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)

Tretinoin tocoferil is an alpha-tocopherol ester of all-trans retinoic acid (RA) and safely used in the treatment of skin ulcer. Tretinoin tocoferil inhibited proliferation of human promyelocytic leukemia HL-60 cells and induced granulocytic differentiation of the cells, but less than RA. alpha-Tocopherol did not affect differentiation of HL-60 cells, but at high concentrations enhanced its nitroblue tetrazolium (NBT)-reducing activity and expression of surface antigen CD11b, which are markers of myelomonocytic differentiation induced by RA. Tretinoin tocoferil increased NBT reduction in HL-60 cells treated with RA. It also enhanced the differentiation of HL-60 cells induced by dimethyl sulfoxide, phorbol-12-myristate 13-acetate or 1alpha,25-dihydroxyvitamin D3 (VD3). In combination with a low concentration of VD3, it induced the NBT-reducing activity of human monoblastic U937 cells very effectively. Moreover, it enhanced the differentiation of human myelomonocytic ML-1, THP-1, P39/TSU, and P31/FUJ cells induced by VD3. In combination with VD3, it synergistically inhibited the proliferation of HL-60, U937, ML-1, THP-1, P39/TSU, and P31/FUJ cells and decreased the effective concentration of VD3 to a 10(-10) mol/L level. Because tretinoin tocoferil was reported to induce neither retinoid-related toxicity nor teratogenicity, the therapeutic advantage of the use of it in treatment of myelomonocytic leukemia is suggested.
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PMID:Enhancement of activity of 1alpha, 25-dihydroxyvitamin D3 for growth inhibition and differentiation induction of human myelomonocytic leukemia cells by tretinoin tocoferil, an alpha-tocopherol ester of all-trans retinoic acid. 860 56

All-trans retinoic acid (ATRA) is successfully used in the cyto-differentiating treatment of acute promyelocytic leukemia (APL). Paradoxically, APL cells express PML-RAR, an aberrant form of the retinoic acid receptor type alpha (RAR alpha) derived from the leukemia-specific t(15;17) chromosomal translocation. We show here that AM580, a stable retinobenzoic derivative originally synthesized as a RAR alpha agonist, is a powerful inducer of granulocytic maturation in NB4, an APL-derived cell line, and in freshly isolated APL blasts. After treatment of APL cells with AM580 either alone or in combination with granulocyte colony-stimulating factor (G-CSF), the compound induces granulocytic maturation, as assessed by determination of the levels of leukocyte alkaline phosphatase, CD11b, CD33, and G-CSF receptor mRNA, at concentrations that are 10- to 100-fold lower than those of ATRA necessary to produce similar effects. By contrast, AM580 is not effective as ATRA in modulating the expression of these differentiation markers in the HL-60 cell line and in freshly isolated granulocytes obtained from the peripheral blood of chronic myelogenous leukemia patients during the stable phase of the disease. In NB4 cells, two other synthetic nonselective RAR ligands are capable of inducing LAP as much as AM580, whereas RAR beta- or RAR gamma-specific ligands are totally ineffective. These results show that AM580 is more powerful than ATRA in modulating the expression of differentiation antigens only in cells in which PML-RAR is present. Binding experiments, using COS-7 cells transiently transfected with PML-RAR and the normal RAR alpha, show that AM580 has a lower affinity than ATRA for both receptors. However, in the presence of PML-RAR, the synthetic retinoid is a much better transactivator of retinoic acid-responsive element-containing promoters than the natural retinoid, whereas, in the presence of RAR alpha, AM580 and ATRA have similar activity. This may explain the strong cyto-differentiating potential of AM580 in PML-RAR-containing leukemic cells.
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PMID:AM580, a stable benzoic derivative of retinoic acid, has powerful and selective cyto-differentiating effects on acute promyelocytic leukemia cells. 860 43

Human THP-1 leukemia cells differentiate along the monocytic lineage following exposure to phorbol-12-myristate-13-acetate (PMA) or 1,25-dihydroxyvitamin D3 (VD3). In the monocytic cell line THP-1, PMA treatment resulted in a more differentiated phenotype than VD3, according to adherence, loss of proliferation, phagocytosis of latex beads, and expression of CD11b and CD14. Both differentiating substances induced similar effects in the release of superoxide anions (O2-). VD3-differentiated cells did not release prostaglandin E2 (PGE2), in contrast to PMA-differentiated cells, and in PMA-differentiated cells phospholipase A2 (PLA2) activity and expression was increase. Lipopolysaccharide (LPS)-stimulated tumor necrosis factor-alpha (TNF-alpha) release was higher in PMA-treated cells. PMA- but not VD3-differentiation resulted in a translocation of protein kinase C (PKC) isoenzymes to membrane fractions. Both differentiating agents up-regulated the expression of PKC isoenzymes. Whereas VD3 elevated mainly the expression of PKC-beta, PMA caused a strong increase in PKC-delta and a weak increase in PKC-alpha, PKC-epsilon, and PKC-zeta expression. These results indicate that phorbol ester and the active metabolite of vitamin D induce different signal pathways, which might result in different achievement of differentiation.
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PMID:Differences in the state of differentiation of THP-1 cells induced by phorbol ester and 1,25-dihydroxyvitamin D3. 861 4

Investigating 208 patients with acute haematological malignancies, we found that stem cell factor receptor (SCFR) was expressed on high numbers of blast cells from the vast majority of patients (93%) with refractory anaemia with excess of blasts in transformation. SCFR was also detected in 62% of AMLs, in which it was directly associated to the expression of CD7, interleukin 6 receptor and CD34, and inversely to that of CD11b and CD14. SCFR-positive cases were preferentially represented in AML-M1 (70%) and in AML-M2 (83%) subsets, whereas only 45% of the remaining samples (M3-M4-M5) exhibited SCFR positively. Interestingly, 50% of cases with acute promyelocytic leukaemia expressed SCFR and this molecule was heterogenously regulated by in vitro treatment with all-trans retinoic acid.
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PMID:Stem cell factor receptor (c-kit, CD117) is expressed on blast cells from most immature types of acute myeloid mallignancies but is also a characteristic of a subset of acute promyelocytic leukaemia. 861 17

The in vivo induction of the differentiation of murine WEHI-3B D+ myelomonocytic leukemia cells was measured by flow cytometry, simultaneously staining leukemia cells for the marker exogenous beta-galactosidase and for differentiation by the antigen Mac-1 (CD11b/CD18). The WEHI-3B D+ leukemia cells were transfected with the E. coli lac-Z gene by electroporation and subclones that constitutively expressed high levels of the lac-Z gene product beta-galactosidase were established. Flow cytometric analyses of cells in the peritoneal cavities of mice bearing leukemia cells showed that cells continued to express beta-galactosidase for at least 14 days, and they were distinguishable from host-derived cells in vivo by their expression of the transfected gene. Simultaneous determination of the beta-galactosidase activity and Mac-1 content of cells in the peritoneal cavities of mice revealed that administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF) to the mice enhanced the expression of Mac-1 antigen by beta-galactosidase-positive cells. The results demonstrate that G-CSF may have clinical potential as a therapeutic differentiating agent, and that flow cytometric analysis provides a useful in vivo system to evaluate the therapeutic potential of agents capable of inducing terminal differentiation.
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PMID:Detection of in vivo differentiation of murine WEHI-3B D+ leukemia cells transfected with the lac-Z marker gene using two-color flow cytometry. 864 45

The authors examined the expression of myeloid antigens (MyAg): CD11b, CD13, CD14, CD15, and CD33 in 249 adults with lymphoid neoplasms using flow cytometric analysis. In this study, acute leukemia that was myeloperoxidase negative by light microscopy and had at least one lymphoid antigen was defined as acute lymphoblastic leukemia (ALL). The patients were classified as follows: 6 with unclassified ALL, 35 early B precursor ALL, 32 T-ALL, 25 B-cell chronic lymphocytic leukemia (B-CLL) and its variants, 24 B-cell non-Hodgkin's lymphoma (B-NHL), 7 plasma cell disorders, 8 T-CLL, 2 adult T-cell leukemia, and 10 T-NHL. CD11b and CD15 were present in a wide range of lymphoid disorders irrespective of B/T lineage and maturity. Unclassified ALL and phenotypically immature ALL frequently expressed CD13 and CD33, and occasionally expressed CD14. Among early B precursor ALL, CD13, and/or CD33 were significantly associated with the presence of stem cell marker CD34 and the chromosomal abnormality t(9;22). In addition, ALL with deletion of chromosome 7 commonly expressed CD13 and CD33. Taken together, CD13 and/or CD33 positive ALL may originate from a multipotential stem cell. Among mature neoplasms, CD14 was frequently, and CD13 and CD33 were occasionally expressed in B-cell, but not T-cell tumors. These results suggest that CD13, CD14, and CD33 are preferentially expressed in two types of lymphoid neoplasms, namely undifferentiated ALL and mature B-cell lymphoproliferative disorders.
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PMID:Myeloid antigen, CD13, CD14, and/or CD33 expression is restricted to certain lymphoid neoplasms. 865 52

Based upon earlier reports of synergism in cells of lymphoid origin, we have examined interactions between the organotellurium compound AS101 and the protein kinase C (PKC) activator bryostatin 1 with respect to differentiation and Ara-C-induced apoptosis in human myeloid leukemia cells (HL-60). Although preincubation with bryostatin 1 (10 nM) for 24 h significantly increased DNA fragmentation and apoptosis in cells subsequently treated with 10 microM Ara-C for 6 h, this effect was not enhanced by co-administration of AS101 (1.5 microM). However, while exposure of cells to AS101 or bryostatin 1 alone for 72 h was ineffective in inducing cellular maturation, combined treatment resulted in the induction of differentiated features in a subset of cells, manifested by an increase in cell adherence, CD11b expression, cytoplasmic granularity and cell spreading. In addition, cells exposed to the combination of AS101 and bryostatin 1, in contrast to cells incubated with these agents individually, displayed a significant decline in the S-phase and a corresponding increase in the G0/G1 cell populations. These events were accompanied by an increase in protein expression of the cyclin-dependent kinase inhibitor, p21 (WAF1/CIP1/MDA6), and a decline in expression of the c-myc protein. AS101 failed to increase intracellular free Ca2+ ([Ca2+]i) in HL-60 cells, or reverse the profound PKC down-regulation induced by bryostatin 1. Whereas treatment of cells with 1.5 microM AS101 or 10 nM bryostatin 1 for 24 h exerted minimal growth inhibitory effects, combined exposure to these agents reduced colony formation by over 70%. Finally, although addition of AS101 did not potentiate apoptosis induced by the bryostatin 1/Ara-C combination, it did lead to a further reduction in clonogenicity. Together, these findings demonstrate that AS101 partially restores the ability of bryostatin 1 to trigger a differentiation program in an otherwise unresponsive HL-60 cell line, possibly by facilitating bryostatin 1-mediated G1 arrest. They also indicate that AS101 potentiates the antiproliferative effects of bryostatin 1 administered alone or in combination with Ara-C through a mechanism other than, or in addition to, induction of apoptosis.
Leukemia 1996 Jul
PMID:Effect of AS101 on bryostatin 1-mediated differentiation induction, cell cycle arrest, and modulation of drug-induced apoptosis in human myeloid leukemia cells. 868 95

We have investigated the expression of the dual specific adhesion molecule, VLA-4 (CD49d/CD29) on lymphocytes obtained from 62 patients with B-CLL and compared it with normal controls, patients with other hematological malignancies, and umbilical cord blood. The mean CD49d expression in patients with CLL was lower than the other group of leukemia and the CD19+, CD5+ cells of normal peripheral blood and umbilical cord blood (P < 0.001). The patients in RAI stage 0, I and II (early stage) had even lower CD49d expression, whereas patients in RAI stage III and IV (advanced stage) had relatively higher CD49d levels. In vitro adhesion of lymphocytes to fibronectin, being the extracellular matrix ligand of CD49d, was also investigated. Lymphocytes obtained from B-CLL were found to have lower adhesion to fibronectin than that from controls (P < 0.03). Furthermore, CD49d(low) B-CLL cells had lower adhesion to fibronectin, whereas CD49d(high) B-CLL cells showed normal adhesion ratios (P < 0.002). Further phenotypic analyses revealed the presence of myeloid markers (CD13 and CD33) in most of the advanced stage patients, although these were negative in early stage cases. Expressions of CD11a and sIgM were also low but CD11b was relatively higher in the early stages of the disease. On the basis of these results, we concluded that early stages of CLL are correlated with the expression of CD49d(low), CD11a(low), CD11b(high), CD13-, CD33-, sIgM(low) and also had lower fibronectin adhesion, whereas advanced stages of CLL are associated with CD49d(high), CD11a(high), CD11b(low), CD13+, CD33+, SIgM(high) and show normal fibronectin adhesion.
Leukemia 1996 Aug
PMID:Variable expression of CD49d antigen in B cell chronic lymphocytic leukemia is related to disease stages. 870 39

The human promyelocytic leukemic HL60 cells are immortal and as such express high levels of telomerase activity. All-trans retinoic acid (ATRA) and 1 alpha, 25 dihydroxyvitamin D3 (VD3) induce differentiation of HL60 cells into CD11b+ mature granulocytes and monocytes, respectively. We studied telomerase activity after differentiation of HL60 cells. A marked inhibition of the enzyme activity was observed in the differentiated CD11b+ cells after 72-120 h treatment with either differentiating agent. In contrast, the VD3-treated CD11b- HL60 cells, which failed to undergo differentiation and human erythroleukemic cell line K562, exposed to ATRA retained high levels of telomerase activity. This finding suggests, that telomerase activity is repressed as a differentiation-associated event in HL60 cells. Our results provide the first evidence that immortal leukemic cells, like normal human cells, have a telomerase repressing mechanism which can be activated by differentiation and thus lead to the suppression of telomerase activity. This in vitro model may be useful for studies of the mechanisms controlling telomerase activity and in the search for physiological telomerase modulators.
Leukemia 1996 Aug
PMID:Supression of telomerase activity in HL60 cells after treatment with differentiating agents. 870 42

1,25 Dihydroxyvitamin D3 (calcitriol) induces differentiation of HL-60 leukemia cells. We studied the in vitro effect of a physiological concentration of ascorbate as potentiator of 1,25 dihydroxyvitamin D3 [(OH)2D3] activity by determining different markers of differentiation: nitroblue tetrazolium reduction, nonspecific esterase activity, and the expression of CD11b and CD14 surface antigens. Nitroblue tetrazolium reduction and nonspecific esterase activity increased up to 50% in the presence of both 1,25 (OH)2D3 plus 0.2 mM ascorbate (ASC), compared with (OH)2D3 as a unique agent. ASC also increased the expression of specific surface antigens (CD11b and CD14) during differentiation induced by 1,25 (OH)2D3, the effect being more pronounced after 48 hours of treatment with 10(-8) M 1,25 (OH)2D3. Furthermore, 1,25 (OH)2D3 alone increased intracellular cAMP level during differentiation, and the addition of ASC increased its concentration from 60 to 100% above the level reached with 1,25 (OH)2D3 as unique agent. ASC did not enhance the antiproliferative effect of calcitriol, suggesting that it only affects the ability of 1,25 (OH)2D3 to promote differentiation of HL-60 cells.
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PMID:Ascorbate increases the 1,25 dihydroxyvitamin D3-induced monocytic differentiation of HL-60 cells. 878 Oct 52


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