Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pharmacologic differentiation of the promyelocytic leukemia HL60 is associated with an increase in cellular tyrosine phosphatase activity. We asked (a) if this increase might, at least in part, be due to changes in a transmembranous protein-tyrosine phosphatase, CD45; and (b) if CD45 changes similarly in other differentiating leukemias. Differentiation of HL60, several chronic myelogenous leukemias, a monocytic leukemia (THP-1), and a monoblastoid leukemia (U-937) could be induced by phorbol ester, 1,25-dihydroxy vitamin D3, dimethyl sulfoxide, or cyclic AMP analogues. This differentiation was associated with a marked increase in (a) total cellular tyrosine phosphatase activity (2-4-fold as measured by the ability to dephosphorylate a tyrosine-phosphorylated peptide); (b) CD45-specific tyrosine phosphatase activity (2-4-fold); (c) CD45 cell surface expression by flow cytometry (2-5-fold); (d) synthesis of both exon B-dependent M(r) 205,000 and exon ABC- M(r) 185,000 CD45 proteins, as revealed by immunoprecipitation with antisera specific for CD45 isoforms. Both isoforms have enhanced electrophoretic mobility when isolated from the differentiated cells. This enhanced mobility did not appear to be due to decreased stoichiometry of CD45 phosphorylation on serine/threonine residues. Interestingly, 12-O-tetradecanoylphorbol-13-acetate transiently reduced CD45 protein-tyrosine phosphatase activity in the chronic myelogenous leukemia cell RWLeu4 without altering the CD45 amount (as measured by cell surface immunofluorescence). Modulation of CD45 tyrosine phosphatase activity (and protein levels) may play a role in differentiation or in maintaining cells in a nonproliferative state or may represent a phenotypic marker of differentiation.
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PMID:Differentiation-induced changes in protein-tyrosine phosphatase activity and commensurate expression of CD45 in human leukemia cell lines. 153 52

Several new cytostatic drugs have entered clinical phase I-II studies for the treatment of leukemia: the most promising are pyrimidine analogs such as 5-aza-cytidine, 5-aza-2'-deoxycytidine, 5-aza-cytosine arabinoside, and 2',2'-difluorodeoxycytidine. Fludarabine, a fluorinated purine analog, appears to be active in CLL and multiple myeloma. Deoxycoformycin, an adenosine analog, showed good activity in the treatment of hairy cell leukemia and T-cell neoplasias. 2-chloro-deoxyadenosine has recently been introduced into the treatment of CLL and hairy-cell leukemia refractory to deoxycoformicin. Tiazofurin, an antimetabolite which interferes with nicotine-adenine-dinucleotide (NAD) metabolism, has been applied in CML blast crisis. Other agents include 13-cis retinoic acid and 1, 25-dihydroxy vitamin D3 as differentiation inducers, and homoharringtonine, an alkylating agent which is widely used for ANLL treatment in China. Among new anthracyclines, aclarubicin, idarubicin, THP-adriamycin and fluoro-adriamycin should be mentioned. Mitoxantrone, a substituted anthraquinone, has successfully been applied in the treatment of relapsed and refractory ANLL. Amsacrine (m-AMSA), finally, is a synthetic aminoacridine which intercalates into DNA and inhibits DNA topoisomerase II. m-AMSA is not cross-resistant to anthracyclines and has been particularly active in ANLL treatment. Studies using m-AMSA alone or in combination revealed comparable results to anthracycline--containing regimens. Cardiotoxicity of the anthracycline congestive type has not been observed with m-AMSA. The EORTC Leukemia Cooperative Group has successfully used m-AMSA in several trials prepositioning this drug stepwise: from relapsed and refractory ANLL, into intensive maintenance treatment during first remission in ANLL, and, still on-going, into intensive consolidation.
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PMID:New drugs in the treatment of acute and chronic leukemia with some emphasis on m-AMSA. 206 23

We investigated the in vitro action of recombinant tumor necrosis factor alpha (TNF) on the clonal growth of normal and malignant myeloid cells. Clonogenic cells from six of nine myeloid leukemia cell lines were very sensitive to the effects of TNF with 50% of the colonies inhibited (ED50) by concentrations of TNF that ranged between 6 and 150 U/mL. A decrease in DNA, RNA, and protein synthesis and in cloning efficiency occurred within three hours of exposure of HL-60 promyelocytes to TNF. The TNF in combination with recombinant interferons produced an additive or synergistic inhibition of colony formation of HL-60 and THP-1 myelomonoblasts. Normal human CFU-GM are sensitive to TNF (ED50 between 100 and 50,000 U/mL), but their sensitivity to TNF depends on the source of colony stimulating factor (CSF) with T lymphocyte derived GM-CSF (recombinant or natural) partially protecting the CFU-GM from the suppression exerted by TNF (and interferons). In eight of 15 cases the clonogenic myeloid leukemia cells from patients with acute or chronic myeloid leukemia were more sensitive than normal CFU-GM using GM-CSF as a source of colony stimulating activity. Further studies showed that the action of TNF on myeloid leukemia cells probably can be only partially explained by differentiation. Our finding of a possible selective cytotoxicity to leukemic clonogenic cells by TNF suggests that TNF may have value in the therapy of some patients with myeloid leukemia.
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PMID:In vitro action of tumor necrosis factor on myeloid leukemia cells. 243 41

Most Hodgkin's mononuclear cells and Reed-Sternberg (H-RS) cells are characterized by the expression of the antigen CD30, but not of T or B cell markers. A few H-RS cells, however, may express a limited number of T or B cell markers. Whether this expression is sufficient to allow the conclusion that H-RS cells are derived from T and/or B cells has been debated vigorously. The present study examined whether CD30 and aberrant T and B cell markers are expressed in cell lines that are well documented as being derived from the granulocyte/monocyte/histiocyte lineage. These cells included HL-60, KG-1, ML-1, THP-1, and U-937. Four other cell lines derived from patients with leukemias/lymphomas of monocytic or granulocytic origins also were studied. These cells included BV173, CML-Brown, CTV-2, and SU-DHL-1. If aberrant expression is detected, by analogy one may expect that rare T or B cell marker expression may occur in H-RS cells, because abundant evidence has indicated that H-RS cells may be related to cells in histiocyte lineage. In all nine of the cell lines studied, it was confirmed that numerous monocyte/granulocyte markers were expressed. The marker expression was enhanced after cells were induced to differentiate with phorbol ester (TPA) and tumor necrosis factor (TNF). It was noted that several T and B cell markers also were expressed by these cells. Unlike the expression of monocyte/granulocyte markers, the expression of T or B cell markers was not affected, or only minimally affected, by treatment of the cells with TPA or TNF. Five of the cell lines (BV173, CML-Brown, CTV-2, SU-DHL-1, and THP-1) were shown to be CD30-positive. In CTV-2 and BV173, the expression of CD30 was greatly increased after induction with phorbol ester or TNF. Based on these studies, the following conclusions were reached: 1) The expression of aberrant B or T cell markers is not an uncommon finding in granulocyte/monocyte/histiocyte-related neoplastic cells. 2) The expression of granulocyte/monocyte markers in these cells is related to the state of cell differentiation, whereas the expression of T or B cell markers is not. 3) CD30 is not necessarily a proliferation-related antigen, and its expression is not a sole property of T or B cells, but can be present in granulocyte/monocyte/histiocyte-related cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Aberrant expression of T cell and B cell markers in myelocyte/monocyte/histiocyte-derived lymphoma and leukemia cells. Is the infrequent expression of T/B cell markers sufficient to establish a lymphoid origin for Hodgkin's Reed-Sternberg cells? 249 2

Several new cytostatic drugs have entered clinical Phase I-II studies for treatment of leukemia: most promising are pyrimidine analogues such as 5-Azacytosine arabinoside, 5-Aza-2-deoxycytidine, 5-Azacytidine, cyclocytidine, and 2'-2'-difluorodeoxycytidine. They act on different biochemical levels towards DNA-synthesis. Fludarabine is a purin analogue and seems very active in treating CLL. Tiazofurin is an antimetabolite counter-acting nicotinic acid with most promising activity in CML blast crisis. Other substances include deoxycoformycin, an adenosine analogue for treatment of T-cell neoplasias, 1, 25-dihydroxy vitamin D 3 as differentiation inducer, and homoharringtonine, an alkylating agent widely used for treating de novo AML in China. New anthracyclines are THP-adriamycin, fluoroadriamycin, and 4-demethoxydaunorubicin. Amsacrine (mAMSA) finally, is a synthetic aminoacridine with DNA-intercalating properties. The intact acridine ring appears essential for antitumor activity. The plasma clearance of both total amsacrine and unchanged parent species is biphasic. There is a considerable influence of hepatic and renal impairment on plasma clearance. Clinical toxicities include marked myelosuppression, gastrointestinal symptomes, phlebitis, mucocutaneous lesions, occasionally alopecia and neurotoxities. It is a very active drug, particularly in treating AML. Studies using mAMSA alone or in combination revealed comparable results to the anthracyclines. The E.O.R.T.C. Leukemia Cooperative Group has used successfully mAMSA in several trials: relapsed and refractory AML, intensive maintenance treatment during first remission in AML, and, still on-going, during intensive consolidation randomized against BMT in AML-patients under the age of 45 years, and randomized against standard consolidation between the age of 45 and 60 years.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:New drugs in the treatment of acute and chronic leukaemia: current role of mAMSA. 269 2

Herbimycin A, a benzoquinonoid ansamycin antibiotic, is found to reduce intracellular phosphorylation by tyrosine protein kinase. The human chronic myelogenous leukemia cell line K562 expresses a structurally altered c-abl protein with tyrosine kinase activity. When K562 cells are induced to undergo erythroid differentiation by hemin, reduction in the intracellular level of tyrosine phosphorylation occurs. In order to understand the relationship between induction of differentiation and reduction of tyrosine phosphorylation by the c-abl gene product, the effect that herbimycin A, a selective inhibitor of intracellular tyrosine kinase activity, exerts on the differentiation of K562 cells was examined. Reduction of tyrosine phosphorylation in K562 cells by herbimycin A was observed within 1 h. Noncytotoxic concentrations of herbimycin A induced erythroid differentiation of K562 cells but not of murine erythroleukemia 745A cells. The other human myeloid leukemia cell lines (HL-60, THP-1, and U937) tested were not induced to undergo cell differentiation by this antibiotic. Herbimycin A and the other well-known inducers such as hemin, butyric acid, Adriamycin, and 1-beta-D-arabinofuranosylcytosine had additive or more than additive effects on induction of erythroid differentiation of K562 cells. With respect to inhibition of cell growth, the sensitivity of K562 cells to herbimycin A was highest in the human leukemia cell lines we tested. Noncytotoxic concentrations of herbimycin enhanced the antiproliferative effect of Adriamycin or 1-beta-D-arabinofuranosylcytosine on K562 cells. Combination therapy with herbimycin A and its derivatives may be considered for use in the treatment of some types of leukemia where tyrosine kinase activities are implicated as determinants of the oncogenic state.
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PMID:Induction of erythroid differentiation of K562 human leukemic cells by herbimycin A, an inhibitor of tyrosine kinase activity. 291 Apr 52

Interleukin-8 (IL-8) is produced by many cell types upon stimulation with bacterial products or inflammation-associated cytokines such as tumor necrosis factor-alpha and IL-1. Interferons (IFNs) represent another group of cytokines that are induced by similar stimuli in inflammatory reactions. We show now that type-I IFNs are potent inhibitors of IL-8 expression in vitro and in vivo. A significant reduction of both secretion of IL-8 protein and accumulation of IL-8 mRNA in vitro was observed in several cell types comprising peripheral blood mononuclear cells (PBMNC) from healthy donors and from patients with chronic myelogenous leukemia (CML), the myelomonocytic cell line THP-1, and bone marrow (BM) stromal cells as a representative model for BM microenvironment. By contrast, in lipopolysaccharide-stimulated polymorphonuclear phagocytes IFN failed to suppress IL-8 expression. In untreated patients with CML, a constitutive expression of IL-8 mRNA was detected in freshly isolated PBMNC that was markedly reduced 5 hours after therapeutic application of IFN-alpha. The mechanism of IL-8 downregulation was studied more in detail in the THP-1 cell line. The experiments showed that de novo protein synthesis was not required for the inhibitory effect. RNA decay analysis and nuclear run-on assays suggest that in THP-1 cell line the inhibition of IL-8 expression is predominantly regulated at the posttranscriptional level.
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PMID:Type-I interferons are potent inhibitors of interleukin-8 production in hematopoietic and bone marrow stromal cells. 840 Feb 88

Our group recently cloned the cDNA-encoding bomapin, a member of the serine protease inhibitor (serpin) superfamily, from a human bone marrow cDNA library (J Biol Chem 270:2675, 1995). To understand its expression within the hematopoietic compartment, RNA extracted from bone marrow or peripheral blood from normal donors and patients with leukemia was reverse transcribed and analyzed by polymerase chain reaction (PCR). Bomapin PCR products were readily detected in normal bone marrow, which was designated as a medium mRNA level. In peripheral blood, bomapin expression was low or undetectable in normal donors (n = 6) and patients with chronic lymphocytic leukemia (n = 6). Blood from patients with chronic myeloid leukemia (n = 6), chronic myelomonocytic leukemia (n = 6), acute myeloid leukemia (n = 5), and acute lymphocytic leukemia (n = 5) exhibited low to medium levels of bomapin expression. Furthermore, a high level of bomapin expression was detected in one individual with acute monocytic leukemia. These data suggest that bomapin expression may be elevated in hematopoietic cells of monocytic lineage. Therefore, we analyzed the expression of bomapin within cell lines that exhibited characteristics of the monocytic lineage. Bomapin PCR products were detected in the monocytic THP-1 and AML-193 cell lines but not in CRL 7607, CRL 7541, KG-1, or K562 cells. Induction of bomapin transcripts was not detected in the latter series of cell lines following a 24-hour treatment with phorbol myristate acetate (PMA, 10(-8) mol/L) or tumor necrosis factor-alpha (TNF-alpha, 30 U/mL), whereas treatment of THP-1 or AML-193 cells with these agents reduced the intensity of the bomapin PCR products. Northern blotting confirmed these results and showed that the expression of bomapin in THP-1 cells was downregulated over a 4-day period by PMA and, to a lesser extent, TNF-alpha. Immunoblotting was used to show the presence of a 40-kD protein in THP-1 cytosol preparations. Bomapin antigen levels were correspondingly reduced after treatment with PMA. Because PMA and TNF-alpha induce monocytic differentiation in THP-1 and AML-193 cells, these data increase the possibility that bomapin may play a role in the regulation of protease activities specifically in early stages of cellular differentiation.
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PMID:Expression of bomapin, a novel human serpin, in normal/malignant hematopoiesis and in the monocytic cell lines THP-1 and AML-193. 945 55

Advanced glycation end product (AGE) activation of the signal-transducing receptor for AGE (RAGE) has been linked to a proinflammatory phenotypic change within cells. However, the precise intracellular signaling pathways involved have not been elucidated. We demonstrate here that human serum albumin modified with N(epsilon)-(carboxymethyl)lysine (CML), a major AGE adduct that progressively accumulates with aging, diabetes, and renal failure, induced nuclear factor (NF)-kappaB-driven reporter gene expression in human monocytic THP-1 cells. The NF-kappaB response was blocked with a synthetic peptide corresponding to the putative ligand-binding domain of RAGE, with anti-RAGE antiserum, and by coexpression of truncated receptors lacking the intracellular domain. Signal transduction from RAGE to NF-kappaB involved the generation of reactive oxygen species, since reporter gene expression was blocked with the antioxidant N-acetyl-L-cysteine. CML-modified albumin produced rapid transient activation of tyrosine phosphorylation, extracellular signal-regulated kinase 1 and 2, and p38 mitogen-activated protein kinase (MAPK), but not c-Jun NH(2)-terminal kinase. RAGE-mediated NF-kappaB activation was suppressed by the selective p38 MAPK inhibitor SB203580 and by coexpression of a kinase-dead p38 dominant-negative mutant. Activation of NF-kappaB by CML-modified albumin increased secretion of proinflammatory cytokines (tumor necrosis factor-alpha, interleukin-1beta, and monocyte chemoattractant protein-1) severalfold, and inhibition of p38 MAPK blocked these increases. These results indicate that p38 MAPK activation mediates RAGE-induced NF-kappaB-dependent secretion of proinflammatory cytokines and suggest that accelerated inflammation may be a consequence of cellular activation induced by this receptor.
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PMID:Requirement for p38 and p44/p42 mitogen-activated protein kinases in RAGE-mediated nuclear factor-kappaB transcriptional activation and cytokine secretion. 1137 53

Glucose can react non-enzymatically with amino groups of, for example, proteins, to yield derivatives termed advanced glycation end products (AGE), which contribute to many chronic progressive diseases associated with microvascular complications. The study aimed to determine the effect of AGE-modified albumin on THP-1 cells and human monocyte-derived macrophages. Bovine serum albumin (BSA) or human serum albumin (HSA), modified by glucose-derived AGE, was prepared by incubation with glucose for differing periods of time. Alternatively, BSA was incubated with sodium cyanoborohydride and glyoxylic acid to produce N(epsilon)-(carboxymethyl)lysine-modified BSA (CML-BSA). Stimulation for 24h of THP-1 cells with BSA, incubated for 6-8 weeks with glucose, induced significant VEGF release. Human monocyte-derived macrophages stimulated with extensively glycated HSA also showed significant VEGF release, as well as upregulation of IL-8 production, incubation for 6h with extensively glycated HSA increased release of TNFalpha and expression of tissue factor. Finally, addition of CML-BSA resulted in significant induction of TNFalpha and VEGF release. We demonstrate that a range of different methods of glycation of BSA and HSA, including CML-BSA, resulted in the induction of VEGF, TNFalpha, IL-8 and expression of tissue factor, according to length of stimulation and different glycation products used, suggesting that AGE-induced activation of macrophages may contribute to vascular complications by regulation of angiogenic, inflammatory and pro-coagulant processes.
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PMID:Advanced glycation end products upregulate angiogenic and pro-inflammatory cytokine production in human monocyte/macrophages. 1534 24


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