relapsed acute leukemic cells, and reduce the P-gp expression of refractory/relapsed acute leukemic cells and consequently reverse multidrug resistance(MDR).