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

Urokinase-type plasminogen activator receptor (UPA-R-CD87) is a GPI-anchored membrane protein which promotes the generation of plasmin on the surface of many cell types, probably facilitating cellular extravasation and tissue invasion. A flow cytometric quantitative analysis of expression levels for UPA-R was performed on fresh blast cells from patients with acute myeloid leukaemia (AML, n = 74), acute lymphoblastic leukaemia (ALL, n = 24), and biphenotypic leukaemia (BAL, n = 3) using two CD87 monoclonal antibodies (McAbs) (3B10 and VIM5). Peripheral blood and bone marrow (BM) cells from 15 healthy adults served as controls. Using 3B10 McAb, UPA-R was expressed (>99%) by blood monocytes, neutrophils, and BM myelomonocytic precursors in controls, whereas resting T and B lymphocytes, and CD34+ cells were UPA-R negative. We also attempted to clarify whether UPA-R has a role in mediating neutrophil functions. Oriented locomotion induced by different chemotaxins and lysozyme release by granules stimulated with fMLP or PMA were significantly decreased when UPA-R was neutralized by CD87 McAb. In contrast, the anti-UPA-R McAb had no effect on superoxide anion generation of normal neutrophils. Blasts from AML showed a heterogenous pattern of expression for the UPA-R McAbs, with reactivity strictly dependent on FAB subtype. The highest UPA-R expression was seen in the M5 group: all patients tested (n = 20) showed strong positivity for the UPA-R McAb whereas only 12% (3/24) of ALL patients were CD87 positive, and 2/3 of BAL patients showed a dim expression for CD87. The number of receptors expressed by blast cells in 6/74 (8.1%) AML patients was higher than those of normal samples: in addition, since co-expression of UPA-R and CD34 was not found in normal haemopoietic cells, it may be postulated that CD87 can be used alone (when overexpressed) or in combination with CD34 for the detection of minimal residual disease. Results also indicated that patients with UPA-receptors >12 x 10(3) ABC/cell, irrespective of FAB subtype, had a greater tendency for cutaneous and tissue infiltration and a higher frequency of chromosome abnormalities, thus suggesting the concept that cellular UPA-R content positively correlates with the invasive potential of AML cells. The combination of higher UPA-R positivity, abnormalities of chromosome 11, and M5 FAB morphology may identify a peculiar subset of AML, characterized by a more aggressive clinical course.
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PMID:Expression and functional role of urokinase-type plasminogen activator receptor in normal and acute leukaemic cells. 979 97

Glibenclamide is well known to interact with the sulphonylurea receptor (SUR) and has been shown more recently to inhibit the cystic fibrosis transmembrane conductance regulator protein (CFTR), both proteins that are members of the ABC [adenosine 5'-triphosphate (ATP)-binding cassette] transporters. The effect of glibenclamide and two synthetic sulphonylcyanoguanidine derivatives (dubbed BM-208 and BM-223) was examined on P-glycoprotein, the major ABC transporter responsible for multidrug resistance (MDR) in cancer cells. To this end, we employed different cell lines that do or do not express P-glycoprotein, as confirmed by Western blotting: first, a tumour cell line (VBL600) selected from a human T-cell line (CEM) derived from an acute leukaemia; second, an epithelial cell line derived from a rat colonic adenocarcinoma (CC531(mdr+)) and finally, a non tumour epithelial cell line derived from the proximal tubule of the opossum kidney (OK). Glibenclamide and the two related derivatives inhibited P-glycoprotein because firstly, they acutely increased [3H]colchicine accumulation in P-glycoprotein-expressing cell lines only; secondly BM-223 reversed the MDR phenomenon, quite similarly to verapamil, by enhancing the cytotoxicity of colchicine, taxol and vinblastine and thirdly, BM-208 and BM-223 blocked the photoaffinity-labelling of P-glycoprotein by [3H]azidopine. Furthermore, glibenclamide is itself a substrate for P-glycoprotein, since the cellular accumulation of [3H]glibenclamide was low and substantially increased by addition of P-glycoprotein substrates (e. g., vinblastine and cyclosporine) only in the P-glycoprotein-expressing cell lines. We conclude that glibenclamide and two sulphonylcyanoguanidine derivatives inhibit P-glycoprotein and that sulphonylurea drugs would appear to be general inhibitors of ABC transporters, suggesting an interaction with some conserved motif.
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PMID:P-glycoprotein inhibition by glibenclamide and related compounds. 1008 41

Leukaemia inhibitory factor (LIF) is a neuropoietic cytokine, which promotes the development of enteric neurons in vitro, particularly when administered together with neurotrophin-3 (NT-3). The purpose of this study was to map the LIF immunoreactivity in the human enteric nervous system in foetuses, children, adults, and in patients with Hirschsprung's disease. Normal bowel specimens were obtained at postmortem examination of 13 foetuses, at 13-31 weeks of gestation, and at surgery in five children and two adults. Bowel resected in seven patients with Hirschsprung's disease was also investigated. Immunohistochemical analysis was performed on material fixed in formalin and embedded in paraffin. The specimens were exposed to antibodies raised against LIF. The ABC-complex method was used to visualise binding of antibodies to the corresponding antigen. LIF immunoreactivity was disclosed in the myenteric and submucous ganglion cells at 13-31 weeks of gestation, in childhood cases, and adults. LIF-immunoreactive ganglion cells were absent in aganglionic bowel, where the ganglia in the intermuscular layer were replaced by hypertrophic nerve bundles. These morphological findings indicate that LIF may play a role in the development of the enteric nervous system.
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PMID:Expression of leukaemia inhibitory factor during the development of the human enteric nervous system. 1094 48

To study the change of suppressing cancer gene P16 in acute leukemia, the P16 antigen expression of leukemia cell surfaces in 61 cases were investigated with ABC assay and gene structural defects in 51 cases of acute leukemia were examined with multiple comparative PCR method. It was found that antigen expression of P16 in leukemia was obviously lower than that innormal subjects (P < 0.001). At the same time, antigen expression in All was lower than that AML (P < 0.05). No significant difference was found between the complete remission (CR) and non-remission (NR) subjects from AML and ALL groups (P > 0.05). THe exon 2 of P16 gene showed homozygous deletion only inn 4 cases out of 30 cases in ALL. No structural defect was revealed in 21 cases of AML. It was suggested that expression defect of P16 gene was a main cause in development and progression of acute leukemia, and structural defect of exon 2 was not a primary molecular event.
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PMID:Study on P16 gene in acute leukemia. 1121 50

The breast cancer resistance protein (BCRP), also known as mitoxantrone resistance protein (MXR) or placenta ABC protein (ABC-P), is the second member of the ABCG subfamily of ABC transport proteins (gene symbol ABCG2). BCRP has been detected in acute myeloid leukaemia and in breast, colon and gastric cancer but there has been no reports regarding BCRP expression in acute lymphoblastic leukaemia (ALL). We report the first results of BCRP expression in childhood ALL. Sixty-seven children (47 initial stage, 20 relapses) with ALL were analysed for BCRP gene expression by TaqMan real-time polymerase chain reaction. The expression of BCRP in mononuclear cells obtained from the bone marrow (BM) and peripheral blood (PB) of healthy donors was also investigated. There was no relationship between BCRP expression and age, sex, initial blast cell count, prednisolone response or BM response on d 15 and 33. Patients with T-lineage ALL showed a lower expression of BCRP (P = 0.044). Kaplan-Meier analysis of the relapse-free interval showed no prognostic significance of BCRP expression when different levels of BCRP expression were used as cut-off points. No significant difference in expression of BCRP mRNA was measured between initial-stage and relapsed-stage ALL or between normal MNC obtained from BM and ALL patients. The results indicate a low expression of BCRP in childhood ALL. Relationships between BCRP and clinical, molecular or in vivo resistance characteristics of the patients were not observed.
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PMID:Expression of the BCRP gene (ABCG2/MXR/ABCP) in childhood acute lymphoblastic leukaemia. 1210 Jan 41

Breast cancer resistance protein (BCRP), also known as mitoxantrone resistance protein (MRX) or placenta ABC protein (ABC-P), is the second member of the ABCG subfamily of ABC transport proteins (gene symbol ABCG2). Transfection and enforced expression of BCRP in drug-sensitive cells confers resistance to mitoxantrone, doxorubicin, daunorubicin and topotecan. In this study the expression of BCRP gene was measured using TaqMan real-time PCR in 59 children with newly diagnosed AML. Nine patients were also analyzed in relapse. The median of BCRP gene expression was more than 10 times higher in patients who did not achieve remission after the first phase of chemotherapy (n = 24) as compared to patients who did achieve remission at this stage (n = 21; P = 0.012). In first relapse the expression of the BCRP gene was higher than at diagnosis (P = 0.038). Although high levels of BCRP gene expression were more frequent in subtypes of AML with a favorable prognosis, we found that within both risk groups (high and low risk), patients who expressed high levels of BCRP had a worse prognosis (P = 0.023). Our results strongly suggest that the expression of the BCRP gene reduces the response to chemotherapy in AML and that BCRP expression is higher at the time of relapse.
Leukemia 2002 Aug
PMID:BCRP gene expression is associated with a poor response to remission induction therapy in childhood acute myeloid leukemia. 1214 83

Our study examines the ability of LY335979 (Zosuquidar trihydrochloride) to modulate 3 distinct ABC transporters that are mechanisms of drug resistance: P-glycoprotein (Pgp, ABCB1), multidrug resistance associated protein (MRP1, ABCC2) and breast cancer resistance protein (BCRP, ABCG2). Pgp-mediated resistance can be modulated by coadministration with the highly potent, selective inhibitor, LY335979. Modulation of resistance by mitoxantrone and vinorelbine, 2 drugs used to treat certain solid tumors, was examined in a 3-day cytotoxicity assay using a panel of HL60 leukemia cell lines or MCF-7 breast cancer transfectants. LY335979, at 0.5 microM, substantially reversed mitoxantrone resistance and fully reversed vinorelbine resistance of Pgp-expressing HL60/Vinc cells. However, LY335979 did not modulate drug resistance in the MRP1-expressing HL60/ADR or drug-sensitive parental HL60 cells. To ascertain if LY335979 modulates BCRP-mediated drug resistance, the sensitivity of 26-fold mitoxantrone resistant, BCRP-transfected MCF-7 cells was evaluated. Addition of 5 microM LY335979, a concentration approximately 100-fold higher than the affinity of Pgp, had little to no effect on the BCRP transfectant. [(125)I]Iodomycin photolabeled Pgp in CEM/VLB(100) membranes and was inhibited by 5 microM LY335979 and GF120918. No photolabeling of MRP or BCRP occurred in H69AR or MCF-7/BCRP membranes, respectively. These results further demonstrate that LY335979 is highly specific for Pgp and does not modulate MRP1- or BCRP-mediated resistance and can be used in combination with mitoxantrone and vinorelbine in tumor cells.
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PMID:Modulation of P-glycoprotein but not MRP1- or BCRP-mediated drug resistance by LY335979. 1245 64

To explore Bcl-2 and P53 gene proteins expression on human leukemia cells and their relationship with chemotherapeutic efficacy, Bcl-2 and P53 gene proteins expression was assayed by ABC immunohistochemical staining. Results showed that the expression rates of Bcl-2 and P53 gene proteins were 67% and 41% respectively in leukemia cells from 52 patients. While there was no difference of Bcl-2 protein level in ALL and ANLL, the P53 protein level was higher in ANLL than that in ALL (P < 0.05). When CML patients got into the blast crisis phase, the level of Bcl-2 and P53 proteins became very high. Compare with previously untreated AL, relapse/refractory AL patients had higher Bcl-2 and P53 protein level, lower marrow complete remission, and was easy to relapse. The expression of Bcl-2 and P53 protein could be used as new predictors of chemotherapeutic efficacy and prognosis in patients with leukemia. The high protein expression of Bcl-2 and P53 demonstrated that CML was conversion to blast crisis phase.
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PMID:[Expression of Bcl-2 and P53 Gene Proteins on Leukemia Cells and Its Correlation with Chemotherapeutic Efficacy] 1257 96

1. Our previous studies revealed that the immunosuppressive agent, FTY720, mainly induces mitochondria-involved apoptosis in some types of cancer cells, since Bcl-2 overexpression prevents the FTY720-induction of apoptotic stimuli. Furthermore, FTY720 induces G0/G1 cell cycle arrest. The present study further examines the correlation between intracellular signaling kinases with FTY720-induced mitochondria-involved apoptosis. 2. Human T cell leukemia Jurkat was exposed to FTY720. Dephosphorylation of Akt occurred in a time- and concentration-dependent manner. FTY720 also induced Bad (Ser(136)) and ribosomal p70S6 kinase (p70(S6k)) (Thr(389)) dephosphorylation. 3. FTY720-induced Akt dephosphorylation was not because of Akt upstream phosphatidylinositol 3'-kinase (PI 3-kinase) pathway inhibition. 4. FTY720 also induced Akt dephosphorylation in human B cell leukemia BALL-1. BALL-1 cells were resistant to FTY720-induced apoptosis. 5. Okadaic acid (OA) inhibited the FTY720-induced dephosphorylation of Akt and p70(S6k), suggesting that FTY720 promotes Ser/Thr protein phosphatase (PP) activity. 6. OA partially inhibited FTY720-induced caspase-3 activation. 7. PP2A or PP2A-like phosphatase was temporarily activated in cells exposed to FTY720. In addition, FTY720 activated purified PP2A (ABC). 8. Overall, the results suggest that FTY720 activated PP2A or PP2A-like phosphatase and dephosphorylated Akt pathway factors resulting in the enhancement of apoptosis via mitochondria.
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PMID:A novel immunosuppressive agent FTY720 induced Akt dephosphorylation in leukemia cells. 1271 31

The multidrug resistance (MDR) phenotype, induced by the overexpression of several ABC transporters or by antiapoptotic mechanisms, has been identified as the major cause of drug resistance in the treatment of patients with acute myeloid leukemia (AML). In this study, we have shown that valproic acid (VPA) (a histone deacetylase inhibitor) can inhibit the proliferation of both P-glycoprotein (P-gp)- and MDR-associated protein 1 (MRP1)-positive and -negative cells. VPA also induced apoptosis of P-gp-positive cells. VPA induced apoptosis in K562 cells led to decrease in Flip (FLICE/caspase-8 inhibitory protein) expression with Flip cleavage, which could not be observed in HL60 cells. In HL60/MRP cell line, which proved to be resistant to apoptosis by VPA, we observed an abnormal expression of apoptotic regulatory proteins, overexpression of Bcl-2 and absence of Bax. Also, the Bcl-2 antagonist HA14-1 rapidly restored apoptosis in this cell line. Cotreatment with cytosine arabinoside induced very strong apoptosis in both K562/DOX and HL60/DNR cell lines. VPA also induced apoptosis in AML patient cells expressing P-gp and/or MRP1. Our findings show VPA as an interesting drug that should be tested in clinical trials for overcoming the MDR phenotype in AML patients.
Leukemia 2004 Jul
PMID:Valproic acid inhibits proliferation and induces apoptosis in acute myeloid leukemia cells expressing P-gp and MRP1. 1511 23


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