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)

In previous structure-activity studies, we have demonstrated that attachment of a glucose molecule to the chloroethylnitrosourea cytotoxic group produces a compound with reduced murine bone marrow toxicity and retention of full antitumor activity. To further define this protective role conferred by the glucose moiety in bone marrow cells, we have replaced the nitrosourea cytotoxic group with another class of alkylating agent, a bifunctional nitrogen mustard. In a detailed structure-activity analysis, we have now characterized four analogues, with the mustard cytotoxic group positioned at carbon 2 [1,3,4,6-tetra-O-acetyl-2-(di-2-chloroethyl)amino-2-deoxy-D-glucopyranos e (TGM)], carbon 6, or carbon 1 (D- and L-isomers) of the aminoglucose molecule. On a molar basis, TGM was most toxic to normal BALB/c X DBA/2 F1 mice, with a 10% lethal dose (LD10) of 3.8 mumol/kg. The D- and L-isomers of 2,3,4,6-tetra-O-acetyl-N,N-bis(2-chloroethyl)glucopyranosylamine (C-1) were the least toxic, with an LD10 of 73 mumol/kg for both. Optimal antitumor activity against the murine P388 leukemia (single i.p. administration of the LD10) did not differ significantly among the four analogues, with increased life span ranging from 83-86%. P388 antitumor activity for nitrogen mustard (HN2) was significantly less, 60% increased life span (P = 0.01), while p-di(2-chloroethyl)amino-L-phenylalanine produced an increased life span of greater than 101%. An LD10 of 6-bis-(2-chloroethyl) amino-6-deoxy-D-glucose (C-6) or TGM produced significantly less depression of WBC counts than did an equitoxic dose of the C-1 isomers, HN2, or p-di(2-chloroethyl)amino-L-phenylalanine. The mean nadir WBC count for C-6 equaled 86% of control, and for TGM, 80% of control. Consistent with this sparing effect on the peripheral WBC, C-6 and TGM produced significantly less in vivo murine bone marrow DNA synthesis depression, 77 and 64% of control, respectively, as compared to the depression nadir produced by HN2 (27% of control), the D-isomer of C-1 (17%), the L-isomer of C-1 (18%), and p-di(2-chloroethyl)amino-L-phenylalanine (2%). These structure-activity studies demonstrate that conjugation of the mustard cytotoxic group to carbon 6 or carbon 2 of glucose produces an analogue that retains P388 antitumor activity significantly greater than that of HN2, with a concomitant reduction in murine bone marrow toxicity.
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PMID:Antitumor activity and bone marrow toxicity of aminoglucose mustard anticancer agents in mice. 293 28

The common acute lymphoblastic leukemia antigen (CALLA/CD10) is a nonintegral membrane glycoprotein expressed on normal and neoplastic cells of hematopoietic and nonhematopoietic origin. We have undertaken a series of experiments to examine 1) the structural homology between leukemia cell and neutrophil CALLA/CD10 and 2) the putative function CALLA/CD10 subserves to human neutrophils. Biosynthetic labeling, peptide mapping, and two-dimensional gel electrophoresis indicate that neutrophils synthesize and express a CALLA/CD10 molecule that is similar, but not identical, to leukemic cell CALLA/CD10. The level of CALLA/CD10 expression is similar on the two cell populations, and neutrophil CALLA/CD10 (like its leukemic cell counterpart) undergoes antigenic modulation. Finally, we report that neutrophil cell surface-bound anti-CALLA/CD10 monoclonal antibodies inhibit the chemotactic response to both N-Formyl-methionyl-leucyl-phenylalanine (F-mlp) and zymosan-activated sera (ZAS), but had no inhibitory effect on random migration, degranulation, or aggregation. The anti-class I monoclonal antibody W6/32 exerted a similar effect on chemotaxis. We conclude that CALLA/CD10 has no clearly defined role in neutrophil function but may play a role in some distal event in chemotaxis.
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PMID:Structure/function studies of the common acute lymphoblastic leukemia antigen (CALLA/CD10) expressed on human neutrophils. 294 84

Phorbol-12,13-dibutyrate (PDBU), a tumor-promoting and protein kinase C-activating phorbol ester, inhibited formylmethionylleucyl-phenylalanine-induced generation of inositol mono-, bis-, and tris-phosphates from the hydrolysis of phosphoinositides in human leukemia (HL-60) cells, which had been differentiated to polymorphonuclear leukocyte-like cells by pretreatment with dibutyryl cyclic adenosine 3':5'-monophosphate. PDBU did not alter the binding of formylmethionylleucyl-phenylalanine to the cells. Other protein kinase C-activating substances such as 12-O-tetradecanoylphorbol-13-acetate and 1-oleoyl-2-acetyl-glycerol could substitute for PDBU, but 4 alpha-phorbol-12,13-didecanoate, which is inactive for both tumor promotion and protein kinase C activation, was ineffective in this capacity. Prolonged treatment of the cells with PDBU resulted in the down-regulation and decrease of protein kinase C activity to the level of 30-40% of that in the control cells. In the down-regulated cells, formylmethionylleucylphenylalanine still induced generation of the phosphorylated inositols to the same extent as that in the control cells, but the inhibition of this reaction by PDBU was reduced to 30-50% as compared with that in the control cells. These results strongly suggest that tumor-promoting phorbol esters inhibit the agonist-induced phosphoinositide hydrolysis through the activation of protein kinase C in the differentiated HL-60 cells.
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PMID:Inhibition of chemotactic peptide-induced phosphoinositide hydrolysis by phorbol esters through the activation of protein kinase C in differentiated human leukemia (HL-60) cells. 301 Dec 48

Inositol trisphosphate (InsP3) production and cytosolic free Ca2+ ([Ca2+]i) elevations induced by leukotriene B4 (LTB4)-receptor activation were studied in the human promyelocytic-leukaemia cell line HL60, induced to differentiate by retinoic acid. The myeloid-differentiated HL60 cells respond to LTB4 by raising their [Ca2+]i with a dose-response relationship similar to that shown by normal human neutrophils. The observations of the LTB4 transduction mechanism were compared with those of the transduction mechanism of the chemotactic peptide fMet-Leu-Phe in HL60 cells differentiated with dimethyl sulphoxide. Both LTB4 and fMet-Leu-Phe triggered a rapid (less than 5 s) elevation of [Ca2+]i, which occurred in parallel with the InsP3 production from myo-[3H]inositol-labelled cells. The threshold concentrations of the agonists, for InsP3 production, were found at 10(-9) M, a slightly higher concentration than that required to detect [Ca2+]i elevations. No significant changes were noted in the phosphoinositide levels upon stimulation with LTB4. Exposure to Bordetella pertussis toxin before LTB4 stimulation abolished both the increased formation of InsP3 and the rise of [Ca2+]i. LTB4 and fMet-Leu-Phe elicited elevations of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] with no detectable lag time, followed by slower and more sustained inositol 1,3,4-trisphosphate elevations. Stimulation with various leukotriene analogues revealed a good correlation between both total InsP3 as well as Ins(1,4,5)P3 formation and elevations of [Ca2+]1. Thus LTB4 receptor activation results in an increased production of Ins(1,4,5)P3 via a transduction mechanism also involving a nucleotide regulatory protein, as previously described for the fMet-Leu-Phe transduction mechanism.
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PMID:Leukotriene B4 stimulation of phagocytes results in the formation of inositol 1,4,5-trisphosphate. A second messenger for Ca2+ mobilization. 302 73

A monoclonal antibody, TM316, IgM kappa, was raised against the human monocytoid leukaemia cell line THP-1, and was shown to inhibit polymorphonuclear leucocyte (PMN) chemotaxis. The molecular weight (MW) of the protein on the PMN membrane with which TM316 bound was about 78,000. TM316 inhibited the chemotactic response of human PMN induced by at least three kinds of chemotactic factors (activated serum, N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP), and a lymphocyte-derived chemotactic factor (LDCF)) to the same extent. The extent of inhibition of chemotaxis by TM316 was strongly correlated with the quantity of cellular surface antigen recognized by TM316, when a cell sorter was used for analysis. TM316 did not alter the number of Fc or complement receptors of PMN, nor did it affect luminol-enhanced chemiluminescence (CL), lysosomal enzyme release, adherence, or superoxide anion generation by PMN. TM316 seemed to recognize a common surface antigen which was necessary only for the process of chemotaxis.
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PMID:Inhibition of neutrophil chemotaxis by a monoclonal antibody (TM316). 306 89

Sequence analysis of the mutant Dbm13, Dbm14, and Dbm24 genes indicate that they differ from the parental Db gene by 4, 1, and 8 nucleotides, respectively. The mutant sequences substituted into Dbm13 and Dbm24 are identical to those found in the Kb gene, at the homologous positions. Thus, similar to the Kb gene, the Db gene is able to undergo micro-recombination (gene conversion) events with other class I genes. Such data suggest that micro-recombination events could be an important mechanism for the diversification of all H-2 genes. The Db mutant products share a common theme: the alterations in all occur at amino acid residues whose side chains in the homologous class I HLA-A2 molecule project into the postulated peptide antigen-binding cleft, and hence, would be expected to alter the binding of foreign or self peptides. Due to such changes, the bm14 mouse has become a nonresponder in the CTL response to Moloney murine leukemia virus (M-MuLV), as the alteration of one amino acid residue at position 70 (a Gln to His) is sufficient to entirely abrogate the cell-mediated response to the virus. On the other hand, the bm13 mouse has shifted the major part of its M-MuLV restriction to Kb, a profound alteration in CTL responsiveness due to the alteration of three amino acids (Leu to Gln at 114, Phe to Tyr at 116, and Glu to Asp at 119) in a peptide stretch of beta-pleated sheet structure lining the bottom of the antigen-binding cleft. Thus, study of these mutants reveals that, in one step, micro-recombination at the genetic level has resulted at the protein level in profound changes in the immune response to viral infection. Such a mechanism operating at the population level can be a driving force during evolution for modulating the character of CTL immunity.
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PMID:Three spontaneous H-2Db mutants are generated by genetic micro-recombination (gene conversion) events. Impact on the H-2-restricted immune responsiveness. 319 70

Rat RNK-16 leukemia cells kill YAC-1, which are the cells lysed by rodent natural killer lymphocytes. We found chymotrypsin-like proteinase ('chymase') activity in the RNK-16 dense granules that also contain cytolytic activity. The chymase activity hydrolyzed the thiobenzyl peptide substrate Suc-Phe-Leu-Phe-SBzl and, in comparison to RNK-16 tryptase activity, was selectively inhibited by three different types of serine proteinase inhibitors. The selective inhibitors were the fungal aldehyde chymostatin, the chloromethylketone Z-Gly-Leu-Phe-CH2Cl, and the mechanism-based or 'suicide' inhibitor 7-amino-4-chloro-3-(2-phenylethoxy)isocoumarin. These proteinase inhibitors also blocked RNK-16 granule-mediated cytolysis. Chymostatin, a reversible inhibitor, delayed granule-mediated cytolysis, whereas the irreversible chloromethylketone and isocoumarin proteinase inhibitors completely abrogated granule-mediated cytolysis. The two irreversible inhibitors displayed biphasic inhibition of the chymase activity, indicating that at least two chymases are present in the granules. By Northern blot analysis, we found that RNK-16 mRNA hybridized strongly with a cDNA probe of CCPI, a mouse cytotoxic T lymphocyte serine proteinase gene. These data imply that chymase activity in the cytotoxic granules is important for cytolytic function and is likely to belong to a new subfamily of serine proteinases.
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PMID:Localization, implications for function, and gene expression of chymotrypsin-like proteinases of cytotoxic RNK-16 lymphocytes. 326 87

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

Guanidinobenzoatase is a proteolytic enzyme capable of degrading fibronectin and is a tumour associated enzyme. Guanidinobenzoatase has been shown to be an arginine selective protease and is distinct from trypsin, plasminogen activator, plasmin, thrombin and a newly described tumour associated enzyme specific for guanidino phenylalanine residues. These conclusions have been derived from inhibition studies employing 4-methyl-p-guanidinobenzoate as substrate. Three active site titrants for trypsin have been shown to be good substrates for guanidinobenzoatase. A new active site titrant for trypsin, rhodamine bisguanidinobenzoate, can also be used to assay guanidinobenzoatase in a stoichiometric manner. This active site titrant can be employed to label guanidinobenzoate on the surface of leukaemia cells.
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PMID:Further inhibition studies on guanidinobenzoatase, a trypsin-like enzyme associated with tumour cells. 333 44

N-(all-trans-Retinoyl)amino acids were synthesized via all-trans-retinoyl chloride and an ester of the amino acid. The retinoyl derivatives of leucine, phenylalanine, alanine, tyrosine, and glutamic acid were prepared. The 13-cis-retinoyl derivatives of leucine, phenylalanine, alanine, and glycine were prepared similarly from 13-cis-retinoic acid. In assays of the retinoylamino acids for reversal of squamous metaplasia in hamster trachea organ cultures, these compounds were less active than retinoic acid, but the leucine, alanine, and phenylalanine derivatives were similar in activity to several retinamides that suppress bladder carcinogenesis in vivo. Two of the retinoylamino acids, as well as two simple retinamides, were shown to be moderately cytotoxic to murine leukemia and human epidermoid carcinoma cells in culture.
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PMID:N-(Retinoyl)amino acids. Synthesis and chemopreventive activity in vitro. 333 18


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