Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.1.1.105 (MDR)
 4,410 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

AIM:To compare the expression level of Fas gene and Bcl-2 gene in gastric cancer cells SGC7901 and gastric cancer MDR (multidrug resistant) cells SGC7901/VCR,to transduce Fas cDNA and Bcl-2 antisense nucleic acid into SGC7901/VCR cells respectively, and to observe the expression of two genes in transfectants and non-transfectants as well as their drug sensitivity.METHODS:Eukaryotic expression vector pBK-Fas cDNA and pDOR-anti Bcl-2 were constructed and transfected into SGC7901/VCR cells by lipofectamine,respectively.Northern blot and Western blot were used to detect the expression of mRNA and protein in SGC7901/VCR and SGC7901 cells and transfectants, and drug sensitivity of transfectants for VCR, CDDP and 5-FU was analyzed with MTT assay.RESULTS:After gene transfection, 80 for Fas and 120 for antisense Bcl-2 drug-resistant clones were selected from 2 X10(5) cells, transfection rate being 0.04% and 0.06%. Two clones of SGC7901 Fas/VCR cells and SGC7901 anti Bcl-2/VCR cells were randomly selected for further incubation. Hybridization results showed that the expression level of Fas mRNA and protein in SGC7901/VCR cells was much lower,but that of Bcl-2 mRNA and protein was higher than that in SGC7901 cells. The expression of Fas mRNA and protein in SGC7901 Fas/VCR cells was higher,and of Bcl-2 mRNA and protein was lower in SGC7901 anti Bcl-2/VCR cells than that in non-transfectants. MTT assay showed that transfectants were more sensitive to VCR, CDDP, 5-FU than non-transfectants. CONCLUSION:Bcl-2 gene displayed high expression while Fas gene had low expression in drug resistant gastric cancer cells. Expression of Bcl-2 protein was effectively blocked in SGC7901 anti Bcl-2/VCR cells by gene transfection. In contrast, the expression of Fas mRNA and protein in SGC7901 Fas/VCR cells increased. Fas gene and Bcl-2 antisense nucleic acid transfection sensitized drug resistant gastric cancer cells to chemotherapeutic drugs. These results suggest cell apoptosis plays an important role in the mechanism of MDR, and enhancing apoptosis might reverse MDR.
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PMID:Transduction of Fas gene or Bcl-2 antisense RNA sensitizes cultured drug resistant gastric cancer cells to chemotherapeutic drugs. 1181 36

AIM:To construct Hsp90 antisense RNA eukaryotic expression vector, transfect it into SGC7901 and SGC7901/VCR of MDR-type human gastric cancer cell lines, HCC7402 of human hepatic cancer and Ec109 of human esophageal cancer cell lines, and to study the cell cycle distribution of the gene transected cells and their response to chemotherapeutic drugs.METHODS:A 1.03kb cDNA sequence of Hsp90beta was obtained from the primary plasmid phHSP90 by EcoR I and BamH I nuclease digestion and was cloned to the EcoR I and BamH I site of the pcDNA by T4DNA ligase and an antisense orientation of Hsp90beta expression vector was constructed. The constructs were transfected with lipofectamine and positive clones were selected with G418. The expression of RNA was determined with dot blotting and RNase protection assay, and the expression of Hsp90 protein determined with western blot. Cell cycle distribution of the transfectants was analyzed with flow cytometry, and the drug sensitivity of the transfectants to Adriamycin (ADR), vincrinstine (VCR), mitomycin (MMC) and cyclophosphamide (CTX) with MTT and intracellular drug concentration of the transfectants was determined with flow cytometry.RESULTS:In EcoR I and BamH I restriction analysis, the size and the direction of the cloned sequence of Hsp90beta remained what had been designed and the gene constructs were named pcDNA-Hsp90.AH-SGC7901, AH-SGC7901/VCR, AH-HCC7402 and AH-Ec109 cell clones all expressed Hsp90 anti-sense RNA. The expression of Hsp90 was down-regulated in AH-SGC7901, AH-SGC7901/VCR, AH-HCC7402 and AH-Ec109 cell clones. Cell cycle distribution was changed differently. In AH-SGC7901/VCR and AH-Ec109 cells, G(1) phase cells were increased; S phase and G(2) phase cells were decreased as compared with their parental cell lines. In AH-SGC7901 cell, G(1)phase cells were decreased, G(2) phase cells increased and S phase cells were not changed, and in AH-HCC7402 cells G(1), S and G(2) phase cells remained unchanged as compared with their parental cell lines. The sensitivity of AH-SGC7901, AH-SGC7901/VCR, AH-HCC7402 and AH-Ec109 to chemotherapeutic drugs, the sensitivity of AH-SGC7901/VCR to ADR, VCR, MMC and CTX the sensitivity of AH-HCC7402 to ADR and VCR, and the sensitivity of Ec109 to ADR, VCR and CTX all increased as compared with their parental cell lines. The mean fluorescence intensity of ADR in AH-SGC7901, AH-SGC7901/VCR, AH-HCC7402 and AH-Ec109 was also significantly elevated (P < 0.05).CONCLUSION: Down-regulation of Hsp90 could change cell cycle distribution and increase the drug sensitivity of tumor cells.
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PMID:Down-regulation of Hsp90 could change cell cycle distribution and increase drug sensitivity of tumor cells. 1181 30

AIM:To observe the drug sensitizing effect and related mechanisms of fas gene transduction on human drug-resistant gastric cancer cell SGC7901/VCR (resistant to Vincristine).METHODS:The cell cycle alteration was observed by FACS. The sensitivity of gastric cancer cells to apoptosis was determined by in vitro apoptosis assay. The drug sensitization of cells to several anti-tumor drugs was observed by MTT assay. Immunochemical method was used to show expression of P-gp and Topo II in gastric cancer cells.RESULTS:Comparing to SGC7901 and pBK-SGC7901/VCR, fas-SGC7901/VCR showed decreasing G2 cells and increasing S cells, the G2 phase fraction of pBK-SGC7901/VCR was about 3.0 times that of fas -SGC7901/VCR but S phase fraction of fas -SGC7901/VCR was about 1.9 times that of pBK-SGC7901/VCR, indicating S phase arrest of fas-SGC7901/VCR. FACS also suggested apoptosis of fas-SGC7901/VCR.fas-SGC7901/VCR was more sensitive to apoptosis inducing agent VM-26 than pBK-SGC7901/VCR. MTT assay showed increased sensitization of fas-SGC7901/VCR to DDP, MMC and 5-FU, but same sensitization to VCR according to pBK-SGC7901/VCR. SGC7901, PBK-SGC7901/VCR and fas -SGC7901/VCR had positively stained Topo II equally. P-gp staining in pBK-SGC7901/VCR was stronger than in SGC7901, but there was little staining of P-gp in fas-SGC7901/VCR.CONCLUSION:fas gene transduction could reverse the MDR of human drug-resistant gastric cancer cell SGC7901/VCR to a degree, possibly because of higher sensitization to apoptosis and decreased expression of P-gp.
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PMID:Suppression of P-gp induced multiple drug resistance in a drug resistant gastric cancer cell line by overexpression of Fas. 1181 71

The cytokines IL-6, initially recognized as a regulator of immune and inflammatory response and IL-8, a potential regulator of angiogenesis, also regulate the growth of many tumor cells. Human cancer cells selected for multidrug resistance to common chemotherapeutic agents demonstrate increased expression of IL-6 and IL-8. To determine whether IL-6 or IL-8 overexpression contributes directly to the drug resistant phenotype, IL-6 or IL-8 cDNA were introduced into the paclitaxel sensitive human osteosarcoma cell line U-2OS using the pIRESneo bicistronic expression vector. Interleukin-6 and IL-8 transfectants were selected for either high IL-6 or IL-8 secretion and evaluated in drug resistance assays. Two IL-6 and two IL-8 secreting clones express IL-6 or IL-8 levels of 10 ng/ml and 1 ng/ml in culture, while parental U-2OS and pIRESneo vector transfected control cells express IL-6 and IL-8 levels of 0.005 ng/ml and 0.1 ng/ml, respectively. MTT cytotoxicity with IL-6 transfected cells demonstrates a five-fold increase in resistance to paclitaxel and a four-fold increase in resistance to doxorubicin as compared to U-2OS. There are no changes in mitoxantrone or topotecan resistance in the IL-6 transfectants as compared to parental U-2OS. Northern analysis of IL-6 transfectants demonstrates that the resistant phenotype is not related to increased levels of MDR-1, MRP-1, or LRP. Western analysis also confirms that P-glycoprotein levels are not altered in IL-6 transfectants. Further supporting an MDR-1 independent mechanism of drug resistance, verapamil cannot reverse paclitaxel resistance in transfected cells, findings further supported by rhodamine 123 exclusion data. Treatment of IL-6 transfected cells with paclitaxel, compared with drug-sensitive parental U-2OS, shows U-2OS(IL-6) are significantly more resistant to apoptosis induced by paclitaxel and exhibit decreased proteolytic activation of caspase-3. In contrast U-2OS(IL-8) transfectants demonstrate no appreciable increase in paclitaxel resistance when compared with parental cells. In summary, while both IL-6 and IL-8 are overexpressed in paclitaxel resistant cell lines, only IL-6 has the potential to contribute directly to paclitaxel and doxorubicin resistance in U-2OS. This resistance is through a non-MDR-1 pathway.
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PMID:Overexpression of IL-6 but not IL-8 increases paclitaxel resistance of U-2OS human osteosarcoma cells. 1202 4

We conducted the present study to determine the chemoresistance mechanisms in clear cell carcinoma of the ovary (CCC). Five human CCC cell lines (HAC-2, RMG-I, RMG-II, KK, and KOC-7c) were used in this study. The sensitivity of the cells to the anticancer agents was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and we assessed drug sensitivity by calculating assay area under the curve (AUC) for each agent. The expression of multi-drug resistance genes (MDR-1, MRP-1, MRP-2) was detected by reverse transcription-polymerase chain reaction (RT-PCR). Glutathione (GSH) concentration was measured by an enzymatic assay. Topoisomerase (topo) I activity was assayed in terms of relaxation of supercoiled plasmid substrate DNA. The IC(50) to anticancer agents ranged widely. The assay AUC indicated that 3 of 5 cell lines (RMG-I, RMG-II, and KK) were sensitive to paclitaxel (PTX), 3 (HAC-2, RMG-I, and RMG-II) were sensitive to 7-ethyl-10-hydroxycamptothecin (SN-38), which is an active metabolite of camptothecin (CPT-11), and only one (HAC-2) was sensitive to cisplatin (CDDP). All cell lines were resistant to mitomycin-C (MMC) and etoposide (VP-16). The MRP-1 gene was detected in all cell lines. Only one cell line showed both MRP-2 and MDR-1 gene expression. Except for HAC-2 cells, expression of MRP genes was related to CDDP resistance, and MDR-1 gene expression was associated with PTX resistance. GSH concentrations increased after exposure to CDDP or MMC in all cell lines. There was a significant correlation between topo-I enzymatic activity and the response to SN-38. The present study revealed several resistance mechanisms in CCC and the results suggested that PTX and CPT-11 might be effective agents to treat CCC.
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PMID:Sensitivity to anticancer agents and resistance mechanisms in clear cell carcinoma of the ovary. 1207 22

We examined the effects of suppressing multidrug resistance-associated protein (MRP) and multidrug resistance 1 (MDR1) gene expression in HCT-8DDP human colon cancer cell lines, which showed both cisplatin and multidrug resistance. Hammerhead ribozymes, designed to cleave MRP mRNA (anti-MRP Rz) and MDR1 mRNA (anti-MDR1 Rz), were transfected into the HCT-8DDP cells. Drug sensitivity was estimated by MTT assay in vitro. The HCT-8DDP/anti-MRP Rz cells were more sensitive to doxorubicin (DOX) and etoposide (VP-16) by 2.5- and 4.1-fold, respectively, compared with HCT-8DDP cells. The HCT-8DDP/anti-MDR Rz cells were more sensitive to DOX and VP-16 by 2.3- and 3.8-fold, respectively. The anti-MRP Rz and anti-MDR1 Rz significantly down-regulated resistance to DOX and VP-16, while anti-MRP Rz and anti-MDR1 Rz did not affect resistance to cisplatin, methotrexate and 5-fluorouracil. The hammerhead ribozyme-mediated specific suppression of MRP or MDR1 was sufficient to reverse multidrug resistance in the human colon cancer cell line.
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PMID:Reversal of drug resistance using hammerhead ribozymes against multidrug resistance-associated protein and multidrug resistance 1 gene. 1237 Jul 50

The anti-tumour activity of pyrido[1',2':1,2]imidazo[4,5-h]quinazoline (PIQ) was investigated in vitro and in vivo with a human tumour model. In vitro PIQ cytotoxicity was evaluated on two different human parental-sensitive cancer cell lines (HL60S and A2780S) and their multidrug-resistant variant sublines (HL60R and A2780R). Proliferation was assessed using the MTT assay and PIQ showed activity, particularly with resistant cell lines. Drug activity was not affected by MDR resistance. After LD50 determination using Swiss mice, in vivo activity with A2780 ovarian carcinoma was carried out using xenografted Swiss nude mice. We performed either a weekly intra-peritoneal injection of 64 mg.kg-1 PIQ or an intra-venous injection of 10 mg.kg-1 PIQ during 2 months. After 60 days of treatment, no toxicologically meaningful differences were observed in macroscopic and microscopic parameters compared to controls. Both regimens demonstrated efficacy against xenografted tumours. However, the decrease in tumoural volume of the xenografted mice was significant only in the PIC i.v. injection group. Pharmacokinetics and the accumulation of PIQ in normal and tumour tissues were also assessed using a chromatographic method. The lack of activity using the i.p. route was explained by the four-fold reduction of its AUC in comparison to the i.v. route. After an i.v. injection, the highest concentrations of PIQ were accumulated in the tumour and spleen. Drug analysis has shown that PIQ intercalates into DNA. PIQ derivatives are effective new antitumour agents in cancer chemotherapy.
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PMID:In vitro and in vivo pharmacological characterisation of the antitumour properties of pyrido[1',2':1,2]imidazo[4,5-h]quinazoline. 1253 88

To explore the relationship of multidrug resistance formation in K562/A02 cells with the intracellular concentration of [Ca(2+)]i, the cytotoxicities of daunorubicin (DNR) were assayed by MTT method, the variations of [Ca(2+)]i of K562 cells and K562/A02 cells after treatment of Tet, DRL and DNR alone or in combination were detected by using Fura-2/AM. The results showed as follows: (1) The cytotoxicities of DNR to cell line K562/A02 were enhanced by 1 micro mol/L Tet or 5 micro mol/L DRL. Their IC(50) was (7.28 +/- 2.06) micro g/ml and (7.58 +/- 3.44) micro g/ml; multiple of their reversal effect was 2.94 and 2.82, but IC(50) of combined Tet and DRL was (1.66 +/- 0.41) micro g/ml. Its reverse effect distinctly increased by 12.9 times. (2) The [Ca(2+)]i in K562/A02 cells were higher than that in K562 cells. (3) One micro mol/L Tet and 5 micro mol/L DRL alone increased the [Ca(2+)]i in K562/A02 cells time-dependently and there was antagonism when both were used. It is concluded that high [Ca(2+)]i is supposed to be a reason of MDR in K562/A02 cells, the action of resistance modifying agents (RMA) in MDR reverse course, however, needs further research.
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PMID:[Study on the relationship between [Ca2+]i and the MDR formation in K562/A02 cells]. 1515 24

To study the effects of hypoxia-on the expression of P-gp and mutltidrug resistance protein in human lung adenocarcinoma A549 cell line, and to explore the probable mechanism of hypoxia in tumor cell of MDR. The expression of hypoxia inducible factor-1 alpha, P-gp and mutltidrug resistance protein was immunohistochemically detected by culturing human lung adenocarcinoma A549 cell under hypoxia (2 % O2) for 24 h. After interaction with adriamycin or cisplatin under hypoxia (2 % O2) for 24 h, the cell survival rate was detected by MTT. Our results showed that the expression of hypoxia inducible factor-1 alpha, P-gp and mutltidrug resistance protein under hypoxia were higher than the expression under normoxia, and correlations between the expression of HIF-1alpha and P-gp or multidrug resistance-associated protein was observed (P< 0.05). The resistance of adriamycin of A549 cell was enhanced under hypoxia. It is concluded that the resistance of tumor chemotherapy is enhanced in hypoxia. The expression of HIF-1alpha is obviously correlated with the expression of P-gp and mutltidrug resistance protein.
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PMID:Effects of hypoxia on expression of P-gp and mutltidrug resistance protein in human lung adenocarcinoma A549 cell line. 1620 Dec 71

A novel class of molecules with structure N-[3-(4-substituted-1-piperazinyl) propyl]-6-methoxy naphthalene-2-carboxamides were designed by generating a pharmacophore for potent MDR reversal activity, using Elacridar (GF 120918) as a query molecule and using MOE software. They were synthesized by condensing 6-methoxynaphthalene-2-carboxylic acid with N-[3-(4-substituted-1-piperazinyl) propyl] amines in the presence of DCC in DMF. They were evaluated in P388 murine lymphocytic leukemia cell line (P388) in vitro using SRB assay for cytotoxicity and in adriamycin-resistant P388 murine lymphocytic leukemia cell line (P388/ADR) using MTT assay for resistant reversal activity. Test compounds were non-toxic at the doses studied (upto 80 microg/ml). They effectively reversed adriamycin resistance at the doses studied (40 and 80 microg/ml). The percentage enhancement in adriamycin activity was in the range 33.58 -90.67 (at 40 microg/ml) and 8.80-46.04 (at 80 microg/ml) and the corresponding reversal potency values were in the range 1.33-1.90 and 1.08-1.46, respectively. Test compounds 2, 3, and 5 exhibited better activity as compared to the standard resistant reversal agent (Verapamil), at same concentration.
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PMID:Design, synthesis and evaluation of naphthalene-2-carboxamides as reversal agents in MDR cancer. 1673 Sep 93


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