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

Prostaglandin (PG) D(2) is synthesized in platelets at concentrations which could inhibit aggregation via activation of adenylate cyclase. To more directly define platelet-PG interactions, a binding assay has been developed for platelet PG receptors with [(3)H]PGD(2) as ligand. [(3)H]PGD(2) binding to intact platelets was saturable and rapid with the ligand bound by 3 min at 20 degrees C. PG competed with the [(3)H]PGD(2) binding site with a potency series: PGD(2) (IC(50) = 0.08 muM) >> PGI(2) (IC(50) = 2 muM) > PGE(1) (IC(50) = 6 muM) > PGF(2alpha) (IC(50) = 8 muM). Scatchard analysis of binding data from six normal subjects showed a single class of binding sites with a dissociation constant (K(d)) of 53 nM and 210 binding sites per platelet. This PGD(2) receptor assay was then used to study platelets from five patients with myeloproliferative disorders (polycythemia vera, essential thrombocythemia, and chronic myelogenous leukemia), as over 90% of these patients have platelets resistant to the effects of PGD(2) on aggregation and adenylate cyclase activity (1978. Blood.52: 618-626.). In the presence of 50 nM [(3)H]PGD(2), the patients' platelets bound 7.1+/-2.9 fmol ligand/10(8) platelets compared with 15.1+/-1 fmol/10(8) platelets in normals, a decrease of 53% (P < 0.01). Scatchard analysis showed that the K(d) of [(3)H]PGD(2) binding (33 nM) was comparable to normal platelets, which indicates that the decreased PGD(2) binding in these platelets represented fewer receptors rather than altered affinity of the ligand for the binding site. The 53% decrease in [(3)H]PGD(2) binding correlated with a 48% decrease in PGD(2)-activated platelet adenylate cyclase. The characterization of the platelet PGD(2) binding site provides further direct evidence that there are at least two PG receptors on platelets, one for PGE(1) and PGI(2), and a separate receptor for PGD(2). Direct binding analysis will be a useful tool for studying the role of PG in regulating platelet function, as demonstrated by the selective loss of PGD(2) binding sites in patients with myeloproliferative disorders.
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PMID:Characterization of the platelet prostaglandin D2 receptor. Loss of prostaglandin D2 receptors in platelets of patients with myeloproliferative disorders. 22 13

In order to clarify the alterations of granuloblastic cells in chronic and acute myeloid leukemia, the colony growth behavior of cultured CFU-GM from the peripheral blood of normal and leukemic subjects was examined in basal conditions and after adding to the medium T3 or T4 and/or thioproline and/or flurbiprofen. These drugs had in previous investigations proved their ability to modify cellular receptors and the uptake of thyroid hormones. The study was carried out in semisolid (double agar layer) and liquid medium, utilizing the techniques described previously. Both thyroid hormones enhanced the colony growth from normal peripheral blood CFU-GM and the response was more evident with T4 than T3. The effect on leukemic CFU-GM (from CML and AML) was less clear, probably due to the presence in leukemic cells of a defect of cellular uptake and to the utilization of T3 and T4. Indeed, on addition to the culture medium of thioproline, which modifies membrane permeability, and of fluorbiprofen, which inhibits PGE synthesis, the colony number and growth from leukemic CFU increased considerably in accordance with the results of our previous studies on these substances showing that they are able to modify cellular receptors for thyroid and several other hormones.
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PMID:The influence of thyroid hormones on colony growth of peripheral CFU-GM from normal and leukemic subjects. 321 84

The authors investigated the behaviour of steroid hormone uptake in leukaemic cells (CML, CLL, AML, ALL), in basal conditions and after incubation with drugs which modify the cellular concentration of cAMP, PGE and PGF. The results demonstrated the presence in leukaemic cells of an alteration in the incorporation of steroid hormones. This alteration was scarcely modified by incubation with theophylline, which increases cellular concentration of cAMP. On the other hand, it was moderately counteracted by thioproline and was evidently inhibited by flurbiprofen, which also reduced cellular concentrations of prostaglandins, particularly PGE2, with the exception of PGF2 which showed a poor response. Differences were observed in the behavior of hormonal uptake of CML, in contrast to that of AML, CLL and ALL peripheral leucocytes.
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PMID:Drugs affecting the hormonal receptors of normal and leukaemic peripheral leucocytes. 651 20

The behaviour of phagocytosis and that of PGE1 and PGE2 in the circulating granulocytes of normal and leukaemic subjects was investigated by the comparison of latex particles and the PAP (peroxidase-antiperoxidase) immuno-enzymatic method respectively. Generally speaking, it was found that chronic myeloid leukaemia and acute myeloblastic leukaemia were accompanied by a marked reduction in phagocyting capacity, whereas this is apparently normal in CLL and ALL. PCE values, on the other hand, were well down in lymphatic leukaemia, AML and AMML, but not in CML, where high PGE (especially PGE2) was noted both basally and after phagocytosis. That the PGE take part in phagocytosis is shown by their redistribution in phagocyting cells, with elective accumulation in the membrane and around the engulfed material.
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PMID:[Behavior of PGE1 and PGE2 in the granulocytes of normal and leukemic subjects during phagocytosis in vitro]. 695 84

The effect of prostaglandin E1 (PGE1) on the in vitro proliferation of peripheral blood granulocyte/macrophage progenitors (CFUc) from the patients with chronic myeloproliferative disorders was examined. PGE1 was found to be a dose-dependent inhibitor of normal peripheral blood and bone marrow CFUc. Peripheral blood CFUc from patients with chronic myelogenous leukemia (CML) showed normal inhibition when cultured in the absence of exogenous colony stimulating factor (CSF). The addition of CSF to CML peripheral blood cultures resulted in complete abrogation of normal PGE1 inhibition. Dose-titration studies in which increasing amounts of CSF were added to CML cultures showed decreasing PGE1 inhibition with increasing CSF concentration. This observation indicated increased efficiency of competition between the colony stimulating effect of CSF and the colony inhibitory effect of PGE1 in CML. Peripheral blood CFUc from patients with myelofibrosis/myeloid metaplasia (MM) showed heterogeneous responses to PGE1 with complex dose-effect curves showing variable combinations of stimulation and inhibition of CFUc proliferation. Further studies showed that these effects of PGE1 were blocked by the prostaglandin antagonist SC-19220, and were not due to elaboration of CSF or non-CSF enhancers of CFUc proliferation from MM adherent cells. Cell fractionation studies in 2 patients, with MM showed dual populations of CFUc, one responding abnormally, and another normally to PGE1, accounting in part for the complex dose-response curves. These studies indicate that significant abnormalities exist in the in vitro response to PGE1 by CFUc from patients with chronic myeloproliferative disorders. Deficiencies in PGE 1 inhibition may contribute to the excess myelopoiesis seen in these disorders.
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PMID:Abnormal modulation of granulocyte/macrophage progenitor proliferation by prostaglandin E in chronic myeloproliferative disorders. 697 57

The behaviour of prostaglandins A, B, E 1, E 2, F 1 and F 2 has been examined in the granulocytes and lymphocytes of the peripheral blood of normal subjects and in circulating leucocytes of patients with CML, AML, CLL and ALL. At the same time, modifications of PGE 2 in the granulocytes of normal subjects and in patients with CML or AML before and after phagocytosis of latex particles were monitored. The general observation was a lowering in PGE and PGF in acute myeloid and lymphatic leukaemia, while the variations in CML and CLL were rather complex. Also observed was a reduction in PGE 2 in AML but not in CML, including a reduced response to phagocytosis in granulocytes. The data are compared with previous reports of AMPc and GMPc in the same cells and commented on, taking into consideration their possible reflexion on the proliferative and functional activity of the cells examined.
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PMID:[Behavior of several prostaglandins (PGA, PGB, PGE 1, PGE 2, PGF 1, PGF 2) in normal and leukemic leukocytes. Radioimmunological method on intact cells]. 724 9

Our previous studies have shown that overexpression of MDR1 and cyclooygenase-2 (COX-2) resulted in resistance development to imatinib in chronic myelogenous leukemia (CML) K562 (IR-K562) cells. In the present study, the regulatory mechanism of MDR1 induction by COX-2 was investigated. A gradual overexpression of MDR1 and COX-2 during the process of development was observed. Furthermore, down regulation of MDR1 upon COX-2 knockdown by siRNA showed a decrease in the PKC levels and activation of PKC by addition of PGE(2) to K562 cells, suggesting a role for PKC in the COX-2 mediated induction of MDR1. The present study demonstrates COX-2 induction by HDACs and MDR1 induction by COX-2 via PGE(2)-cAMP-PKC-mediated pathway.
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PMID:Bcr-Abl-independent mechanism of resistance to imatinib in K562 cells: Induction of cyclooxygenase-2 (COX-2) by histone deacetylases (HDACs). 2020 83