Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pathway for de novo biosynthesis of purine nucleotides contains two one-carbon transfer reactions catalyzed by glycinamide ribotide (GAR) and 5-aminoimidazole-4-carboxamide ribotide (AICAR) transformylases in which N10-formyltetrahydrofolate is the one-carbon donor. We have found that the antifolates methotrexate (MTX) and piritrexim (PTX) completely block the de novo purine pathway in mouse L1210 leukemia cells growing in culture but with only minor accumulations of GAR and AICAR to less than 5% of the polyphosphate derivatives of N-formylglycinamide ribotide (FGAR) which accumulate when the pathway is blocked completely by azaserine. This azaserine-induced accumulation of FGAR polyphosphates is completely abolished by MTX, indicating that inhibition of the pathway is at or before GAR transformylase (reaction 3; Lyons, S. D., and Christopherson, R. I. (1991) Biochem. Int. 24, 187-197). Three h after the addition of MTX (0.1 microM), cellular 5-phosphoribosyl-1-pyrophosphate has accumulated 3.4-fold while 6-methyl-mercaptopurine riboside (25 microM) induces a 6.3-fold accumulation. These data suggest that amido phosphoribosyltransferase catalyzing reaction 1 of the pathway is the primary site of inhibition. In support of this conclusion, we have found that dihydrofolate-Glu5, which accumulates in MTX-treated cells, is a noncompetitive inhibitor of amido phosphoribosyltransferase with a dissociation constant of 3.41 +/- 0.08 microM for interaction with the enzyme-glutamine complex in vitro. Folate-Glu5, MTX-Glu5, PTX, dihydrotriazine benzenesulfonyl fluoride, and AICAR also inhibit amido phosphoribosyltransferase.
 ...
PMID:Antifolates induce inhibition of amido phosphoribosyltransferase in leukemia cells. 159 45

Germline p53 mutations have been identified in the Li-Fraumeni syndrome but the role of such mutations in familial leukemia is not established. The p53 gene was examined by single-strand conformation polymorphism analysis of exons 4-8 in 10 families with multiple members affected with leukemia. The diagnoses included acute and chronic leukemias and Hodgkin's disease. Identified in two families were p53 mutations that were nonhereditary. These included a 2-bp deletion in exon 6 found in the lymphoblast DNA of one child whose sibling, cousin, and several adult relatives had acute leukemia. The other nonhereditary p53 mutation was a transition at codon 248 (CGG to CAG, arginine to glutamine) found in the lymphoblasts of a patient with a preleukemic syndrome and acute lymphoblastic leukemia (ALL) whose brother is a long-term survivor of ALL. Thus, p53 mutations were found to occur in two families but both were nonhereditary. Moreover, in the remaining eight families no p53 mutation was identified in the regions of p53 where most mutations have been found in other cancers. Although p53 mutations sometimes may be present, they do not appear to be a primary event responsible for hereditary susceptibility to familial leukemia. This study suggests involvement of other genes or mechanisms.
 ...
PMID:Absence of hereditary p53 mutations in 10 familial leukemia pedigrees. 164 30

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.
 ...
PMID:Regional localization of the human glutaminase (GLS) and interleukin-9 (IL9) genes by in situ hybridization. 168 Jun 6

Glutamine depletion strongly inhibits the replication of Rauscher murine leukaemia retrovirus (RLV) in vitro. Pseudomonas 7A glutaminase-asparaginase (PGA), capable of depleting glutamine and asparagine for prolonged periods, was used to determine the therapeutic effectiveness of glutamine depletion in mice infected with RLV or Friend virus. During PGA treatment of viraemic animals, serum reverse transcriptase activity fell to control levels and infected animals did not develop splenomegaly. The therapeutic results obtained with PGA compared favourably with those of azidothymidine given intraperitoneally at 30 mg/kg/day. Western blots performed on splenic tissue from control and treated animals indicated that glutamine depletion prevented readthrough of an amber codon at the gag-pol junction, stopping translation of viral mRNA at that point. Treatment of RLV-infected animals with PGA resulted in nearly a 200% increase in mean survival time even when therapy was initiated late in the course of the disease. To our knowledge, this is the first demonstration that a nutrient required for viral replication can be enzymically depleted in vivo to inhibit viral replication.
 ...
PMID:Inhibition of mouse retroviral disease by bioactive glutaminase-asparaginase. 170 10

gamma-Glutamyl hydrolase (also known as conjugase) is a ubiquitous enzyme that has the capacity to cleave folyl- and antifolylpolyglutamates. This study has revealed that the enzyme is secreted by primary cultures of rat hepatocytes and by H35 hepatoma cells. H35 cells have lower cellular levels of gamma-glutamyl hydrolase than do hepatocytes but secrete a greater proportion of gamma-glutamyl hydrolase. More than 99% of the total enzyme from H35 cells accumulated in the medium after 48 h. The cells were shown to remain intact during the secretion period since lactate dehydrogenase, dihydrofolate reductase, and lysosomal hydrolases other than gamma-glutamyl hydrolase were retained within the cell. Using the substrate 4-amino-10-methyl-pteroyldiglutamate (4-NH2-10-CH3-Pte-Glu2), the intracellular and secreted enzyme form(s) from H35 cells were found to have the following properties (a) Km values of 24.3 +/- 3.7 microM and 34.8 +/- 8.6 microM, respectively, and (b) maximal activity at pH 5 to 7 and apparent molecular weights of 120,000 by gel filtration. Both the cellular and secreted enzymes convert 4-NH2-10-CH3-PteGlu4 and pteroylpentaglutamate acid, to the corresponding monoglutamates with little or no appearance of intermediate chain length polyglutamates. This suggests that both act primarily as endopeptidases. Thus far, the cellular and secreted enzymes cannot be differentiated although the current studies do not establish this point unequivocally. Alterations in the cellular and secreted H35 cell gamma-glutamyl hydrolase levels in response to changes in culture conditions revealed that glutamine enhances activity while insulin diminishes it. Other transformed cells found to secrete this protein are Hep-G2 human hepatoma, JAR human choriocarcinoma, HeLa, and rat glioma. gamma-Glutamyl hydrolase could not be detected in medium conditioned by human MCF-7 breast cancer cells, and relatively low activities were found in the medium from CCRF-CEM or K562 leukemia cells. These studies directly establish for the first time the secretion of gamma-glutamyl hydrolase in vitro.
 ...
PMID:Secretion of gamma-glutamyl hydrolase in vitro. 171 22

The development of successful chemotherapy for cancers, including leukaemia, is based on the exploitation of significant toxic differentials of the agents, between the cancer cells and their normal counterparts. A concentration of 0.1 mumol/L of the amino acid analogue acivicin (L-(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid) was sufficient to inhibit [3H]-DNA synthesis in mitogen stimulated murine splenic lymphocytes and WEHI 7.1 murine leukaemic cells in vitro, at glutamine concentrations up to 0.5 mmol/L. However, at concentrations of glutamine of 1.0 mmol/L and above, more acivicin was required to inhibit WEHI 7.1 cells than to inhibit the splenic lymphocytes. At 1.0 mmol/L glutamine, 18 h of exposure to an optimal inhibitory concentration of acivicin (0.5 mumol/L) in vitro was sufficient to inhibit [3H]-DNA synthesis in the mitogen stimulated lymphocytes, whereas 24 h of exposure to an optimal inhibitory acivicin concentration of 2.0 mumol/L was required for inhibition of [3H]-DNA synthesis in the WEHI 7.1 leukaemic cells. When an acivicin inoculation regime that was sufficient to control the growth of intraperitoneally (i.p.) implanted WEHI 7.1 leukaemic cells was administered to Balb/c mice, the primary immune response was significantly inhibited to an antigen given either during or after the acivicin treatment. These results indicate that lymphocytes replicating in vivo in a specific primary immune response could be as sensitive to acivicin as leukaemic cells.
 ...
PMID:The effects of a leukaemia-controlling dose of acivicin on murine splenic lymphocytes in vitro and in vivo. 181 88

The effects of the linkage of daunorubicin (DNR) and the synthetic biodegradable polymer polyhydroxyethyl-L-glutamine (PHEG) on general toxicity, therapeutic efficacy, and acute organ toxicity were investigated. General toxicity was assessed by means of mortality, or body weight changes of male CBA mice weighing 22-25 g after a single-dose i.p. administration of 5 or 2.5 mg/kg DNR, free or bound. Linked DNR at a larger lethal dose significantly increased mean survival time (18 versus 12 days). Surprisingly, free DNR at a smaller dose produced larger increases in body weight as compared with linked DNR. The linkage of DNR and PHEG did not markedly change the therapeutic activity in three murine hemoblastoses--plasmacytoma MOPS 406, leukemia P388 and hemoblastosis La. Acute (24 h) changes in cardio- and hepatotoxicity were studied on female Wistar rats weighing 208 +/- 5 g after a single dose of 5 mg/kg i.v. both free and linked DNR, as well as after an administration of the PHEG polymer alone (200 mg/kg i.v.). Free DNR caused a three-fold increase in creatine kinase (CK) activity, the identical dose of linked DNR caused only a 1.7-fold increase. Free DNR administration resulted in a decrease in heart rate, other tested drugs did not significantly change either blood pressure or heart rate. Free DNR did not change the kinetics of bromsulphalein (BSP) except for a decrease in extraction effectivity. Both linked DNR and polymer alone significantly changed some kinetic parameters of BSP. The results showed that the biodegradable polymer PHEG cannot be clinically used due to its hepatotoxic action. On the other hand, a decrease in total toxicity and cardiotoxicity resulting from the linkage of DNR and PHEG, the therapeutic efficacy being preserved, stimulates the efforts to find a suitable polymer carrier of anthracyclines without more serious side-effects.
 ...
PMID:Changes in the toxicity and therapeutic efficacy of daunorubicin linked with a biodegradable carrier. 185 47

HTLV-I, II, HIV-1, 2 and other retroviruses possess genes for the transcriptional activators, tax and tat, the expression of which is closely related with the pathogenesis of leukemia and human immunodeficiency syndrome (AIDS) and induced by the virus infection. The effects of these activators on the expression of host cell genes, however, are still largely unknown. Recently the authors have discovered that infection with HIV or Mo-MuLV causes a specific acceleration of the synthesis of an UAG suppressor glutamine tRNA in the host cell; they could demonstrate that this phenomenon is based on transcriptional promotion of tRNA genes which is due to a new transcriptional activator synthesized as a function of viral infection and/or increased virus levels. The present paper discusses the significance of the suppressor tRNA and explains the role of the virus in the regulation of its expression.
 ...
PMID:Cell biological aspects of HIV-1 infection: effect of the anti-HIV-1 agent Avarol. 189 96

Among Moloney murine leukemia viruses (Mo-MuLVs) having stop codons other than UAG at the gag-pol junction, Mo-MuLV with UAA, but not with UGA, had a replication disadvantage. Mo-MuLV with a glutamine codon (CAG) at the junction did not replicate. A revertant of this virus consisted of the original virus and a virus with a deletion of the pol region. Protease and Pr65gag encoded by their respective genomes complemented each other.
 ...
PMID:Analysis of Moloney murine leukemia virus revertants mutated at the gag-pol junction. 192 Jun 40

We compared the ability of human leukemia cell lines of various origins to grow in glutamine-deficient media. The growth of B lymphoblastoid cell lines, including promyelocytic HL-60, is highly dependent on glutamine, whereas T-cell lines are able to proliferate in glutamine-free media. Such glutamine dependency has a good inverse correlation with the activity of glutamine synthetase. Moreover, glutamine synthetase can be induced in glutamine-deficient media, especially in glutamine-independent cells. In HL-60 cells, glutamine deprivation results in the decrease of both ATP and dATP levels. The addition of adenine to the culture medium abolishes these changes without restoring cell growth, indicating that the effects of glutamine deprivation on cell growth cannot be fully explained by the perturbation of adenine nucleotide pools.
 ...
PMID:Metabolic basis for differential glutamine requirements of human leukemia cell lines. 196 19


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>