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)

Prostaglandins (PGs) are bioregulatory substances and are widely distributed in a variety of tissues. Numerous facts have been described in relation to cancer biology with PGs. The purpose of our study lies in the creation of anti-tumor PGs. We have described that PGD2 has strong cell growth inhibitory activity; furthermore, we discovered that PGJ2, 9-deoxy-delta 9-PGD2, has 3 times stronger activity than the mother compound, PGD2. In vivo experiments showed that only PGA2 and PGJ2 exert antitumor activity. Thus, cyclopentenone ring structure in PG seems to be an essential moiety for cytotoxicity of PG. On the basis of the above facts, we propose tha name of antineoplastic PGs for PGA and PGJ derivatives which have cyclopentenone ring. Recently, we developed several antineoplastic PGs which showed IC50 value less than 0.3 microgram/ml against L1210 leukemia cells, and these compounds also showed antitumor activity against Ehrlich ascites tumor in vivo comparable to that of cyclophosphamide. The action mechanism seems to be in its alkylation activity of the cyclopentenone structure and not in receptor-cAMP route. Spectrum of anti-tumor activity and its toxicity in vivo are now under investigation. In this brief review, mainly our recent approaches in this field are discussed.
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PMID:[Development of antineoplastic prostaglandins]. 657 12

In 19 normal subjects an increase in the number of circulating neutrophils was observed after intramuscular injection of 1 mg glucagon. The response began at the end of the 1st hour following the injection and persisted beyond the 8th hour, with a peak between 2 and 5 hours. No response was obtained in patients with bone marrow aplasia, either primary or associated with acute leukaemia. In 20 patients with chronic primary neutropenia, the degree of response was proportional to the percentage of medullary polymorphonuclears. A comparison between the kinetics of the glucagon-induced granulocyte response and that of the response induced by other neutrophil mobilizing agents suggested that glucagon acts by releasing granulocytes from the bone marrow reserve compartment. The finding that an infusion of dibutyryl cyclic AMP results in granulocyte mobilization suggests that the effects of glucagon are mediated by cAMP at cell level. Since the glucagon response test is harmless and gives rapid and pronounced results, it may be useful in investigation of patients with neutropenia. In addition, the glucagon-induced granulocyte mobilization might improve leucocyte yield in blood donors used for transfusion in agranulocytosis.
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PMID:[Glucagon-induced neutrophil mobilization (author's transl)]. 707 58

Dipyridamole (DP, Persantin) was examined for its effects on the proliferation of mitogen-stimulated murine splenocytes and L1210 leukemia cells. In keeping with its reported activity as an inhibitor of nucleoside transport, DP inhibited incorporation by lymphoid cells of labeled thymidine and uridine ino macromolecules. That this inhibition resulted from activities in addition to suppression of nucleoside transport was verified by measured decreases of cellular DNA and viable cell numbers. In addition, protein synthesis was also decreased as indicated by labeled valine incorporation and total protein content of the cells. The rapid accumulation of cAMP in phytohemagglutinin-stimulated splenocytes in the presence of DP may provide an explanation for the anti-proliferative effect of DP on lymphoid cells.
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PMID:Inhibition of lymphoproliferation by dipyridamole. 709 28

A functional cDNA for the human prostacyclin receptor was isolated from a cDNA library of CMK cells, a human megakaryocytic leukaemia cell line. The cDNA encodes a protein consisting of 386 amino acid residues with seven putative transmembrane domains and a deduced molecular weight of 40,956. [3H]Iloprost specifically bound to the membrane of CHO cells stably expressing the cDNA with a Kd of 3.3 nM. This binding was displaced by unlabelled prostanoids in the order of iloprost = cicaprost >> carbacyclin > prostaglandin E1 (PGE1) > STA2. PGE2, PGD2 and PGF 2 alpha did not inhibit it. Iloprost in a concentration-dependent manner increased the cAMP level and generated inositol trisphosphate in these cells, indicating that this human receptor can couple to multiple signal transduction pathways.
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PMID:Cloning and expression of a cDNA for the human prostacyclin receptor. 751 39

We examined the effect of dibutyryl cAMP (dbcAMP) on the expression of LFA-1 (CD11a/CD18), Mac-1 (CD11b/CD18), and VLA-4 (CD49/CD29) and on eosinophilic differentiation of a human leukemia cell line, EoL-1. Dibutyryl cAMP induced eosinophilic differentiation of EoL-1 cells from 6-9 days after the start of culture with down-regulation of CD11a, CD18, and CD49 expression and up-regulation of CD11b expression. Changes in integrin expression, except for CD18, were seen predominantly in the fraction containing eosinophilic granule-positive cells, suggesting that the changes were dependent on eosinophilic differentiation. On the other hand, dbcAMP-induced changes of integrin expression were reversible and were not seen on day 9 when dbcAMP was removed on day 3, whereas eosinophilic differentiation was still present. A combination of G-CSF and TNF-alpha, which also induced eosinophilic differentiation of EoL-1 cells, increased CD11b expression slightly but had no significant effect on the expression of the other integrins. Butyrate and PMA up-regulated CD11b expression without eosinophilic differentiation. The results collectively suggest that the regulation of integrin expression on EoL-1 cells is partly dependent and partly not dependent on eosinophilic differentiation. The possible involvement of protein kinase A and protein kinase C in these changes is suggested.
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PMID:Effects of cyclic AMP on expression of LFA-1, Mac-1, and VLA-4 and eosinophilic differentiation of a human leukemia cell line, EoL-1. 752 82

The expression of the cystic fibrosis transmembrane conductance regulator (CFTR) gene can be down-regulated by inflammatory stimuli such as phorbol myristate acetate (PMA). Since the respiratory manifestations of cystic fibrosis (CF) are characterized by intense chronic airway inflammation very early in life, successful gene therapy for CF will require that expression of the transferred normal CFTR gene be resistant to down-regulation by inflammatory mediators. To evaluate the concept that a viral promoter--human CFTR cDNA unit would be resistant to this form of down-regulation, a retrovirus promoter (5' long terminal repeat of the Moloney murine leukemia virus)--human CFTR cDNA unit was transferred to T84 human colon carcinoma cell line using a retrovirus vector. Exposure of the retrovirus-modified T84 cells to PMA resulted in down-regulation of the endogenous CFTR mRNA transcripts (6.5 kb), but did not affect the level of exogenous CFTR transcripts (8.0 kb). Importantly, in parallel with the persistence of the exogenous CFTR transcripts, the modified cells still maintained cAMP-regulated CI- secretion in the presence of PMA. These in vitro data suggest that a constitutive viral promoter--CFTR cDNA unit should be resistant to modulation by inflammatory stimuli, a likely requirement for successful gene therapy for CF.
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PMID:Transfer of a constitutive viral promoter-cystic fibrosis transmembrane conductance regulator cDNA to human epithelial cells conveys resistance to down-regulation of cAMP-regulated Cl- secretion in the presence of inflammatory stimuli. 752 42

In previous in vitro studies we found that contact between mouse primordial germ cells and other cell types (neighbouring somatic cells or established TM4 or STO cell lines) is crucial for supporting primordial germ cell survival and proliferation and for activating their motility. We have studied primordial germ cell adhesion to different cell monolayers (STO, TM4, COS and F9 cells) as an in vitro model for interactions between primordial germ cells and cellular substrates. The results suggest that these cell interactions are mediated by multiple mechanisms involving Steel factor and its receptor encoded by c-kit, carbohydrates and possibly other unknown factors. We find that Steel factor and leukaemia inhibitory factor are survival rather than proliferation factors for primordial germ cells. Both molecules prevent primordial germ cell death in culture by suppressing apoptosis. Morphological and molecular features of primordial germ cell apoptosis in vitro are reported. Activation of protein kinase C does not promote primordial germ cell proliferation, but compounds known to enhance intracellular levels of cAMP (i.e. dibutyryl cAMP and forskolin) markedly stimulate primordial germ cells to proliferate in culture. We have preliminary results indicating that neuropeptides PACAP-27 and PACAP-28 are possible physiological activators of adenylate cyclase in primordial germ cells.
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PMID:Interactions between migratory primordial germ cells and cellular substrates in the mouse. 753 Jun 18

Aromatase cytochrome P450 mRNA and activity was strongly expressed in THP 1 myeloid leukaemia cells after treatment with phorbol-myristate-acetate (PMA) and dexamethasone, low level expression was caused by calcitriol. mRNA species of 4.0, 3.0, 2.4 and 1.1 kb size were differentially stimulated. After calcitriol-mediated differentiation (72 h, measured by CD 14 expression) mRNA expression was further enhanced by PMA (45-fold), dexamethasone (15-fold), oestradiol (3.7-fold), testosterone (2.5-fold) and androstenedione (3.5-fold). Forskolin, cAMP and follicle stimulating hormone had no stimulatory effect. Oestradiol formation from testosterone (oestradiol radioimmunoassay in culture supernatants) increased to > 2000 pg/ml/10(6) cells/24 h after PMA-stimulation, mirrored mRNA expression and was suppressed below 10% of original values in the presence of 4-OH-androstenedione. Exons I.2 and I.4 were expressed in PMA-stimulated cells only, exon I.3 in both PMA- and dexamethasone-stimulated cells. A new splicing variant was expressed after calcitriol-stimulation, which did not hybridize to an exon II-derived oligonucleotide but to an exon III-derived one. Local aromatisation of androgens into oestradiol may be important in the concerted crosstalk of cells of the monocyte/macrophage lineage with their respective tissues in inflammation and bone metabolism.
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PMID:Expression and regulation of aromatase cytochrome P450 in THP 1 human myeloid leukaemia cells. 754 22

Apoptosis has been investigated in NB4, a t(15;17) human promyelocytic leukemia cell line susceptible to maturation by all-trans or 9-cis retinoic acid, and in NB4-R1, a subclone resistant to differentiation. Maturation resistant NB4-R1 cells exhibited an onset of cell death after RA-treatment (72 h), whereas maturation responsive NB4 cells showed no such apoptosis, cell death being considerably delayed after cell maturation. Only a few NB4-R1 cells underwent apoptosis in response to low doses of RA (below 0.1 microM), the surviving cells became refractory to higher doses of RA. While these cells became 'resistant' to apoptosis they became competent for maturation. Typically, these RA-'primed' cells responded to cAMP by maturation, then apoptosis followed rapidly. This model furnishes situations where cells are either resistant or susceptible to apoptosis, depending on whether they can or cannot undergo maturation. The potential role of the Bcl-2 protein in the regulation of apoptosis was analyzed. In NB4 and NB4-R1 cell lines, a high expression of the Bcl-2 protein was detected by immunocytology and Western blotting. NB4 cells treated with either all-trans or 9-cis retinoic acid (1 microM) were induced to differentiate and the level of Bcl-2 protein decreased to undetectable levels during terminal maturation when only a few apoptotic cells were detected. In NB4-R1 cells, while treatment with retinoids does not induce maturation, as much as 64% of cells became apoptotic, and immunocytological labelling of NB4-R1 showed a strong cytoplasmic labelling of Bcl-2. Although the expression of Bcl-2 remained high, cells were not protected from apoptosis. To assess whether Bcl-2 expression could be modulated as a consequence of differentiation, NB4-R1 cells previously 'primed' for maturation were triggered with cAMP. Downregulation of Bcl-2 protein occurred concomitant with maturation, followed by apoptosis. Clearly, NB4 and NB4-R1 cells show reciprocal behavior with regards to proliferation, maturation, Bcl-2 regulation and apoptosis in response to RA. Our results suggest, first, that the Bcl-2 downregulation in NB4 cells belongs to the maturation program rather than to apoptosis, and second, that neither a high Bcl-2 expression in NB4 cells is sufficient to protect cells from 9-cis RA induced apoptosis, nor is its full downregulation sufficient to produce apoptosis. Finally, this work suggests that apoptosis and maturation programs include events which cannot occur simultaneously.
Leukemia 1995 Jul
PMID:Distinct apoptotic responses in maturation sensitive and resistant t(15;17) acute promyelocytic leukemia NB4 cells. 9-cis retinoic acid induces apoptosis independent of maturation and Bcl-2 expression. 763 Jan 93

Novel (Rp)-cAMPS analogs differed widely in ability to antagonize cAMP activation of pure cAMP-dependent protein kinase I and II and to antagonize actions of cAMP on gene expression, shape change, apoptosis, DNA replication, and protein phosphorylation in intact cells. These differences were related to different abilities of the analogs to stabilize the holoenzyme form relative to the dissociated form of cAMP kinase type I and II. (Rp)-8-Br-cAMPS and (Rp)-8-Cl-cAMPS were the most potent cAMP antagonists for isolated type I kinase and for cells expressing mostly type I kinase, like IPC-81 leukemia cells, fibroblasts transfected with type I regulatory subunit (RI), and primary hepatocytes. It is proposed that (Rp)-8-Br-cAMPS or (Rp)-8-Cl-cAMPS should replace (Rp)-cAMPS as the first line cAMP antagonist, particularly for studies in cells expressing predominantly type I kinase. The phosphorylation of endogenous hepatocyte proteins was affected oppositely by (Rp)-8-Br-cAMPS and increased cAMP, indicating that (Rp)-8-Br-cAMPS inhibited basal cAMP-kinase activity. The inhibition of basal kinase activity was accompanied by enhanced DNA replication, an effect which could be reproduced by microinjected mutant cAMP-subresponsive RI. It is concluded that the basal cAMP-kinase activity exerts a tonic inhibition of hepatocyte replication. (Rp)-8-Br-cAMPS and microinjected RI also desensitized hepatocytes toward inhibition of DNA synthesis by interleukin-1 beta. This indicates that basal cAMP-kinase activity can have a permissive role for the action of another (interleukin-1 beta) signaling pathway.
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PMID:Novel (Rp)-cAMPS analogs as tools for inhibition of cAMP-kinase in cell culture. Basal cAMP-kinase activity modulates interleukin-1 beta action. 765 38


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