Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multi-drug resistance (MDR) phenotype contributes to the ineffectiveness of chemotherapy. P-glycoprotein (PgP) and lung resistance protein (LRP) are proteins implicated in chemoresistance. We analysed the expression of PgP and LRP respectively in 17 and 15 cases of lymphoproliferative disease of granular lymphocytes (LDGL) including 10 cases of clonal large granular lymphocytic (LGL) leukaemia, six cases of oligoclonal (n = 5) and polyclonal (n = 1) CD3+ lymphoproliferation and one case of CD3- NK lymphocytosis. Functional PgP activity, as determined by Rh123 dye efflux assay, was found in all the patients. The mean percentage of effluxing cells was 47 +/- 22%, compared to 35 +/- 8% on normal lymphocytes (P<0.04). The efflux was blocked in the presence of verapamil, a PgP revertant agent. A high proportion of CD57+ cells (66 +/- 10%) from these patients expelled Rh123. Functional PgP activity was associated with expression of MDR1 mRNA. By using immunocytochemistry, LRP expression was detected in 11/15 patients (73%). 7/10 LGL leukaemia patients presented a LRP+/Efflux+ phenotype and 5/7 had LRP+/Efflux+/MDR1 mRNA+ phenotype. These findings suggest that the PgP+/LRP+ phenotype is frequently observed in LDGL. Its clinical relevance in aggressive cases remains to be determined.
 ...
PMID:Multidrug resistance analysis in lymphoproliferative disease of large granular lymphocytes. 950 33

Overexpression of P-glycoprotein (P-gp), the protein product of the multidrug resistance gene (MDR1), confers a drug resistant phenotype on cells. This phenotype is reminiscent of human T-cell leukemia virus (HTLV)-transformed leukemic cells, for which no consistently effective chemotherapeutic regime has been found. The presence of an active multiple drug resistance (MDR) phenotype in freshly isolated peripheral blood mononuclear cells (PBMC) from HTLV-I-infected subjects was investigated. Significant P-gp-mediated efflux activity and enhanced MDR1 mRNA expression was observed in nine of 10 HTLV-infected subjects. The development of MDR phenotypes was found to be independent of disease type or status with significant MDR activities being observed in adult T-cell leukemia (ATL), HTLV-associated myelopathy (HAM)/tropical spastic paraparesis (TSP), and asymptomatic HTLV-infected individuals. P-gp-mediated drug efflux was also found to be restricted to CD3+ T-cell populations. Furthermore, we show the novel finding that the MDR1 gene promoter is transcriptionally activated by the HTLV-I tax protein, suggesting a molecular basis for the development of drug resistance in HTLV-I infections. These observations open up the possibility of new chemotherapeutic approaches to HTLV-associated diseases through the use of P-gp inhibitors.
 ...
PMID:Enhanced MDR1 gene expression in human T-cell leukemia virus-I-infected patients offers new prospects for therapy. 951 47

In this article we review the in vivo model systems that have been developed for studying P-glycoprotein-mediated multidrug resistance (MDR) in the preclinical setting. Rodents have two mdr genes, both of which confer the MDR phenotype: mdr 1a and mdr 1b. At gene level they show strong homology to the human MDR1 gene and the tissue distribution of their gene product is very similar to P-glycoprotein expression in humans. In vivo studies have shown the physiological roles of P-glycoprotein, including protection of the organism from damage by xenobiotics. Tumors with intrinsic P-glycoprotein expression, induced MDR or transfected with an mdr gene, can be used as syngeneic or xenogenic tumor models. Ascites, leukemia, and solid MDR tumor models have been developed. Molecular engineering has resulted in transgenic mice that express the human MDR1 gene in their bone marrow and in knockout mice missing a murine mdr gene. The data on pharmacokinetics, efficacy, and toxicity of chemosensitizers of P-glycoprotein in vivo are described. Results from studies using monoclonal antibodies directed against P-glycoprotein and other miscellaneous approaches for modulation of MDR are mentioned. The importance of in vivo studies prior to clinical trials is being stressed and potential pitfalls due to differences between species are discussed.
 ...
PMID:In vivo model systems in P-glycoprotein-mediated multidrug resistance. 953 18

To overcome the problem of multidrug resistance, we investigated the effectiveness of phosphrothioate antisense oligonucleotides (MDR1-AS) in suppressing multidrug resistance gene (mdr1) expression in drug-resistant acute myelogenous leukemia (AML) blast cells and the K562 adriamycin-resistant cell line K562/ADM. The percentage of cells with the mdr1 gene product P-glycoprotein (P-gp) was decreased from 100% to 26% by 20 micromol/L MDR1-AS in the K562/ADM cells, and from 48.1% to 10.2% by 2.5 micromol/L MDR1-AS in the AML blast cells. Western blot analysis also showed a decrease in the amount of P-gp in the MDR1-AS-treated K562/ADM cells. This effect was specific to MDR1-AS, and not observed with sense or random control oligonucleotides. The expression of mdr1 mRNA in K562/ADM and AML blast cells treated with MDR1-AS was decreased compared with the random control. Intracellular rhodamine retention and [3H]daunorubicin also increased after antisense treatment. Chemosensitivity to daunorubicin increased in MDR1-AS-treated blast cells up to 5.9-fold in the K562/ADM cells and 3.0- to 6.4-fold in the AML blast cells. The expression of mdr1 mRNA derived from colony cells decreased in the MDR1-AS-treated groups. No inhibitory effect of the oligonucleotides on normal bone marrow progenitors was observed. These findings suggest that MDR1-AS is useful to overcome multidrug resistance in the treatment of leukemia.
 ...
PMID:Inhibition of P-glycoprotein and recovery of drug sensitivity of human acute leukemic blast cells by multidrug resistance gene (mdr1) antisense oligonucleotides. 955 71

Multidrug resistance (MDR) in leukemia and the reversal of MDR by cyclosporin A (CsA) in vitro have been studied through intracellular accumulation of daunorubicin (DNR) in leukemic myeloblasts. The study was carried out with real-time flow cytometry and relative expression levels of MDR, which is estimated by RNA in situ hybridization in 26 patients suffering from leukemia. The change of intracellular DNR accumulation in vitro after adding CsA was also analyzed. The results showed that intracellular DNR accumulation in newly diagnosed and treated patients (MDR1 negative) with remission increased significantly than that in refractory and relapsing patients (P < 0.01). Good reversal effect was obtained in refractory patients and MDR1 positive relapsing patients by adding CsA (P < 0.01). It is suggested that MDR detection by the two above-mentioned methods could help to project the chemotherapy schedule clinically, CsA had obvious reversal effect on the drug-resistant leukemic cells in vitro.
 ...
PMID:[Detection of multidrug resistance in patients with leukemia by using flow cytometry and RNA in situ hybridization]. 959 51

Cells with multidrug resistance (MDR) phenotype express P-glycoprotein (P-gp) on the cell membrane, which functions as a drug-efflux pump. To quantify the expression of the gene encoding P-gp (multidrug resistance 1; MDR1) and assess P-gp function, we developed competitive reverse transcription-polymerase chain reaction (RT-PCR) assay using heterologous competitor RNA and flow cytometric analysis using rhodamine 123 (Rh123; an artificial substrate for P-gp), respectively. First, we adjusted the assays by analyzing leukemia sublines showing various levels of MDR1 expression. The MDR1 expression in leukemia sublines quantified by competitive RT-PCR assay showed linearity over a wide range, and the results were parallel with those of MDR1 expression measured by Northern blot analysis, the P-gp antigen expression measured by flow cytometric analysis using MRK16, P-gp function analysis by Rh123 dye-efflux assay, and MDR phenotype. Then, we applied these assays to leukemic cells from patients with hematological malignancies. All 69 samples from 64 patients were successfully assayed, and the range of MDR1 expression was from 1.6 to 100 amol/microgram RNA. Since subpopulations of normal lymphocytes show a low degree of P-gp function, strict gating of leukemia cells was mandatory for dye-efflux assay of clinical samples. MDR1 expression in normal lymphocytes was below 8 amol/microgram RNA. By comparison to MDR1 expression quantified by competitive RT-PCR assay with P-gp function assessed by Rh123 dye-efflux assay in gated leukemic cells, more than 8 amol/microgram RNA was regarded as positive MDR1 expression in the leukemic cells themselves. These data suggest that these assays are suitable for evaluating P-gp expression and function in clinical samples when the proper cut-off value is used and may provide insights into the contribution of P-gp to drug resistance in hematological malignancies.
 ...
PMID:[Quantitative analysis of multidrug resistance phenotype in hematological malignancies]. 959 30

We examined the cytotoxic effects of free daunorubicin (DNR) and liposome-encapsulated DNR on multidrug-resistant (MDR1) leukemia cells of patients with acute leukemias who had failed primary induction treatment that included DNR. This was analyzed ex-vivo with DNR concentrations and exposure times that normally can be achieved in-vivo for both drugs with induction treatment. The leukemic blasts of patients both with drug-resistant AML and drug-resistant ALL were, ex-vivo, very sensitive to DNR concentrations and exposure times that can be achieved in-vivo by liposome-encapsulated DNR. However, under identical conditions, free DNR and liposome-encapsulated DNR had a similar cytotoxic profile, arguing against a unique mechanism of cytotoxicity by the liposomal constructure. These data suggest that liposome-encapsulated DNR may be preferable to free DNR for the treatment of acute leukemias.
 ...
PMID:Multidrug-resistant acute leukemia cells are responsive to prolonged exposure of daunorubicin: implications for liposome-encapsulated daunorubicin. 961 16

We evaluated a real time quantitative PCR assay using dual-labeled fluorogenic probes for clinical application. Preliminary study using the house-keeping gene, beta-actin confirmed that this method was accurate and reproducible for the quantitative detection of the genes. The system also has merit with regard to the dynamic range of the starting target molecule determination. We then investigated DNA copies of cytomegalovirus (CMV) gene in vivo. The results demonstrated on association between the quantitation of CMV-DNA copies and clinical manifestation associated with CMV infection of immunodeficiency states or infantile hepatitis. It was also successful for quantitative estimation by RT-PCR. Namely, the assay made it possible to discriminate drug-sensitive leukemia cells from resistant cells based on the MDR1 gene and dCK gene. Real time quantitative PCR assay may be useful in a variety of clinical fields.
 ...
PMID:[Quantitative PCR system]. 962 89

Treatment-induced secondary drug resistance of tumor cells is a major cause of relapsed disease and therapeutic failure in cancer patients. It has been shown that the expression of the multidrug resistance MDR1/P-glycoprotein gene could be induced by short-term in vitro exposure of cells to protein kinase C (PKC) agonists or different chemotherapeutic drugs. We studied whether other genes involved in drug resistance are regulated by similar signaling pathways. Transient (up to 24 h) treatment of HL-60 or K562 leukemia cells with phorbol 12-myristate 13-acetate (TPA) resulted in increased steady-state level of LRP (lung resistance-related protein) mRNA and protein. Among conventional chemotherapeutic drugs tested, only cytarabine (Ara C) induced the LRP mRNA expression though no increase in LRP protein was detected. LRP gene activation was not detectable in either H9 T-cell leukemia or in solid carcinoma cell lines (BT-20, ZR-75-1, and SW 1573). None of the agents influenced the levels of MRP (multidrug resistance-associated protein) mRNA in any cell line tested. In HL-60 cells, the LRP activation by TPA or Ara C was sustained for at least 23 days after withdrawal of inducing agents. bis-Indolylmaleimide I, a potent PKC inhibitor, attenuated TPA-induced LRP activation. In contrast, the inhibitor had no effect on the LRP induction by Ara C. These data indicate that the LRP gene can be activated by different mechanisms, some of which involve PKC.
 ...
PMID:Activation of the LRP (lung resistance-related protein) gene by short-term exposure of human leukemia cells to phorbol ester and cytarabine. 977 89

P-glycoprotein (P-gp), a transmembrane efflux pump encoded by the MDR1 gene, has been found to be expressed in many normal bone marrow and peripheral blood cells. Among normal leukocytes, CD3(-)CD16(+) or CD3(-)CD56(+) lymphocytes, ie, natural killer (NK) cells, express relatively high levels of P-gp, but little is known about P-gp in abnormally expanded NK cells. In this study, we examined the expression and activity of P-gp on NK cells derived from three normal donors, six patients with indolent NK cell-lineage granular lymphocyte-proliferative disorder (NK-GLPD), three patients with aggressive NK cell tumors (one NK cell leukemia and two nasal NK cell lymphoma), and two NK cell lines. By flow cytometric analysis using the monoclonal antibody (MoAb) MRK16 and rhodamine 123 dye (Rh123), P-gp expression and the efflux of Rh123 were found in all NK samples except one NK cell line. The Rh123 efflux of NK cells was inhibited by cyclosporin A (CsA) and its analogue PSC 833, but the aggressive NK tumor cells were less inhibited than were the other NK cells. The percent inhibition of efflux in the normal NK cells, indolent NK-GLPD cells and aggressive NK cell tumors was 81.8% +/- 0. 9%, 93.4% +/- 3.1% and 36.9% +/- 11.7%, respectively, by 1 micromol/L CsA, and 80.2% +/- 3.6%, 91.7% +/- 2.6% and 32.7% +/- 10. 1%, respectively, by 1 micromol/L PSC833. In reverse transcription-polymerase chain reaction (RT-PCR) analysis, the low inhibitory effect of P-gp modulators in aggressive NK cell tumors did not correlate to the expression level of MDR1 gene, multidrug resistance-associated protein gene, or human canalicular multispecific organic anion transporter gene. This phenomenon could be related to the presence of other transporters or to unknown cellular or membrane changes. Some patients with NK cell tumors have been reported to show a highly aggressive clinical course and to be refractory to chemotherapy, and this could be related to the expression of P-gp on NK cells. Our results suggest that, although the inhibitors for P-gp have been used in combination with chemotherapy in some hematologic tumors, these inhibitors may be less effective against aggressive NK cell tumors.
 ...
PMID:P-glycoprotein expression on normal and abnormally expanded natural killer cells and inhibition of P-glycoprotein function by cyclosporin A and its analogue, PSC833. 988 21


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>