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)

Interleukin 3 (IL-3) derived from mouse T cells was biosynthetically labeled with either [35S]methionine or [3H]mannose, affinity-purified using various anti-IL-3 antibodies, and analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Autoradiography revealed the same three major bands with Mr values of 21,500-22,500, 27,000-31,000, and 32,000-36,000, irrespective of whether the anti-IL-3 antibody had been directed to the N or C termini of the IL-3 polypeptide. Bioassay of eluates from the gels confirmed that all three bands exhibited IL-3 bioactivity. IL-3 produced from two nonphysiological sources, the myelomonocytic leukemia WEHI-3B or Cos 7 cells that had been transfected with an IL-3 cDNA clone, had in each case a different pattern of microheterogeneity. Treatment with either tunicamycin or N-glycanase resulted in IL-3 running as one band with Mr 16,000, corresponding to its 140-amino acid polypeptide chain. No evidence for proteolytic processing was detected. These results show that the Mr heterogeneity of IL-3 was highly dependent on the cellular source and is due to N-linked glycosylation.
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PMID:Multiple glycosylated forms of T cell-derived interleukin 3 (IL-3). Heterogeneity of IL-3 from physiological and nonphysiological sources. 326 13

Besides its effect on bone marrow progenitors, GM-CSF is able to modulate functions of mature cells such as neutrophils. It inhibits random migration and chemotaxis through action on both cells and chemotactic factors, and stimulates oxidative metabolism as well as elastase release. Furthermore, it strongly enhances the response of the cells to the usual stimulants such as f-Met-Leu-Phe and phorbol esters. The role of neutral proteinases and activated oxygen species in different diseases such as ARDS, emphysema, coagulation defects, arthritis, and inflammation, is recognized. The remarkable in vitro release of neutral proteinases and activated oxygen species from granulocytes after GM-CSF stimulation may be of importance in vivo. This should be considered in clinical application of GM-CSF, particularly with high-dose therapy.
Leukemia 1988 Dec
PMID:Modulation of functions of granulocytes by recombinant human GM-CSF and possible complications of GM-CSF therapy. 326 66

We detected phosphorylation of the major Moloney murine leukemia virus (M-MuLV) capsid polypeptide, p30, by using 32Pi-labeled virions. This was observed both on two-dimensional polyacrylamide gels directly or on one-dimensional gels of viral lysates that had been immunoprecipitated with monospecific goat anti-p30 serum. The phosphorylation event had been difficult to detect because pp12 the major virion phosphoprotein incorporates almost all of the 32P label added to infected cells (Y. Yoshinaka and R. B. Luftig, Virology 116:181-195, 1982). When immunoprecipitates from M-MuLV lysates labeled with 32Pi were compared with those labeled with [35S]methionine, it was calculated that the degree of phosphorylation at the p30 domain of Pr65gag was only 0.22 to 0.54% relative to phosphorylation at the p12 domain. Two-dimensional gel electrophoresis of the 32P-labeled p30 immunoprecipitates showed that there were three phosphorylated p30 forms with isoelectric points (pIs) of 5.7, 5.8, and 6.0. These forms were generally more acidic than the [35S]methionine-labeled p30 forms, which had pIs of 6.0, 6.1, 6.3 (the major constituent with greater than 80% of the label), and 6.6. The predominant phosphoamino acid of the major phosphorylated p30 form (pI 5.8) was phosphoserine. Further, tryptic peptide analysis of this p30 form showed that only one peptide was predominantly phosphorylated. Based on a comparison of specific labeling of p30 tryptic peptides with [14C]serine, [35S]methionine, and 32Pi, we tentatively assigned the phosphorylation site to a 2.4-kilodalton NH2-terminal peptide containing triple tandem serines spanning the region from amino acids 4 to 24.
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PMID:Detection of phosphorylated forms of Moloney murine leukemia virus major capsid protein p30 by immunoprecipitation and two-dimensional gel electrophoresis. 333 49

Decarboxylated S-adenosylmethionine (SAM) is an aminopropyl donor in the synthesis of the polyamines, spermidine and spermine. The decarboxylation of SAM is inhibited by the toxic cytostatic drug methylglyoxalbis-(guanylhydrazone) (MGBG). To achieve more specific and less toxic effects of MGBG, this drug was combined with cycloleucine, which inhibits SAM synthesis, and with nitrous oxide, which inhibits methionine synthetase. This treatment thus aimed at sequential inhibition of the synthesis of decarboxylated SAM, and was studied in a rat leukemia model (BNML). Combined treatment further decreased the level of spermine, but not of spermidine, in leukemic cells, compared to the effects of MGBG alone. The therapeutic effects of this combination were additive or less than additive, however. MGBG was not very effective in reducing leukemic growth and severely toxic, although less with combined treatment. Another inhibitor of SAM decarboxylase, berenil, was also used, and although this drug was about equally active in inhibition of leukemic growth, alterations in intracellular polyamines were not observed. The combination of nitrous oxide and cycloleucine, which effectively reduced leukemic growth at non-toxic dosages, selectively inhibited spermine synthesis, and therefore may be used to interfere with polyamine metabolism. The relevance of this polyamine deprivation to the treatment of leukemia could not be demonstrated.
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PMID:The reduction of intracellular polyamines by sequential inhibition of the synthesis of decarboxylated S-adenosylmethionine: effects on rat leukemia. 340 8

Databases of protein information derived from the analysis of two-dimensional gels have been established from transformed human amnion cells (AMA) and peripheral blood mononuclear cells (PBMCs). A total of 1781 [35S]methionine-labeled AMA proteins (1274 IEF, 537 NEPHGE) and a total of 1311 proteins from PBMC (948 IEF, 363 NEPHGE) were resolved and recorded using computerized (PDQ-SCAN and PDQUEST softwares) two-dimensional gel electrophoresis. AMA and PBMC proteins (total, 454: 301 IEF, 153 NEPHGE) were matched both manually and by the computer. Information entered in the AMA database (in most cases for some major proteins) includes: molecular weight, protein name, HeLa protein catalogue number, mouse protein catalogue number, nuclear proteins, phosphorylated proteins, distribution of proteins in Triton X-100 supernatants and cytoskeletons, proliferation- and transformation-sensitive proteins, cell cycle-specific proteins, mitochondrial proteins, proteins matched in normal human embryonal lung MRC-5 fibroblasts and PBMC cells, heat shock proteins, proteins affected by interferons, cytoskeletal proteins, and the presence of antibody against protein in human sera. Additional information has been entered for the cell cycle-regulated and DNA replication protein cyclin (PCNA). Information entered in the PBMC database includes molecular weight and potential markers for sorted populations of lymphocyte subtypes. For those proteins that have been matched to AMA proteins, information contained in some entries may be transferred from the AMA database.
Leukemia 1988 Sep
PMID:Towards establishing comprehensive databases of cellular proteins from transformed human epithelial amnion cells (AMA) and normal peripheral blood mononuclear cells. 341 26

We have compared the overall patterns of protein synthesis of normal human lymphocyte subpopulations taken from five volunteers using high resolution two-dimensional gel electrophoresis. The lymphocytes were isolated using density gradient centrifugation, labeled with subtype-specific MoAbs, and separated to a high degree of homogeneity by FACS into CD4+ helper T cells, CD8+ suppressor T cells, CD20+ B cells, and N901 (NHK-1)+ NK cells. The four lymphocyte subpopulations were labeled with [35S]methionine for 14 hr, solubilized in lysis buffer, and analyzed by two-dimensional gel electrophoresis (IEF). Of about 1000 proteins resolved in each case, most were found to be common to all subpopulations. However, eight putative markers for B1+ (proteins 5525, Mr = 63,700; 5621, Mr = 63,700; 8311, Mr = 36,900; 2202, Mr = 36,300; 6121, Mr = 30,300; 106, Mr = 29,300; 5009, Mr = 23,000; 8012, Mr = 11,600) and one for N901+ (protein 8129, Mr = 30,400) were identified. In contrast, no major protein markers were found that could differentiate T4+ and T8+ cells from each other or from B cells and NK cells. With the exception of two B1+ markers (proteins 5525 and 5621), lower but variable levels of the other markers were observed in all cell types. All the putative protein markers have been identified in the protein database of human peripheral blood mononuclear cells (PBMCs) (see accompanying article by Celis et al.). Comparison of the overall patterns of protein synthesis of the unsorted PBMCs with those of the four subpopulations showed that the synthesis of some major PBMC proteins decreased substantially in the sorted subsets. These proteins are most likely not of monocyte origin, as these cells constituted only about 15% of the total PBMCs. Also, the inhibition does not seem to be due to the addition of the single MoAbs or to cell cycle differences. Taken together, the data provide a background for further studies of protein profiles in normal (resting or activated) and malignant hematopoietic cells.
Leukemia 1988 Sep
PMID:Major proteins in normal human lymphocyte subpopulations separated by fluorescence-activated cell sorting and analyzed by two-dimensional gel electrophoresis. 341 27

Delivery of the bifunctional alkylating agent, PTT.119 [p-F-L-Phe-m-bis-(2-chloroethyl)amino-L-Phe-Met-ethoxy-HCl], into tumor cells is significantly greater compared to L-phenylalanine mustard (L-PAM) as demonstrated by the 2-fold reduction in PTT.119 dosage required to reduce the viable L1210 cell fraction by 50% (TCD50). This increased uptake and consequent cytolytic efficacy observed in Dulbecco's phosphate buffer was more apparent in culture medium; under this physiologic condition the TCD50 concentration of PTT.119 was 5 times lower than L-PAM. PTT.119 entry into leukemia cells was examined using competition transport assays assessing the ability of the tripeptide to compete with various amino acids and nonmetabolizable substrates for carrier receptors of the L, A and ASC transport systems. A 1-min exposure to a 1- to 50-fold excess of PTT.119 prior to addition of radiolabeled substrates significantly reduced within 60 s both sodium-dependent and sodium-independent uptake of leucine, methionine, threonine and alpha-[1-14C]-aminoisobutyric acid (AIB), but not MeAIB. In complimentary studies, L1210 cells were protected from PTT.119 cytolysis by an 8,000-fold excess of AIB, whereas beta-2-aminobicyclo[2.2.1]heptane-2-carboxylic acid (BCH) only abrogated tripeptide cytotoxicity by 95-97% even at BCH:PTT.119 ratios of 200,000. Leucine and methionine protection were significantly less effective; the TCD50 of leucine and methionine were 3.23 and 2.4 microM, respectively, compared to 11.41 microM for AIB and 7.96 microM for BCH. In addition, MeAIB and phenylalanine were totally unable to protect L1210 cells from PTT.119-induced cytolysis. The data indicate that L121 cells actively transport PTT.119 primarily by the BCH-sensitive, AIB-sensitive, MeAIB-insensitive L carrier system. A second, BCH-insensitive, AIB-sensitive and MeAIB-insensitive carrier which is also involved in tripeptide uptake is probably the ASC system.
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PMID:Multiple transport pathways for L1210 cells: uptake of PTT.119, a bifunctional alkylator with carrier amino acids. 341 61

The goals of new antifolate development are: 1) improved selectivity, 2) improved penetration into pharmacologic sanctuaries, and 3) effectiveness vs. tumors either with intrinsic or acquired resistance to methotrexate (MTX). The major target for antifolate development has been dihydrofolate reductase (DHFR), but other critical folate-dependent enzymes, i.e., thymidylate synthase, methionine synthetase, and folylpolyglutamate synthetase are also important targets for new antifolate development. The possibility that DHFR from tumor tissue differs significantly from normal tissue DHFR now seems improbable, and the ideas of the late Bill Baker to design specific inhibitors of the tumor enzyme vs. the normal tissue DHFR are unlikely to succeed. However, the experience with triazinate (Baker's antifol; TZT) indicates that transport of antifols could be exploited to provide selective toxicity, as well as to provide agents effective vs. MTX-resistant cells. This work led to a second generation of "nonclassical" folate antagonists, of which trimetrexate (JB-11; TMQ) is now in clinical trial. Uptake of TMQ is via an MTX-independent membrane system, and extremely high intracellular levels of this drug are achieved in human leukemia cells.
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PMID:Design and rationale for novel antifolates. 343 93

Methylglyoxal bis(butylamidinohydrazone) (MGBB) inhibited S-adenosylmethionine decarboxylase (SAMDC) activity competitively with S-adenosylmethionine (SAM) showing the Ki value of 1.8 X 10(-5) M. MGBB showed less SAMDC-stabilizing effect in rat liver in vivo than did methylglyoxal bis-(guanylhydrazone) (MGBG). MGBB inhibited the growth of human erythroid leukemia K 562 cells. Putrescine, spermidine and spermine concentrations in MGBB-treated cells were depressed to 56%, 58% and 88% of the values of control cells, respectively. [35S]Methionine incorporation into trichloroacetic acid-insoluble fraction was decreased in the inhibitor-treated cells.
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PMID:Antitumor effect of methylglyoxal bis(butylamidinohydrazone), a new inhibitor of S-adenosylmethionine decarboxylase, against human erythroid leukemia K 562 cells. 345 77

Granulocytes from patients with chronic myelogenous leukaemia (CML) have been previously shown to have aberrant sialylation of membrane glycoproteins. We have examined the granulocytes from CML patients receiving intermittent chemotherapy to determine the relationship of the oligosaccharide changes to treatment. Compared to cells from non-leukaemic patients, granulocytes from untreated CML patients showed less adherence to nylon wool, decreased reactivity with peanut lectin, and decreased binding of the synthetic chemotactic peptide formyl-methionine-leucine-phenylalanine (FMLP). Granulocytes from CML patients treated with chemotherapy showed nylon wool adherence, peanut lectin reactivity and FMLP binding comparable to non-leukaemic cells. Chemotherapeutic agents may interfere with oligosaccharide synthesis with a resulting change in the composition of cell surface glycoconjugates.
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PMID:Changes in the granulocyte membrane following chemotherapy for chronic myelogenous leukaemia. 345 89


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