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)

The suppressive effect of glucocorticoids (GC) upon antigen-induced phosphatidylinositol phospholipase C (PI-PLC) activity and inositol phosphate formation by rat basophilic leukemia cells (RBL-2H3) has been characterized. Addition of antigen for a period of 1-30 min enhanced production of [3H]inositol monophosphate (IP1), inositol 1,4-biphosphate (IP2) and inositol 1,4,5-triphosphate (IP3) by about 5-10 fold. Pretreatment with hydrocortisone (HC) and dexamethasone (DEX) reduced formation of the various inositol phosphates (IPs) and degradation of phosphatidylinositol-4-5-biphosphate (PIP2) by an average of 50% Antigen-stimulated phosphorylation of an 18 kDA and other proteins was inhibited by about 60% following pretreatment with the GC. This inhibition was in turn prevented by cycloheximide. Moreover, DEX doubled cellular acid phosphatase activity. The results suggest that the inhibitory effect of GC is possibly mediated, among other things, by protein phosphatase activity.
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PMID:Glucocorticoid inhibition of antigen-induced inositol phosphate formation: possible involvement of phosphatases. 166 8

Phosphate-activated glutaminase is found in mammalian small intestine, brain, and kidney, but not in liver. The enzyme initiates the catabolism of glutamine as the principal respiratory fuel in the small intestine, may synthesize the neurotransmitter glutamate in the brain, and functions in the kidney to help maintain systemic pH homeostasis. Interleukin-9 (IL9) is a relatively new cytokine that supports the growth of helper T-cell clones, mast cells, and megakaryoblastic leukemia cells. cDNA clones have recently been obtained for each of these genes. The human loci for phosphate-activated glutaminase (GLS) and IL9 have previously been mapped to chromosomes 2 and 5, respectively, by analysis of somatic cell hybrid DNAs. By using chromosomal in situ hybridization, we have regionally mapped GLS to 2q32----q34 and IL9 to 5q31----q35.
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PMID:Regional localization of the human glutaminase (GLS) and interleukin-9 (IL9) genes by in situ hybridization. 168 Jun 6

The first high performance liquid chromatographic method for determination of the plasma concentration of 2-chloro-2'-deoxyadenosine (CdA) in patients, which is significantly more sensitive than the previously used RIA method, is presented. CdA is a purine analogue with useful clinical activity against lymphoproliferative disorders and it has recently been found to be the single most active agent in the treatment of hairy cell leukaemia. Guaneran (6-nitroimidazol-6-thioguanine) was added to 1 mL plasma as the internal standard and CdA was extracted using ethyl acetate. A Perkin-Elmer C18, 3 mu, 8 cm column was used for the separation of CdA and the internal standard from endogenous compounds in the sample with a mixture of sodium phosphate buffer 10 mM, methanol and acetonitrile (85:10:5, pH = 3.0) as the mobile phase. The sensitivity of the method (1 nM) allows the determination of CdA in plasma 24 h after the administration of 0.14 mg/kg as a 2 h infusion.
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PMID:Determination of 2-chloro-2'-deoxyadenosine in human plasma. 168 27

Lys103 and Lys421 of Moloney murine leukemia virus reverse transcriptase have been implicated in the dNTP binding function as judged by their reactivity to a substrate binding site-directed reagent, pyridoxal 5'-phosphate (Basu, A., Nanduri, V. B., Gerard, G. F., and Modak, M. J. (1988) J. Biol. Chem. 263, 1648-1653). To assess the true catalytic importance of the individual lysine residues in Moloney murine leukemia virus reverse transcriptase, we mutated Lys103 and Lys421 to leucine and alanine, respectively. Analysis of the mutant enzymes revealed that mutation at the 103 position had a drastic effect on the DNA polymerase activity whereas the 421 mutation had no effect. Both mutants exhibited normal RNase H activity as well as the ability to bind to RNA or DNA templates as judged by UV-mediated cross-linking of the enzyme to the template primers. The enzyme with mutation at codon 421 (Lys----Ala) exhibited properties that were indistinguishable from the wild type with respect to its mode of catalysis, i.e. preference of template primer and divalent metal ion, RNA- or DNA-dependent DNA polymerase activity, RNase H activity, and the processive mode of DNA synthesis. These observations suggest that only Lys103 and not Lys421 is the catalytically important residue that is involved in the binding of substrate dNTP in Moloney murine leukemia virus reverse transcriptase.
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PMID:Site-directed mutagenesis of Moloney murine leukemia virus reverse transcriptase. Demonstration of lysine 103 in the nucleotide binding site. 169 72

This article presents data from the phase I and II clinical investigations of Fludara I.V. (fludarabine phosphate) (NSC 312887), which is the 5'-phosphorylated derivative of the novel antimetabolite, 9-beta-D-arabinofuranosyl-2-fluoroadenine. The comprehensive phase I evaluation of this new antitumor agent was conducted in 51 patients with advanced malignancy and 15 additional patients with aggressive forms of leukemia. Three separate phase I schedules of drug administration were examined. Myelosuppression was the dose-limiting toxicity on each schedule administered to patients with solid tumors. The drug was also examined at higher doses in patients with leukemia, and the dose-limiting toxicity on the high-dose protocol was unacceptable: serious neurologic toxicity. The observation of antitumor responses in patients with advanced non-Hodgkin's lymphoma prompted additional phase II investigation in patients with lymphoproliferative malignancy. The encouraging phase II data demonstrate that Fludara I.V. has promise for patients with low-grade histologic subtypes of non-Hodgkin's lymphoma and chronic lymphocytic leukemia. While interesting additional basic and clinical research projects regarding Fludara I.V. remain, it is important to expeditiously pursue approval for this drug. Adequate data exists to demonstrate that the low-dose administration of Fludara I.V. is both safe and effective. While the development of this drug has stimulated renewed interest in the clinical investigation of the chronic lymphoproliferative malignancies, the time for making it readily available to these patients has arrived.
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PMID:A comprehensive phase I and II clinical investigation of fludarabine phosphate. 169 82

The promising results obtained with Fludara I.V. (fludarabine phosphate) treatment in the common indolent B-cell neoplasms have led to their further evaluation in other unusual B-cell malignancies, in Hodgkin's disease, and in T-cell diseases. A significant response rate has been found among patients with macroglobulinemic lymphoma, those with prolymphocytic leukemia or prolymphocytoid variant of chronic lymphocytic leukemia, and those with mycosis fungoides. The limited therapeutic data in hairy-cell leukemia and in Hodgkin's disease are also interesting.
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PMID:Fludarabine phosphate therapy in other lymphoid malignancies. 169 85

Fludara I.V. (fludarabine phosphate) is a purine analogue with a high level of activity in a variety of indolent lymphoproliferative malignancies, including chronic lymphocytic leukemia (CLL), low-grade non-Hodgkin's lymphomas (NHL), cutaneous T-cell lymphoma, macroglobulinemia, and hairy-cell leukemia. The high response rate in relapsed and refractory patients with CLL suggests that Fludara I.V. is the most active single agent for this condition. Nevertheless, a number of issues for the future development of Fludara I.V. must be considered: the optimal dose, schedule, and route of administration (intravenous v oral) remain to be determined. To improve on single-agent results, combinations of Fludara I.V. with other agents are under development for patients with CLL and NHL. Phase III clinical trials will be performed to compare Fludara I.V. with standard therapy versus the combination regimen in previously untreated patients with CLL. A similar study is under consideration for low-grade NHL. Companion immunologic and biologic studies will be an integral component of these trials to provide a more rational approach to staging and treatment, and to increase our knowledge of the biology of these disorders.
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PMID:Issues for the future development of fludarabine phosphate. 169 86

Fludarabine phosphate is a nucleotide analogue of adenine arabinoside with antitumor activity in murine and human lymphoid malignancies; it has occasional, unpredictable neurotoxicity after high dose bolus injections in adults. To avoid this toxicity, we studied a loading dose plus 5-day continuous infusion in 47 evaluable pediatric patients. Dose limiting myelosuppression was seen in children with solid tumors after a loading dose of 8 mg/m2 followed by 23.5 mg/m2/day for 5 days. In children with leukemia, no dose limiting toxicity was seen at dose level 6, consisting of a loading dose of 10 mg/m2 and an infusion of 30.5 mg/m2/day for 5 days. One complete and 3 partial remissions were seen in 26 evaluable children with acute lymphoblastic leukemia. 9-beta-D-arabinofuranosyl-2-fluoroadenine plasma concentrations and the area under the moment curve increased linearly with dose. The terminal half-life was similar, while the total body clearance was shorter than that reported for adults receiving bolus or continuous doses. Lymphoblasts isolated from 2 patients during fludarabine phosphate (9-beta-D-arabinofuranosyl-2-fluoroadenine) treatment increased their ability to convert 1-beta-D-arabinofuranosylcytosine to 1-beta-D-arabinofuranosylcytosine 5'-triphosphate by more than 10-fold. The antileukemic activity of 9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-phosphate and its ability to alter the metabolism of 1-beta-D-arabinofuranosylcytosine indicate that timed combinations of these 2 agents should be tested.
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PMID:Pharmacology of fludarabine phosphate after a phase I/II trial by a loading bolus and continuous infusion in pediatric patients. 169 58

The effects of fludarabine triphosphate (Fara-ATP), 1-beta-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP), and aphidicolin on primer RNA and DNA synthesis in human CCRF-CEM leukemia cells were investigated. RNA-primed Okazaki fragment synthesis was monitored by first incubating whole cell lysates for 10 min in the presence or absence of the compound and then following the incorporation of [alpha-32P]ATP and [3H]dTTP into the primer RNA and DNA portions, respectively, of the Okazaki fragments. In whole cell lysates the degree of DNA synthesis inhibition induced by Fara-ATP was directly related to the extent of primer RNA synthesis inhibition over the entire range of Fara-ATP concentrations tested (10-50 microM). In contrast, primer RNA formation was stimulated by concentrations of ara-CTP (25-200 microM) and aphidicolin (0.5-5 micrograms/ml) that inhibited DNA synthesis. The primer RNA recovered from cell lysates incubated with either Fara-ATP, ara-CTP, or aphidicolin was of normal length, predominately 11 nucleotides. Fara-ATP was a more potent inhibitor of the polydeoxythymidylate primase activity than of the DNA polymerase alpha/delta activities present in the 100,000 x g supernatants of CCRF-CEM cells. Fara-ATP was a noncompetitive inhibitor of DNA primase with respect to ATP [50% inhibitory concentration, 2.3 +/- 0.3 (SD) microM, Ki = 6.1 +/- 0.3 (SE) microM] and the Km(ATP)/Ki (Fara-ATP) was 25. The 50% inhibitory concentration values of Fara-ATP for DNA polymerases alpha/delta activities on calf thymus DNA were 43 +/- 1.6 (SD) microM and greater than 100 microM with respect to dATP and dTTP. The effects of ara-CTP and aphidicolin on these enzymes were opposite those seen with Fara-ATP, since 50% inhibitory concentrations of either ara-CTP or aphidicolin for DNA polymerases alpha/delta did not inhibit polydeoxythymidylate primase activity. The results provide evidence that fludarabine phosphate blocks DNA synthesis in CCRF-CEM cells through inhibition of primer RNA formation. In contrast, the accumulation of primer RNA and RNA-primed Okazaki fragments that is induced by ara-CTP and aphidicolin could lead to the rereplication and amplification of chromosomal DNA segments.
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PMID:Inhibition of primer RNA formation in CCRF-CEM leukemia cells by fludarabine triphosphate. 170 19

Two model substrates were prepared to examine the mechanism of tRNA-primer excision catalyzed by reverse transcriptase associated ribonuclease H (RT-RNase H). The first model substrate contained sequences from the HIV genome and was designed to be structurally similar to the DNA-extended tRNA created by initiation of minus-strand DNA synthesis during retroviral replication. The DNA-extended RNA was a template and was annealed to a DNA oligonucleotide that primed reverse transcription of the RNA in the template. The second model substrate was structurally similar the first substrate but contained sequences unrelated to the HIV viral genome. The RT-RNase H catalyzed excision of the RNA from the template of the two model substrates was examined. Human immunodeficiency virus (HIV) and Moloney murine leukemia virus RT-RNase H hydrolyzed the substrates to leave a single ribonucleotide 5'-phosphate at the 5'-terminus of the model DNA genome. In contrast, avian myeloblastosis virus RT-RNase H hydrolyzed the phosphodiester bond at the DNA-RNA junction. These hydrolytic specificities were not highly dependent on substrate sequence. The importance of these specificities to retroviral integration is discussed. Additional data indicated that the HIV polymerase and RNase H active sites are separated by a distance equivalent to the length of a 15-nucleotide RNA-DNA heteroduplex.
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PMID:Human immunodeficiency virus reverse transcriptase ribonuclease H: specificity of tRNA(Lys3)-primer excision. 171 59


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