Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0032463 (polycythemia vera)
 3,374 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Red blood cell metabolism was studied in male patients with polycythemia rubra vera (Vaquez disease) and compared to a reference sample of 74 healthy adults. A total of seventeen enzyme activities and seventeen metabolite concentrations were determined. In addition to the modifications of the hematological parameters among the polycytemic patients significant variations were detected: a decreased content of hemoglobin in the cells; significantly decreased levels of ATP, ADP and AMP associated to an accelerated turn over of these metabolites; an acceleration of the glycolytic pathway associated with an increase of the energetic charge and levels of 2-3BPG and G1-6BP. In polycythemia rubra vera patients, the modifications of the hematological and biochemical parameters were compared to previous results obtained in high altitude residents (adaptative hypoxia) and in red cells belonging to new borns.
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PMID:Consequences of moderate hypoxia on red cell glycolytic metabolism in polycythemia rubra vera. 204 71

The content of platelet adenine nucleotide in chronic myeloproliferative disorders (CMPD) and multiple myeloma (MM) was measured by a luciferin-luciferase method by Holmsen and Weiss. The release of ATP and ADP from platelet during aggregation induced by collagen and epinephrine were analyzed. The total 42 investigated cases consisted of 11 cases of polycythemia vera (PV), 7 cases of essential thrombocythemia (ET), 7 cases of chronic myeloid leukemia (CML), 9 cases of blastic crisis of CML (BC-CML), and 8 cases of multiple myeloma (MM). The healthy control was 19 cases. In CMPD and MM, the amount of ATP was normal in spite of decrease of ADP; therefore, the ratio of ATP/ADP increased. On the other hand, the ATP significantly increased in BC-CML. MM revealed a remarkable increase of ATP release due to the aggregation by collagen and epinephrine. The maximal rate of aggregation of collagen and epinephrine using Lumi-aggregometer indicated a positive relationship with the ATP release by the Holmsen and Weiss' method. The platelet volume in CMPD increased showing correlation with ATP content and not with ADP. In conclusion, CMPD and MM are regarded as acquired qualitative disorders of platelets or secondary storage pool diseases from the view points of the abnormalities in ATP, ADP contents and their release. However, BC-CML and MM revealed some different change from that of CMPD.
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PMID:[ATP and ADP of platelets in chronic myeloproliferative disorders and multiple myeloma]. 271 95

In recent years, radiolabelled monoclonal antibodies have been evaluated for their use in the diagnosis and treatment of neoplastic disease. One isotope which has not been assessed for antibody targeting is 32P, even though it has many favourable radiobiological characteristics and has been used clinically for the treatment of certain neoplastic disorders such as polycythaemia rubra vera. The main drawback so far in using 32P has been the absence of a general method for phosphorylating antibodies. We have now developed a novel process for the phosphorylation of immunoglobulins which is rapid, efficient and allows high specific activities to be achieved (greater than 10 muCi micrograms-1). The technique involves the chemical conjugation of Kemptide, a synthetic heptapeptide substrate for kinases, to immunoglobulins. The antibody-Kemptide conjugate can then be phosphorylated using protein kinases and [32P]-gamma-ATP. The procedure does not compromise the binding activity of the antibody. The 32P-labelled monoclonal antibodies were stable in human, mouse and rat plasmas in vitro, although they cleared from the bloodstream of mice with a beta-phase half life of 2 days which is approximately two times faster than that of native antibody. The application of this phosphorylation technique should allow the therapeutic potential of targeted 32P to be assessed.
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PMID:Conjugation of monoclonal antibodies to a synthetic peptide substrate for protein kinase: a method for labelling antibodies with 32P. 339 53

Platelet aggregation was studied in 18 patients with myeloproliferative disorders, including 14 patients with chronic myelogenous leukemia, 2 with polycythemia vera, 1 with myelofibrosis and 1 with thrombocythemia. Fourteen patients (78%) were abnormal in epinephrine-induced platelet aggregation, while 3 (17%) and 4 (22%) cases showed impaired ADP or collagen induced platelet aggregation, respectively. A significant decrease of total ADP content in resting unstimulated platelets and of the amount released to the medium after aggregation was found in all six patients who were evaluated. ATP and AMP in resting platelets tended to be slightly higher in patients compared with the control group. Released ATP was also significantly less, and the percentage release of ADP and ATP was significantly decreased in patients. A storage pool deficiency of adenine nucleotides was considered to be responsible for abnormal platelet function in patients with myeloproliferative disorders.
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PMID:Abnormalities of epinephrine-induced platelet aggregation and adenine nucleotides in myeloproliferative disorders. 653 53

Patients with polycythaemia and normal controls have been studied to establish and subsequently test non-conventional criteria for the diagnosis of primary polycythaemia (primary proliferative polycythaemia, polycythaemia vera) as compared with conventional Polycythaemia Vera Study Group (PVSG) assessment. One criterion was erythroid colony formation from peripheral blood in a serum-free system, assayed alone and with the addition of recombinant human erythropoietin (Epo), interleukin 3 (IL3), or alpha interferon (alpha-IFN) (Dudley et al. 1990). The remaining criteria were non-culture associated and comprised platelet distribution width (PDW), platelet nucleotide ratio (ATP:ADP), serum erythropoietin and clinical evidence of ischaemic vascular disease. The combination of culture associated and non-culture associated variables, by use of a simple additive scoring system, gave no false positive and only 6% false negative results in distinguishing primary polycythaemia from other polycythaemias and normal controls in those (34 patients Group A) used in its derivation. Testing the scoring system in a newly presenting group (25 patients Group B) was highly satisfactory with no false positives and only a few false negative results (14%). Use of these non-conventional criteria should allow more confident diagnosis of primary polycythaemia, where conventional clinical and laboratory assessment is inconclusive.
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PMID:Primary polycythaemia: diagnosis by non-conventional positive criteria. 824 12

Jak2 tyrosine kinase is essential for animal development and hyperkinetic Jak2 function has been linked to a host of human diseases. Control of this pathway using Jak2-specific inhibitors would therefore potentially serve as a useful research tool and/or therapeutic agent. Here, we used a high-throughput program called DOCK to predict the ability of 20,000 small molecules to interact with a structural pocket adjacent to the ATP-binding site of murine Jak2. One small molecule, 2-methyl-1-phenyl-4-pyridin-2-yl-2-(2-pyridin-2-ylethyl)butan-1-one (herein designated as Z3), bound to Jak2 with a favorable energy score. Z3 inhibited Jak2-V617F and Jak2-WT autophosphorylation in a dose-dependent manner but was not cytotoxic to cells at concentrations that inhibited kinase activity. Z3 selectively inhibited Jak2 kinase function with no effect on Tyk2 or c-Src kinase function. Z3 significantly inhibited proliferation of the Jak2-V617F-expressing, human erythroleukemia cell line, HEL 92.1.7. The Z3-mediated reduction in cell proliferation correlated with reduced Jak2 and STAT3 tyrosine phosphorylation levels as well as marked cell cycle arrest. Finally, Z3 inhibited the growth of hematopoietic progenitor cells isolated from the bone marrow of an essential thrombocythemia patient harboring the Jak2-V617F mutation and a polycythemia vera patient carrying a Jak2-F537I mutation. Collectively, the data suggest that Z3 is a novel specific inhibitor of Jak2 tyrosine kinase.
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PMID:Z3, a novel Jak2 tyrosine kinase small-molecule inhibitor that suppresses Jak2-mediated pathologic cell growth. 1872 78

Somatic mutations in Janus kinase 2 (JAK2), including JAK2V617F, result in dysregulated JAK-signal transducer and activator transcription (STAT) signaling, which is implicated in myeloproliferative neoplasm (MPN) pathogenesis. CYT387 is an ATP-competitive small molecule that potently inhibits JAK1/JAK2 kinases (IC(50)=11 and 18 nM, respectively), with significantly less activity against other kinases, including JAK3 (IC(50)=155 nM). CYT387 inhibits growth of Ba/F3-JAK2V617F and human erythroleukemia (HEL) cells (IC(50) approximately 1500 nM) or Ba/F3-MPLW515L cells (IC(50)=200 nM), but has considerably less activity against BCR-ABL harboring K562 cells (IC=58 000 nM). Cell lines harboring mutated JAK2 alleles (CHRF-288-11 or Ba/F3-TEL-JAK2) were inhibited more potently than the corresponding pair harboring mutated JAK3 alleles (CMK or Ba/F3-TEL-JAK3), and STAT-5 phosphorylation was inhibited in HEL cells with an IC(50)=400 nM. Furthermore, CYT387 selectively suppressed the in vitro growth of erythroid colonies harboring JAK2V617F from polycythemia vera (PV) patients, an effect that was attenuated by exogenous erythropoietin. Overall, our data indicate that the JAK1/JAK2 selective inhibitor CYT387 has potential for efficacious treatment of MPN harboring mutated JAK2 and MPL alleles.
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PMID:CYT387, a selective JAK1/JAK2 inhibitor: in vitro assessment of kinase selectivity and preclinical studies using cell lines and primary cells from polycythemia vera patients. 1929 46

The recent discovery of an acquired activating point mutation in JAK2, substituting valine at amino acid position 617 for phenylalanine, has greatly improved our understanding of the molecular mechanism underlying chronic myeloproliferative neoplasms. Strikingly, the JAK2(V617F) mutation is found in nearly all patients suffering from polycythemia vera and in roughly every second patient suffering from essential thrombocythemia and primary myelofibrosis. Thus, JAK2 represents a promising target for the treatment of myeloproliferative neoplasms and considerable efforts are ongoing to discover and develop inhibitors of the kinase. Here, we report potent inhibition of JAK2(V617F) and JAK2 wild-type enzymes by a novel substituted quinoxaline, NVP-BSK805, which acts in an ATP-competitive manner. Within the JAK family, NVP-BSK805 displays more than 20-fold selectivity towards JAK2 in vitro, as well as excellent selectivity in broader kinase profiling. The compound blunts constitutive STAT5 phosphorylation in JAK2(V617F)-bearing cells, with concomitant suppression of cell proliferation and induction of apoptosis. In vivo, NVP-BSK805 exhibited good oral bioavailability and a long half-life. The inhibitor was efficacious in suppressing leukemic cell spreading and splenomegaly in a Ba/F3 JAK2(V617F) cell-driven mouse mechanistic model. Furthermore, NVP-BSK805 potently suppressed recombinant human erythropoietin-induced polycythemia and extramedullary erythropoiesis in mice and rats.
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PMID:Potent and selective inhibition of polycythemia by the quinoxaline JAK2 inhibitor NVP-BSK805. 2058 63

Myeloproliferative neoplasms (MPNs) are clonal disorders characterized by excessive production of mature cells. In most of the classic Philadelphia-negative MPNs-polycythemia vera (PV), essential thrombocythemia (ET), and MPN-associated myelofibrosis (MPN-MF)-oncogenic mutations affecting JAK2 or MPL lead to constitutive activation of cytokine-regulated intracellular signalling pathways. The traditional therapy for PV and ET is the prevention of thrombotic events with antiproliferative agents in association with aspirin. New drugs such as pegylated interferon and anti-JAK agents are candidates for slowing the evolution to myelofibrosis or leukemia. Conventional therapy for MPN-MF is driven by clinical needs, primarily anemia and splenomegaly. Lenalidomide and pomalidomide are new candidates for treating anemia. JAK2 ATP-competitive inhibitors or drugs that indirectly inhibit the JAK-STAT pathway, like RAD001, are the new candidates for splenomegaly in MPN-MF, but in spite of their strong rationale, they have shown only a palliative benefit. Allogeneic stem cell transplantation remains the only potentially curative approach.
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PMID:Management of myeloproliferative neoplasms: from academic guidelines to clinical practice. 2227 47

The Janus family kinases (JAKs), JAK1, JAK2, JAK3, and TYK2, are involved in cell growth, survival, development, and differentiation of a variety of cells, particularly immune cells and hematopoietic cells. They form a subgroup of the non-receptor protein tyrosine kinases. Activating mutations within each of the JAKs is associated with malignant transformations; the most common are mutations of JAK2 in polycythemia vera (PV) and other myeloproliferative neoplasms (MPN). Identification of the V617F mutation of the JAK2 gene (JAK2 V617F) led to an important breakthrough in the understanding of MPN disease pathogenesis. The JAK2 V617F mutation is present in the majority of PV patients, and about 50% of patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF) are affected. This mutation leads to hyperactivation of JAK2, cytokine-independent signaling, and subsequent activation of downstream signaling networks. JAK2 ATP-competitive inhibitors that indirectly inhibit the JAK-STAT pathway are new candidates for the treatment of MPN. JAK2 inhibitors in development for the treatment of MPN have demonstrated clinical activity with minimal toxicity. These agents consistently alleviate constitutional symptoms and reduce spleen size in PMF and other MPN. However, some of these inhibitors have additional unique effects. Ruxolitinib causes a significant reduction in the level of pro-inflammatory cytokines. Another inhibitor, CYT387, improves anemia. Many other JAK2 inhibitors such as TG101348 or SAR302503, SB1518, CEP701 and LY2784544 are now under investigation for MPN development. In contrast tasocitinib, a predominantly JAK3 inhibitor, is being evaluated in a number of inflammatory and immunological diseases, including rheumatoid arthritis, psoriasis, ulcerative colitis, dry eye disease and in kidney transplant patients. In conclusion the use of JAK inhibitors in MPN and some of the immune-mediated disorders is a promising new strategy for therapy. However, definitive data from ongoing and future preclinical and clinical trials will aid in better defining the status of these drugs in the treatment of these diseases.
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PMID:JAK inhibitors: pharmacology and clinical activity in chronic myeloprolipherative neoplasms. 2331 59


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