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)

The adenine nucleoside analogue, fludarabine phosphate, in combination with cytosine-arabinoside (Ara-C) and granulocyte-colony stimulating factor (G-CSF) (the so called FLAG regimen) has recently been shown to be effective in the treatment of poor-prognosis acute non-lymphoid leukaemia. We used this combination plus novantrone (FLANG regimen) in a case of Ph1+ chronic myeloid leukaemia (CML) unresponsive to interferon alpha that had progressed to an acute phase, after 3 months of treatment with 6-mercaptopurine and hydroxyurea. The patient was treated with two courses of fludarabine 30 mg/m2 (days 1-5) + Ara-C 2 g/m2 (days 1-5) + novantrone 5 mg/m2 (days 1-3) and G-CSF from day 0 to neutrophil recovery. After the first cycle of chemotherapy, bone marrow blasts decreased from 100% to less than 5% (clinical complete remission), with a progressive clearance of Ph1+ metaphases (from 100% to 12%). At the end of the second course, a progressive increase of blasts was observed again and karyotypic detection of Ph+ cells was also documented (from 12% to 42.9%). During this partial remission, the patient underwent an allogeneic bone marrow transplantation from an HLA matched identical brother. At the time of this report, he is still alive and well and in complete karyotypic remission. This partial therapeutic success was compared with the result obtained in another previously reported CML case: differences in the therapeutic efficacy of protocols employing fludarabine nucleosides and the type of blastic cells involved are discussed.
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PMID:FLANG (fludarabine + cytosine arabinoside + novantrone + G-CSF) induces partial remission in lymphoid blast transformation of Ph+chronic myelogenous leukaemia. 872 45

DNA templates suitable for direct synthesis of RNA probes are produced by the polymerase chain reaction. The nucleic acid sequence of interest is amplified using a downstream primer carrying the T7 RNA polymerase promoter sequence. The modified primer is incorporated into the amplified DNA, which is subsequently used for RNA probe synthesis in the presence of T7 RNA polymerase and a hapten-labeled ribonucleotide (digoxigenin-UTP). As a model, we prepared RNA probes specific for the BCR-ABL mRNA characteristic of chronic myelogenous leukemia. The probes are used in time-resolved fluorometric hybridization assays. Mixtures of BCR-ABL positive and negative cells, as well as whole blood samples, are analyzed. The sample mRNA is amplified using a biotinylated upstream primer. The amplified product (target DNA) is captured onto streptavidin-coated wells and hybridized to the RNA probe. The hybrids are detected with an alkaline phosphatase (ALP)-labeled antibody. ALP hydrolyzes the phosphate ester of fluorosalicylic acid, and the fluorosalicylate produced forms highly fluorescent ternary complexes with Tb(3+)-EDTA, which can be quantified by measuring the Tb3+ fluorescence in a time-resolved mode. As low as 0.4 fmol of target DNA can be detected. Also, a single leukemic cell may be detected in the presence of 0.5 million "normal" cells.
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PMID:Time-resolved fluorometric hybridization assays with RNA probes synthesized from polymerase chain reaction-generated DNA templates. 884 29

Conventional antileukemic chemotherapy in relapsed or refractory acute leukemia or myeloid blast crisis of chronic granulocytic leukemia (CGL) is not curative and remissions, if attained, are usually of short duration. The primary goal of antileukemic therapy in these patients should be the identification of agents that are more selective and better targeted in their action. Tiazofurin is known to inhibit inosine 5'-phosphate dehydrogenase (IMPDH), the rate limiting enzyme of de novo guanine ribonucleotide synthesis. The activity of this enzyme is markedly increased in leukemic cells. To prevent de novo GTP synthesis, it is also necessary to block the guanine-salvaging activity of hypoxanthine-guanine phosphoribosyltransferase (HGPRT). This was achieved by increasing the plasma levels of hypoxanthine through the administration of allopurinol. Twenty-seven patients with end stage leukemia or myeloid blast crisis of CGL were treated with tiazofurin. Assays of IMPDH activity and GTP concentrations in leukemic cells, as well as hypoxanthine levels in the serum, provided a method to monitor the impact of tiazofurin/allopurinol therapy and to adjust drug doses. In these poor prognosis patients seven attained a complete response (CR), 3 had a hematologic improvement and an antileukemic effect was seen in 4. An excellent correlation was observed between biochemical and clinical activity of tiazofurin/allopurinol, with biochemical responses preceding clinical results. However, clinical responses were usually short-lived with IMPDH activity starting to increase soon after discontinuation of therapy, but patients responding again after reinstitution. Tiazofurin therapy was generally well tolerated in patients with less than 15 days of treatment and no other major medical complications. Although an antiproliferative effect was observed in some patients, bone marrows remained cellular in most cases with a marked shift from blasts to granulocytes. Severe neutropenia was absent in the majority of cases and patients could be discharged in good clinical condition immediately after completion of therapy. Tiazofurin/allopurinol therapy provided a rational, biochemically targeted and biochemically monitored approach to the treatment of poor prognosis leukemia and should serve as a paradigm in enzyme pattern-targeted chemotherapy.
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PMID:Biochemically targeted therapy of refractory leukemia and myeloid blast crisis of chronic granulocytic leukemia with Tiazofurin, a selective blocker of inosine 5'-phosphate dehydrogenase activity. 904 9

Glucose 6 phosphate dehydrogenase (G6PD) was estimated in the leucocytes of 35 patients with acute non-lymphocytic leukemia (ANLL) and 10 patients with chronic myeloid leukemia (CML). G6PD levels were found to be significantly decreased in majority of the patients with ANLL while it was increased in all CML patients. Variation in G6PD was found to be dependent on the percentage of myelocytes inANLL. Cytogenetic analysis was also carried out in these patients. Correlation analysis of leucocyte G6PD activity and karyotype with prognostic assessment clearly indicated the association of (s) high percentage of chromosomal abnormalities especially translocations, (b) low survival and remission rates, with patients having decreased G6PD activity when compared to patients with normal activity in ANLL. The studies indicate that leucocyte G6PD may be useful as a diagnostic and prognostic tool.
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PMID:Leukocyte glucose 6 phosphate dehydrogenase as prognostic indicator in ANLL and CML. 931 24

The anti-leukemic activity of a series of alkylphosphocholines (APCs) was studied against a panel of human leukemic cell lines (HL-60, K-562, Reh, MOLT-4, Jurkat, Ramos and Raji). Cytotoxic efficacy was measured by the MTT cell survival assay. All cell lines were found to be sensitive, except the multipotential CML-derived K-562 cell line. Flow cytometry of HL-60 cells showed a significant decrease of cells in S phase and the formation of a sub-G fraction. DNA fragmentation typical for programmed cell death was detected by DNA gel electrophoresis in these cells but not in any of the other leukemic lines. At concentrations below the cytotoxic range, mitogenic effects were seen in HL-60 cells after 14-hr exposure. Colony formation by K-562 cells revealed an augmented clonogenicity after exposure to APC with a short alkyl chain. In contrast, cells of lymphoid origin did not undergo DNA fragmentation or show mitogenic stimulation after exposure to APC. Normal bone marrow cells were also investigated for mitogenic and genotoxic effects. No decrease was found in the number of hematopoietic progenitors in long-term bone marrow cell cultures after exposure to APC. On the contrary, a significant increase was found after short exposure. Dodecylphosphocholine, hexadecylphosphocholine (HPC) and (octadecyl-[2-(N-methylpiperidino)-ethyl]phosphate exhibited a mild clastogenicity at equimolar high doses on murine bone marrow cells in vivo, which is unusual for the majority of classical DNA-interacting anti-cancer drugs. In conclusion, APCs are agents with a broad spectrum of in vitro anti-leukemic effects, which lack hematological toxicity.
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PMID:Alkylphosphocholines: Effects on human leukemic cell lines and normal bone marrow cells. 968 13

Crkl, a 39-kD SH2, SH3 domain-containing adapter protein, is constitutively tyrosine phosphorylated in hematopoietic cells from chronic myelogenous leukemia (CML) patients. We recently reported that thrombopoietin induces tyrosine phosphorylation of Crkl in normal platelets. In this study, we demonstrate that thrombopoietin induces association of Crkl with a tyrosine phosphorylated 95- to 100-kD protein in platelets and in UT7/TPO cells, a thrombopoietin-dependent megakaryocytic cell line. With specific antibodies against STAT5, we demonstrate that the 95- to 100-kD protein in Crkl immunoprecipitates is STAT5. This coimmunoprecipitation was specific in that Crkl immunoprecipitates do not contain STAT3, although STAT3 becomes tyrosine phosphorylated in thrombopoietin-stimulated platelets. The coimmunoprecipitaion of Crkl with STAT5 was inhibited by the immunizing peptide for Crkl antisera or phenyl phosphate (20 mmol/L). After denaturing of Crkl immunoprecipitates, Crkl was still immunoprecipitated by Crkl antisera. However, coimmunoprecipitation of STAT5 was not observed. Coincident with STAT5 tyrosine phosphorylation, thrombopoietin induces activation of STAT5 DNA-binding activity as demonstrated by electrophoretic mobility shift assays (EMSA). Using a beta-casein promoter STAT5 binding site as a probe, we have also demonstrated that Crkl antisera supershift the STAT5-DNA complex, suggesting that Crkl is a component of the complex in the nucleus. Furthermore, interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and erythropoietin also induce Crkl-STAT5 complex formation in responding cells in a stimulation-dependent manner. In vitro, glutathione S-transferase (GST)-Crkl bound to STAT5 inducibly through its SH2 domain. These results indicate that thrombopoietin, IL-3, GM-CSF, and erythropoietin commonly induce association of STAT5 and Crkl and that the complex translocates to the nucleus and binds to DNA. Interestingly, such association between STAT5 and Crkl was not observed in cytokine-stimulated murine cells, suggesting an intriguing possibility that components of the human STAT5-DNA complex may be different from those of the murine counterpart.
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PMID:Thrombopoietin induces association of Crkl with STAT5 but not STAT3 in human platelets. 984 31

Methylglyoxal is formed in vivo by spontaneous decomposition of triose phosphate intermediates in aerobic glycolysis. It may also be formed during oxidative degradation of both carbohydrates (pentoses and ascorbate) and lipids (arachidonate). In addition to reaction with arginine residues to form imidazolone adducts, methylglyoxal reacts with lysine residues in protein to form N(epsilon)-(carboxyethyl)lysine (CEL) and the imidazolium crosslink, methylglyoxal-lysine dimer (MOLD). Like the glycoxidation products, N(epsilon)-(carboxymethyl)lysine (CML) and glyoxal-lysine dimer (GOLD) which are formed on reaction of glyoxal with protein, CEL and MOLD increase in lens proteins and skin collagen with age. CML and CEL also increase in skin collagen in diabetes, while all four compounds increase in plasma proteins in uremia. Overall, CML, CEL, GOLD and MOLD are quantitatively the major biomarkers of the Maillard reaction in tissue proteins. GOLD and MOLD, in particular, are present at 10-50 fold higher concentrations than the fluorescent crosslink, pentosidine. Together, these dicarbonyl-derived advanced glycation endproducts (AGEs) represent the major chemical modifications that accumulate in tissue proteins with age and in chronic diseases such as diabetes and atherosclerosis.
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PMID:Chemical modification of proteins by methylglyoxal. 984 96

The initial phase of chronic myelogenous leukemia (CML) is triggered by constitutive protein tyrosine kinase activity of the chimeric kinase p210(bcr-abl) (Bcr-Abl). A major substrate of Bcr-Abl was recently identified as the RasGAP-associated 62 kDa docking protein Dok1. Here, we report complex formation between endogenous Dok1 and the SH2 domain-containing phosphatidylinositol polyphosphate 5-phosphatase SHIP1 in hematopoietic cells expressing Bcr-Abl. Expression of Bcr-Abl induced tyrosine phosphorylation of both Dok1 and SHIP1 and the formation of a Dok1/SHIP1 complex. Tyr(P) SHIP1 was also bound to Shc in Bcr-Abl expressing cells. A small amount of Shc/SHIP1/Dok1 trimolecular complex was detected and this was due to binding of Dok1 to SHIP1 that was bound to Shc. In contrast, association of Dok1 with SHIP1 or RasGAP was mutually exclusive. Both the SH2 domain of SHIP1 and the PTB domain of Dok1 were required for complex formation between the two proteins. Neither the specific activity of SHIP1 as an inositol phosphate 5-phosphatase nor the subcellular localization of SHIP1 appeared to be altered by tyrosine phosphorylation. However, the Dok1/SHIP1 complex was only detected in the cytosolic fraction of Bcr-Abl transformed hematopoietic cells. We propose that interaction between Dok1 and SHIP1 modulates the ability of these two proteins to interact with other cytosolic binding partners.
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PMID:The phosphatidylinositol polyphosphate 5-phosphatase SHIP1 associates with the dok1 phosphoprotein in bcr-Abl transformed cells. 1082 73

Natural killer (NK) cells are deficient in patients with chronic myelogenous leukemia (CML), but the mechanisms responsible for the dysfunction are not completely understood. This study reports that CML cells effectively inhibit the baseline and interleukin-2 (IL-2)-induced NK cell cytotoxicity against a CML cell-derived line (K562). A sizable fraction of NK cells subsequently acquired features characteristic of programmed cell death/apoptosis. The CML cell-mediated inhibition of NK cells required triggering of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-mediated formation of reactive oxygen species (ROS) and was prevented by catalase, a scavenger of ROS, and by histamine, acting via H(2)-receptor-mediated inhibition of ROS production in CML cells. In contrast, nonmalignant neutrophilic granulocytes inhibited NK cells via ROS production without the requirement of exogenous NADPH oxidase-triggering stimuli. We propose that paracrine production of ROS may contribute to the dysfunction of NK cells in CML and that histamine may serve as an autocrine inhibitor of ROS formation in leukemic granulocytes. (Blood. 2000;96:1961-1968)
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PMID:Natural killer cell dysfunction and apoptosis induced by chronic myelogenous leukemia cells: role of reactive oxygen species and regulation by histamine. 1096 1

STI571 (formerly known as CGP 57148B) is a protein-tyrosine kinase inhibitor that is currently in clinical trials for the treatment of chronic myelogenous leukemia. STI571 selectively inhibits the Abl and platelet-derived growth factor (PDGF) receptor tyrosine kinases in vitro and blocks cellular proliferation and tumor growth of Bcr-abl- or v-abl-expressing cells. We have further investigated the profile of STI571 against related receptor tyrosine kinases. STI571 was found to potently inhibit the kinase activity of the alpha- and beta-PDGF receptors and the receptor for stem cell factor, but not the closely related c-Fms, Flt-3, Kdr, Flt-1, and Tek tyrosine kinases. Additionally, no inhibition of c-Met or nonreceptor tyrosine kinases such as Src and Jak-2 has been observed. In cell-based assays, STI571 selectively inhibited PDGF and stem cell factor-mediated cellular signaling, including ligand-stimulated receptor autophosphorylation, inositol phosphate formation, and mitogen-activated protein kinase activation and proliferation. These results expand the profile of STI571 and suggest that in addition to chronic myelogenous leukemia, STI571 may have clinical potential in the treatment of diseases that involve abnormal activation of c-Kit or PDGF receptor tyrosine kinases.
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PMID:Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. 1099 71


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