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)

The results of intensive chemotherapy given to 247 adults at the University of Maryland Cancer Center with previously untreated de novo acute myeloid leukemia (AML) were reviewed with respect to expression of terminal deoxynucleotidyl transferase (TdT) and CD34. Of the 228 patients with data for TdT, 32 (14%) had > 5% of the leukemia cells positive by an immunofluorescence assay. The median age of the TdT-positive patients was approximately 10 years less than the TdT-negative patients (50 versus 60 years). Patients with TdT-positive AML had similar median survival (12 versus 10.5 months) and complete remission (CR) rates (53 versus 59%), but a greater frequency of long-term complete responders (60 of complete remitters versus 20%, p = 0.08) than TdT-negative patients. Of 126 patients tested, 59% were CD34-negative (< 20% reactivity with leukemia cells). These 74 patients (median age 60 years) had a greater CR rate (71 versus 48%, p = 0.008) than the 52 CD34-positive patients (median age 60 years), and improved survival (p = 0.013 by Wilcoxon) although there was no difference in the duration of CR between the CD34-positive and negative groups. Of CD34-positive patients 12/52 remain in continuous CR, and 16/74 CD34-negative patients remain in continuous CR. None of eight patients strongly positive for CD34 (> 70% reactivity) remain disease-free. Positivity for TdT or CD34 was associated with less differentiated AML. Of CD34-positive patients, 44% had FAB M0/M1 morphology versus 13% of CD34-negative patients (p = 0.0001); similarly, 47% of TdT-positive patients were FAB M0/ML1 versus 25% of TdT-negative patients (p = 0.01). Of seven patients with FAB M4E0, five were CD34-positive. Of the 12 CD34-positive survivors, four had FAB M4E0. Thus CD34 expression predicts for CR rate and overall survival in adults with AML. TdT expression does not significantly affect overall outcome but may be associated with longer CR durations.
Leukemia 1992 Nov
PMID:The significance of CD34 and TdT determinations in patients with untreated de novo acute myeloid leukemia. 127 24

We have recently demonstrated that bufalin is a new potent inducer of the differentiation of human myeloid leukemia cells. The present work was carried out to examine further the effect of bufalin on the growth and characteristics of human leukemia-derived cell lines U937, ML1, and HL60. At concentrations of 5-10 nM, bufalin decreased the growth of ML1 cells preferentially at the G2 phase and U937 cells at the S and G2 phases of the cell cycle. Bufalin, under these conditions, induced the differentiation of U937, ML1, and HL60 cells to monocyte/macrophage-like cells by measuring the expression of various differentiation markers, as assessed by morphology and histochemistry, and ability to phagocytose latex particles, to reduce nitroblue tetrazolium, and to develop Fc receptors. U937 and ML1 cells started to differentiate at 4 and 6 h, respectively, after treatment with 10 nM bufalin and showed maximum differentiation 72 h later. At present, a mechanism for the bufalin-mediated induction of the differentiation of these human leukemia cells remains to be determined. The combination of bufalin with all-trans retinoic acid, 1 alpha,25-dihydroxyvitamin D3, 4'-demethylepipodophyllotoxin ethylidene-beta-D-glucoside (VP16), or human gamma-interferon synergistically induced the differentiation of HL60 and U937 cells. A similar effect on ML1 cells was observed with the combination of bufalin with VP16 or human rTNF-alpha. These results suggest that bufalin in combination with VP16, all-trans retinoic acid, 1 alpha,25-dihydroxyvitamin D3, rTNF-alpha, or gamma-interferon may be very useful in the differentiation of human leukemia.
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PMID:Induction by bufalin of differentiation of human leukemia cells HL60, U937, and ML1 toward macrophage/monocyte-like cells and its potent synergistic effect on the differentiation of human leukemia cells in combination with other inducers. 132 88

A novel hematopoietic antigen was identified using a murine monoclonal antibody raised against KG-1 cells. This antigen, termed MKW, was also detected on the surface of the monocytic cell line U937, but not on the K562, ML1, or HL-60 cell lines. On normal hematopoietic cells, the antigen is expressed on the surface of monocytic and myelocytic cells and on a subpopulation of B-cells. During normal hematopoiesis, the surface expression of MKW is greatest and occurs very early on monocytic cells. Alternatively, in myeloid cells, surface expression occurs later and cell maturation is correlated with increased surface expression. When U937 cells are induced to differentiate, surface expression is transiently up-regulated. Surface expression of MKW, however, does not appear to be an activation antigen since activation of purified T- or B-cells failed to increase MKW on the cell surface. Leukemic blasts from 22 of 80 children (27%) with acute myeloblastic leukemia and from 29 of 225 children (13%) with acute lymphoblastic leukemia expressed MKW on the cell surface. Although surface expression of MKW was absent on T-cell lines, peripheral T-cells, and most B-cells, the antigen was identified in the cytoplasm of some B-cells, T-cells, and cell lines. Immunoprecipitation studies showed that MKW is a 52-kDa protein whether expressed on the cell surface or in the cytoplasm, and it appears to be nonglycosylated. Furthermore, studies with phosphatidylinositol-phospholipase C suggested that MKW is not attached to a glycolipid anchor. The biochemical characterization of MKW and its pattern of expression are distinct from any of the previously identified CD groups or published antigens. Since this unique antigen has prognostic significance in leukemia and appears to be associated with cell differentiation, its exact role in hematopoiesis should be investigated.
Leukemia 1992 Oct
PMID:MKW, a novel hematopoietic antigen. 132 77

DNA topoisomerase inhibitors, camptothecin and 4'-demethylepipodophyllotoxin ethylidene-beta-D-glucoside (VP16) had strong differentiation-inducing activity for all five kinds of leukemia cells examined (human HL60, U937, ML1, and K562 cells and mouse M1 cells) as judged from measurements of various differentiation markers. The characteristics that appeared as a result of differentiation induced by these inhibitors were essentially similar in every cell line. Exposure to VP16 for 2 h induced both differentiation and DNA-strand breaks in K562 cells, whereas podophyllotoxin, which lacks topoisomerase II inhibitory activity, induced neither differentiation nor DNA-strand breaks in these cells. These results suggest a parallelism between the induction of differentiation and that of DNA-strand breaks. The combination of VP16 and recombinant tumor necrosis factor alpha (rTNF alpha) synergistically induced differentiation of human U937, ML1, and M1 cells and had an additive effect on HL60 cells. Simultaneous treatment with rTNF alpha plus camptothecin or VP16, or pretreatment with camptothecin or VP16, followed by rTNF alpha induced marked differentiation of M1 cells. These results indicate that inhibition of topoisomerase (either topoisomerase I or II) followed by the action of rTNF alpha was effective in inducing differentiation of leukemia cells.
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PMID:Topoisomerase inhibitors have potent differentiation-inducing activity for human and mouse myeloid leukemia cells. 184 45

Bufalin was found to be a potent inducer of differentiation in human erythroleukemia K562 cells by examination of various differentiation markers (as assessed by the morphology, histochemistry, and the abilities to phagocytose latex particles, to reduce nitro-blue tetrazolium and to develop Fc receptors). Bufalin, at a concentration as low as 10 nM, also produced a strong differentiation-inducing activity in three other human leukemia-derived cell lines (human promyelocytic HL60, monoblastic U937 and myeloblastic ML1). Treatment of K562 cells with other cardiotonic steroids, such as cinobufagin, ouabain and digitoxigenin, at the concentration of 10 nM for four days resulted in weak or no effect on the cells. These findings suggest that bufalin might have potentiality as a new agent in the differentiation therapy for human myelogenous leukemia.
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PMID:Bufalin as a potent inducer of differentiation of human myeloid leukemia cells. 185 24

To explore agents for differentiation therapy of leukemias, various combinations of cytokines and low-molecular-weight inducers were examined for differentiation-inducing activity toward three kinds of human leukemia-derived cell lines. The strongest differentiation inducing activity on promyelocytic HL60 cells and histiocytic U937 cells was obtained by combining recombinant tumor necrosis factor (rTNF), interferon-gamma (IFN-gamma), retinoic acid (RA), and 1 alpha,25-dihydroxyvitamin D3 (1 alpha,25(OH)2D3). For myeloblastic ML1 cells, the combination of rTNF, IFN-gamma, and RA had the strongest differentiation-inducing activity.
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PMID:Induction of differentiation of human leukemia cells by various combinations of cytokines and low-molecular-weight inducers. 219 88

A low concentration of bufalin, a component of bufadienoides in the traditional Chinese medicine chan'su, was shown previously to induce differentiation of a broad range of human leukemia cell lines. In the present study, we found that bufalin at concentrations of 10(-7) M and higher induced apoptosis in human leukemia cells, such as HL60, ML1, but not in mouse leukemia M1 cells. A mere 15 min pretreatment of HL60 cells with 10(-6) M bufalin, followed by incubation for 15 h without bufalin, caused fragmentation of DNA and a decrease in cell viability, indicating that the signal for induction of apoptosis is triggered rapidly upon treatment with bufalin. Bufalin-induced apoptosis in HL60 cells was inhibited by ZnCl2, an inhibitor of endonuclease, but not by cycloheximide, an inhibitor of protein synthesis. Northern blot analysis revealed that the levels of expression of the c-myc and bcl-2 genes in HL60 cells decreased with time after treatment with bufalin. These results suggest that bufalin induces apoptosis specifically in human leukemia cells by altering the expression of these genes involved in apoptosis.
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PMID:Bufalin induces apoptosis and influences the expression of apoptosis-related genes in human leukemia cells. 765 1

In a panel of acute myeloblastic leukemia (AML) cell lines, representative of distinct differentiation stages, we investigated the possible correlation between drug-resistance and both expression and function of the multidrug resistance (MDR)-related P-glycoprotein (P-gp). The AML cell lines were KG1a, KG1, TF1, HEL, ML1, and two non drug-selected P-gp positive subclones originating from HL-60 (HL-60JD) and U937 (U937AQ). All these cells overexpressed the mdr1 gene (analyzed by RT-PCR) and displayed variable levels of P-gp expression. Flow cytometric semi-quantitative evaluation of P-gp with two P-gp specific monoclonal antibodies (MRK16 and UIC2) showed the following P-gp expression hierarchy: TF1 < KG1a < HEL < KG1 < HL-60JD < ML1 < U937AQ; the latter expressing 13 times more P-gp than TF1. When P-gp function was assessed by Rhodamine 123 (Rh123) efflux kinetics, we found that only KG1a and KG1 cells, which have an early (immature) CD34+ CD33- CD38- phenotype, and to a lesser extent TF1, with an intermediate (CD34+ CD33+ CD38+) phenotype, displayed significant P-gp activity which could be inhibited by both verapamil and SDZ PSC 833. In contrast, the other more mature CD33+ CD34- AML cell lines presented no Rh123 efflux capacity although they expressed higher P-gp levels. Daunorubicin (DNR) accumulation studies showed that inhibitors of P-gp increased DNR accumulation only in the immature AML cells whereas they had no impact on the mature AML cell lines. MTT drug cytotoxicity assay confirmed that the immature AML cells were 10-15-fold more resistant to DNR than the mature AML cells. Although P-gp inhibitors were able to increase the cytotoxicity of DNR in AML cells which displayed functional P-gp, they could not increase DNR cytotoxicity to levels comparable to that of the CD34- CD33+ cells, suggesting that DNR resistance of immature AML cells may not solely be related to P-gp. With drug-selection, AML subclones displayed higher levels of P-gp expression and higher extruding capacities, and therefore chemoresistance, and this independently of their initial differentiation phenotype. Finally, this study provides evidence for a lack of correlation between expression and function of P-gp in AML cells; this relationship being dependent upon leukemic cell differentiation in unselected myeloid leukemic cells.
Leukemia 1995 May
PMID:Lack of correlation between expression and function of P-glycoprotein in acute myeloid leukemia cell lines. 776 42

We found that bufalin, an active principle of the Chinese medicine chan'su, has selective inhibitory effects on the growth of various human cancer cells. In order to examine whether the growth-inhibitory effect of bufalin on human cancer cells is associated with apoptosis, human leukemia cells were treated with bufalin. HL-60, ML1, and U937 leukemia cells treated with bufalin at 10(-8) M and above had condensed and fragmented nuclei. Flow cytometric analysis of these cells treated with bufalin showed fragmented DNA smaller than that of the G1 phase. DNA of HL-60 cells treated with bufalin showed a ladder pattern characteristic of apoptosis, as analyzed by agarose gel electrophoretic analysis. DNA synthesis and topoisomerase II activity of HL-60 cells were markedly inhibited as the concentration of bufalin was increased. The concentration needed for inducing apoptosis of HL-60 cells was 10(-8) M, which is comparable to that of camptothecin, but lower than those of other antitumor drugs such as cisplatin, VP16 and all-trans retinoic acid. Apoptosis was not observed when human mononuclear and polymorphonuclear cells were treated with 10(-6) M bufalin for 24 h. These results indicate the association of the growth-inhibitory effect of bufalin with the induction of apoptosis, at least in HL-60 cells, and suggest the usefulness of bufalin for differentiation-apoptosis-inducing therapy for cancer.
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PMID:Selective inhibitory effect of bufalin on growth of human tumor cells in vitro: association with the induction of apoptosis in leukemia HL-60 cells. 806 19

Bufalin, an active principle of the traditional Chinese medicine chan'su, has been proved to be a potent differentiation inducer in human leukemia cells. To study the mechanism of the differentiation of human leukemia ML1 cells induced by bufalin, we measured the effect of 10 nM bufalin on cell growth, activities of various protein kinases, and cell cycle. The ML1 cell growth was inhibited significantly at 24 hr and the inhibiting effect persisted for 6 days. Activities of PKC, PKA, cdc2 kinase and CK II in ML1 cells were changed early by bufalin; PKA and PKC activities were inhibited, and cdc2 kinase and CK II activities were increased. These results suggest that bufalin induces differentiation of ML1 cells by modulating several protein kinase activities in a distinct way from RA and 1 alpha, 25(OH) 2D3. Cell cycle changes, measured by flow cytometry, became evident at 12 hr after treatment of ML1 cells with bufalin and the cells were preferentially arrested in the G2/M phase. This effect of bufalin on the cell cycle of leukemia cells is similar to that of topoisomerase inhibitors. Indeed, the activity of topoisomerase II but not topoisomerase I of ML1 cells was inhibited remarkably by the treatment of the cells with 10 nM bufalin.
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PMID:Cell cycle arrest and protein kinase modulating effect of bufalin on human leukemia ML1 cells. 807 71


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