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)

Forty-two human hematopoietic cell lines were assessed for sensitivity to a four-day incubation with L-asparaginase. Eight of 13 T-leukemia cell lines and 1 of 7 non-T, non-B common acute lymphoblastic leukemia cell lines exhibited an ID50 (50% growth inhibition dose) of less than 0.0001 IU/ml. Seven of these sensitive cell lines were further cultured in L-asparagine-free medium and were found not to proliferate. Five T-leukemia cell lines, 6 non-T, non-B common acute lymphoblastic leukemia cell lines, 10 "abnormal" B-cell lines, 4 "normal" B-cell lines, 3 myeloma cell lines and 5 myeloid leukemia cell lines had ID50 values between 0.1 and 1.0 IU/ml. Twelve of these resistant cell lines were able to proliferate in L-asparagine-depleted medium. The results indicate that some patients with T-cell acute lymphoblastic leukemia might respond to this enzymatic antineoplastic drug, L-asparaginase, at low dose.
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PMID:Distinctive sensitivity of some T-leukemia cell lines to L-asparaginase. 660 60

Tunicamycin was found to specifically inhibit the incorporation of a number of sugars into L1210 leukemia cell glycoproteins. This inhibition of glycoprotein biosynthesis led to a cessation of cell growth which was reversible in a dose-dependent and time-dependent manner. After removal of the antibiotic from L1210 cell cultures resumption of sugar incorporation preceded that of thymidine incorporation and the recovery of cell growth. The treatment of cells with tunicamycin resulted in a significant increase in the intracellular pool of UDP-N-acetylglucosamine which occurred concurrently with alterations in cell ultrastructure including distentions of the endoplasmic reticulum and nuclear membranes. Similar ultrastructural changes and increases in the intracellular pools of UDP-sugars were observed in L1210 cells exposed to 5 mM D-glucosamine, which suggested that the antiproliferative effects of tunicamycin may be related to the accumulation in the endoplasmic reticulum of one or more nucleotide sugar precursors of asparagine-linked glycoprotein biosynthesis. However, the biological effects of tunicamycin could be distinguished from those caused by D-glucosamine. Exposure of L1210 cells to tunicamycin resulted in specific alterations in the biochemical composition of the plasma membrane and in the inhibition of cellular agglutination by wheat germ agglutinin which were not apparent following exposure to equitoxic concentrations of the aminosugar. These studies, together with those which demonstrated that recovery of the cellular capacity to synthesize glycoproteins was obligatory for the recovery of cellular proliferation in tunicamycin-treated cells, suggested that inhibition of the synthesis of glycoproteins was the major factor limiting L1210 leukemic cell proliferation.
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PMID:The biochemical and ultrastructural effects of tunicamycin and D-glucosamine in L1210 leukemic cells. 682 8

The leukaemia-associated cell surface antigen p24/BA-2 is a single polypeptide chain with a molecular weight of 24,000. Treatment with glycosidases or exposure of cells to tunicamycin failed to show any change in the molecular weight of the antigen when examined by SDS-polyacrylamide gel electrophoresis. In addition, it failed to bind to lectin affinity columns of concanavalin A, lentil lectin or ricinus communis lectin. This is consistent with the absence of N-asparagine linked oligosaccharide chains on the antigen. Pulse-chase labelling of protein p24 shows a post-translational modification resulting in a molecular weight increase of approx. 500-1000. Alkaline treatment resulted in a decrease in molecular weight of approximately the same amount, suggesting that p24 contain some O-glycosidically linked oligosaccharide. Protein p24 has a basic pI of 7.3 which is unchanged after neuraminidase treatment. Protein P24/Ba-2 cannot be labelled by either the lipophilic photoactivatable nitrene reagent, hexanoyldiiodo-N-(4-azido-2-nitrophenyl)tyramine, or with [32P]phosphate. This suggests that the molecule is non-integral in nature and that it does not form an intimate association with the lipid matrix. Identical molecular weights, when reduced and non-reduced antigens were compared, suggest that it contains no internal disulphide linkages and failure to detect any other band on gradient gel SDS-polyacrylamide gel electrophoresis from 5-15% suggests that is is not strongly associated with any other structure.
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PMID:Biochemical characterisation of leukaemia-associated antigen p24 defined by the monoclonal antibody BA-2. 695 Jul 91

N-Glycoproteins fucosylated in the core region occur in tumor membranes and virus envelopes. Partial structures of such N-glycoproteins containing fucosylated chitobiosyl asparagine conjugates were synthesized using the allyloxycarbonyl (Aloc) and the tert-butyl ester protecting groups in the peptide portion. As the alpha-fucosidic bond of the conjugates revealed to be very sensitive to acids when carrying ether-type protecting groups, a method for exchanging the protecting groups of the fucose portion of saccharides was developed. Conjugates containing O-acetyl protected fucose proved to be stable against acids used in glycopeptide syntheses. These methods were applied in the synthesis of a fucosyl chitobiose hexapeptide with the partial sequence of a leukemia virus envelope glycoprotein. The glycopeptide was coupled to bovine serum albumin yielding a neoglycoprotein which contains a glycoconjugate of exactly specified structure.
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PMID:Synthesis of glycopeptides and neoglycoproteins containing the fucosylated linkage region of N-glycoproteins. 775 16

We developed previously a resistant cell line, CEM/C2, from the human leukemia cell line CCRF-CEM by stepwise selection in camptothecin. This cell line is 974-fold more resistant to camptothecin than parental cells. Resistance is only partially explained by 2-fold reductions in topoisomerase I protein and mRNA levels. We further investigated biochemical and molecular features of topoisomerase I in the resistant cell line. Sequence analyses of the top1 cDNA from CEM/C2 identified mutations corresponding to two amino acid substitutions, Met370Thr and Asn722Ser. Asn722Ser is next to the catalytic Tyr723 in a region highly conserved among type I eukaryotic DNA topoisomerases. Recombinant top1 with the corresponding substitution was found to be catalytically active and resistant to camptothecin. These results indicate that camptothecin resistance of CEM/C2 is due to the mutation Asn722Ser and strongly suggest that the asparagine immediately flanking the catalytic tyrosine is important for the camptothecin action.
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PMID:Mutation at the catalytic site of topoisomerase I in CEM/C2, a human leukemia cell line resistant to camptothecin. 788 33

The effect of a singular amino acid, asparagine (Asn), glutamine (Gln), or proline deletion in a cultured medium (RPMI 1640 supplemented with 10% fetal calf serum and other ingredients) on adriamycin (ADR) cytotoxicity was evaluated in the growth of P388 murine leukemia cells and CEM human acute lymphoblastic leukemia cells over a 3 day period. No enhancement of ADR cytotoxicity was observed in the assay of IC50 values under the amino acid deleted condition. Singular deletion of Gln or Asn from ADR-free medium apparently inhibited the proliferation of both cells, i.e. both cell lines strongly require them. The cytotoxicity of 5 nM ADR was then examined in medium which included one or the other of them in stepwise levels varied at 80, 60, 40, 20 and 0% of the ordinary level. Change of Asn level caused a difference in ADR toxicity; also, the change of Gln level, especially the 60% level caused ADR toxicity of 5 nM, which is less than the IC50 value, in the proliferation of both cells. This suggested the usefulness of glutamine level modification on the enhancement of ADR cytotoxicity.
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PMID:Inhibition of cultured leukemia cell growth by enhanced adriamycin cytotoxicity with reduction of glutamine or asparagine level in medium. 788 97

The antileukaemic efficacy of L-asparaginase is related to the ability of the enzyme to induce the complete disappearance from plasma of L-asparagine, an amino acid essential to lymphoblastic leukaemia cells. It is not feasible to monitor L-asparagine plasma levels in patients under L-asparaginase treatment using the usual analytical procedures as the enzyme continues the hydrolysis of L-asparagine after blood sampling and during plasma extraction. A method was therefore developed for the determination of L-asparagine in patients receiving L-asparaginase. Sulphosalicylic acid is added to blood samples to deproteinize and inactivate L-asparaginase rapidly. The samples are then analysed by HPLC using a Novapack C18 column and fluorescence detection. With the same method L-asparagine is determined in blood cells and, by difference, plasma levels are calculated. This method is highly specific and sufficiently simple and sensitive for clinical use.
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PMID:Determination of L-asparagine in biological samples in the presence of L-asparaginase. 795 83

C5a is a potent chemoattractant for monocytes, neutrophils and other leukocytes. The receptor for human C5a is a member of the rhodopsin superfamily of G protein-coupled receptors and contains an aspartate residue (Asp82) within the putative second transmembrane domain conserved in all other G protein-linked receptors. We investigated the role of this residue and also the carboxy-terminal 23 residues of the C5a receptor in ligand binding and signal transduction by expressing wild-type and mutant receptors in the rat basophilic leukemia cell line RBL-2H3. Wild-type and truncated receptors coupled efficiently to effector systems, resulting in the C5a-dependent discharge of granule contents. In contrast RBL cells transfected with receptors in which Asp82 had been mutated to asparagine did not respond to human C5a by secretion despite binding human C5a with high affinity. We conclude therefore that Asp82 is not involved in the interaction with ligand but is essential for the proper transduction of the ligand binding signal.
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PMID:Mutation of aspartate 82 of the human C5a receptor abolishes the secretory response to human C5a in transfected rat basophilic leukemia cells. 795 84

The biantennary N-acetyllactosamine type oligosaccharide is attached to asparagine-297 of the human IgG heavy chain, which is an integral part of the tertiary structure of the Fc region, and is quite important in the role of IgG. Pyridylamination and analysis by HPLC can be performed more rapidly and simply than conventional carbohydrate analysis. We applied it to the analysis of the oligosaccharide structures of IgG from the serum of patients with leukemia, CLL and AML. The proportion of oligosaccharide from leukemia patients with a bisecting N-acetylglucosamine residue was almost equal to that of healthy individuals. However, the proportion of fucose and galactose residues differed. These data suggest that the analysis of the fucose and the terminal galactose residue of such oligosaccharides will be useful in the classification of leukemia.
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PMID:Analysis of oligosaccharides of human IgG from serum of leukemia patients. 806 39

The carrier protein for methotrexate and tetrahydrofolate cofactors (GP-MTX) in CCRF-CEM human lymphoblastic leukemia cells in a 117 kDa glycoprotein containing both N- and O-linked oligosaccharides (Matherly et al., J Biol Chem 267: 23253-23260, 1992). Tunicamycin, an inhibitor of N-glycosylation, was used to investigate the roles of asparagine-linked oligosaccharides in the structure, intracellular routing, and transport function of GP-MTX. Tunicamycin was growth inhibitory toward CCRF-CEM cells (IC50-0.80 micrograms/mL) and caused a potent suppression of [3H]mannose incorporation into nascent glycoproteins. From 1-3 micrograms/mL, inhibition of [3H]mannose incorporation was 66-87%, exceeding that for [35S]methionine incorporation by 2 to 4-fold. Tunicamycin (1 and 2 micrograms/mL) exposures decreased the median molecular masses of GP-MTX on immunoblots (to 82 and 67 kDa, respectively) and were accompanied by reduced maximal rates of methotrexate uptake (31 and 37%, respectively, of control levels). Conversely, the Ki values for methotrexate binding to the transporter were unaffected by tunicamycin treatments. The effects of tunicamycin on methotrexate influx closely correlated with lower levels of immunoreactive GP-MTX in plasma membranes and specific [3H]methotrexate binding to intact cells, suggesting that the transport effect was due to decreased numbers of carrier proteins at the membrane surface. The reduced molecular mass values for GP-MTX, which accompanied tunicamycin exposures, were further decreased (to 55 and 50 kDa at 1 and 2 micrograms/mL, respectively) by digestions with N-glycanase. Hence, despite the large loss of N-glycan from GP-MTX in tunicamycin-treated cells, residual core oligosaccharides remained. The sizes of hypoglycosylated GP-MTX following both treatments were similar to that of the functionally homologous methotrexate membrane carrier previously identified in L1210 murine leukemia cells.
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PMID:Role of N-glycosylation in the structure and function of the methotrexate membrane transporter from CCRF-CEM human lymphoblastic leukemia cells. 814 10


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