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)

Fourteen derivatives of sparsomycin (1) were synthesized. Six of them were prepared following a novel synthetic route starting from the L-amino acid alanine. Some physicochemical properties, viz. lipophilicity and water solubility, of selected derivatives were measured. The biological activity was tested in vitro in cell-free protein synthesis inhibition assays, in bacterial and tumor cell growth inhibition assays, and in the L1210 leukemia in vivo model in mice. Also for selected drugs the acute toxicity in mice was determined. Ribosomes from both an eukaryotic and a prokaryotic organism were used in the protein synthesis inhibition systems. A linear correlation between the lipophilicity parameters measured was observed. Water solubility and drug toxicity in mice were found to be linearly correlated with lipophilicity. All the derivatives studied are more lipophilic than 1. The deshydroxysparsomycin analogues (30-33) showed an interesting phenomenon: increase in hydrophobicity was accompanied by a considerable increase in water solubility. We found that an increase in hydrophobicity of the drug as a result of replacing the SMe group of 1 with larger alkylthio groups causes an increase in the biological activity of the drug. However, not only the hydrophobicity but also shape and size of the substituent are important; in the homologous series 1-9-10-11-12, 21-22-23-24, and 30-31-32-33, highest protein synthesis inhibitory and in vitro cytostatic activity is found with compounds 11, 23, and 32, respectively, and in comparison with the highly active n-butyl compound 10, the isomeric tert-butyl compound 13 is rather inactive. Polar substituents replacing the SMe group, i.e. Cl in 17 and 35, also render the molecule inactive. Substituting the bivalent sulfur atom for a methylene group decreases the drug's activity. This effect can be compensated for by increasing the length of the alkylsulfinyl side chain. The agreement between the results derived from cell-free and "in vivo" tests is good. The assays using ribosomes of bacterial and eukaryotic organisms give similar results although the latter seem to be more sensitive to changes in hydrophobicity of the drug. Our results confirm the presence of a hydrophobic region at the peptidyl transferase center of the ribosome; the interaction of sparsomycin with this region is more pronounced in the eukaryotic particles. The sparsomycin analogues 11, 23, and 30 show the highest antitumor activity against L1210 leukemia in mice, their median T/C values are 386, 330, and 216%, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Lipophilic analogues of sparsomycin as strong inhibitors of protein synthesis and tumor growth: a structure-activity relationship study. 275 19

Five murine and 3 human tumor cell lines were transfected with a retroviral vector that carries the EBV encoded EBNA-1 gene. All cell lines expressed intranuclear EBNA-1 as detected by anticomplement immunofluorescence and Western blot assays. The cell lines differed in the level of EBNA-1 expression and the size of the protein. The internal major late promoter of adenovirus was efficient in directing the transcription of EBNA-1 in the human lymphoma line BJAB, the murine T-cell lymphoma Tikaut, RBL-5, EL-4 and in the mouse sarcoma line MSWBS but was less efficient in Ramos, an EBV negative Burkitt lymphoma line, the human T-cell leukemia line 1301TK and the P815-X2 mouse mastocytoma line. All transfected lines except MSWBS contained EBNA-1 in a truncated form. The truncated EBNA-1 polypeptide reacted with the conventional human antibody reagents in an EBNA specific fashion but failed to bind rabbit or human antibody directed against the glycine-alanine repeat sequence. MSWBS contained a truncated as well as a full size EBNA-1 polypeptide. It also reacted with antibody directed against the glycine-alanine repeat. This indicates that the repeat sequence is regularly affected by the truncation.
 ...
PMID:Expression of the Epstein-Barr virus encoded EBNA-1 gene in stably transfected human and murine cell lines. 284 82

In human lymphocytes three dipeptidyl peptidases were discovered in our laboratory. For a correct demonstration of activities of these enzymes discriminating substrates must be used. Dipeptidyl peptidase IV (DPP IV) is revealed with Gly-Pro-4-methoxy-2-naphthylamide (Gly-Pro-MNA) and Fast Blue B (FBB). It is present in the surface membrane of about 40% lymphocytes of the peripheral blood. Only T-lymphocytes bear the reaction. Reacting lymphocytes belong predominantly to OKT4+ subset. Some OKT8+ lymphocytes also react. With more sensitive substrates (Lys-Pro-MNA, Phe-Pro-MNA and Ala-Pro-MNA) a co-reaction of DPP II was demonstrated "in situ" and in zymograms. In haemoblastoses a positive reaction in cells indicates their derivation from the T-lineage of lymphocytes. A negative reaction does not exclude a T-cell malignancy, however. A decreased number of DPP IV positive lymphocytes in the peripheral blood indicates a diminished immunocompetent potential of T-cells, e.g. immunodeficiency in patients with malignant lymphoma, gastric and colocrectal carcinoma, AIDS, etc. DPP II demonstrated with Lys-Ala-MNA occurs in about 60% of lymphocytes belonging to T and B subsets. It is localized in lysosomes. Although Lys-Pro-MNA is a more sensitive substrate a co-reaction of DPP IV must always be considered. Patients with chronic B-lymphocytic leukaemia displaying a high number of DPP II+ cells usually have a worse prognosis. DPP I assessed with Gly-Pro-MNA and nitrosalicylaldehyde occurs in about 20% of T and B lymphocytes. The number of positively reacting cells increases after corticosteroid therapy. The influence of the treatment on the activity can be shown very well in histograms of DPP I activity measured by computer-assisted microfluorometry.
 ...
PMID:Dipeptidyl peptidases of human lymphocytes. 290 80

Proteins that bind IgE play important roles in both the synthesis and function of IgE are therefore intimately involved in IgE-mediated human allergic disorders. This report describes the structure of an IgE-binding protein, as predicted from sequencing a cDNA cloned from rat basophilic leukemia cells. This protein contains two domains: the amino-terminal domain (140 amino acids) consists of a highly conserved repetitive amino acid sequence, Tyr-Pro-Gly-Pro/Gln-Ala/Thr-Pro/Ala-Pro-Gly-Ala, whereas the carboxyl-terminal domain (122 amino acids) shares significant sequence homology with a domain of lymphocyte/macrophage receptor for the Fc portion of IgG. Other proteins with this type of structure but with affinity for other immunoglobulin isotypes may exist and may represent a heretofore unidentified component of the immune system.
 ...
PMID:An IgE-binding protein with a distinctive repetitive sequence and homology with an IgG receptor. 295 48

A splice donor site of pX mRNA of human T-cell leukemia virus type I was elucidated by analyzing a cDNA clone of poly A+ RNA isolated from cat fibroblast cells infected with the virus. The donor site was located near the 5' end of the env gene. The putative N-terminal amino acid sequence of the pX protein was deduced to be Met-Ala-His---.
 ...
PMID:Structure of the pX protein deduced from the nucleotide sequence of a cDNA clone of pX mRNA in cells infected with human T-cell leukemia virus type I. 298 57

The humoral immune response of cats that were naturally infected with the feline leukemia virus (FeLV) was examined after antigenic stimulation with the synthetic antigen poly(L-Tyr, L-Glu)-poly(DL-Ala)-poly(L-Lys). The primary humoral antibody response in FeLV-infected cats was both delayed and greatly reduced, compared with that seen in uninfected control cats. A similar discordance was observed after secondary stimulation with the antigen, in the FeLV-infected cats had both a delayed response and a reduced response, compared with uninfected cats. The levels of total immunoglobulins of the immunoglobulin G and immunoglobulin M classes in the sera of FeLV-infected cats were significantly higher (two- and threefold, respectively) than were those of the uninfected control animals. The presence of an impaired humoral immune response to newly presented antigens in the presence of elevated immunoglobulin levels has been thoroughly documented in the case of people with the acquired immunodeficiency syndrome. This further emphasizes the potential value of FeLV-infected cats as a model for human acquired immunodeficiency syndrome.
 ...
PMID:Humoral immune response of asymptomatic cats naturally infected with feline leukemia virus. 302

The transport of glycine and L-lysine into murine P388 leukemia cells has been examined. Glycine transport appears to be shared by both systems A and ASC in P388 cells. Glycine transport is Na+-dependent and is effectively blocked by alpha-(methylamino)isobutyric acid, threonine and alanine but only a marginal reduction in transport is seen with 100-fold excess cold 2-aminobicyclo[2,2,1]heptane-2-carboxylic acid. System gly is not expressed in P388 cells. Lysine is largely transported by a Na+-independent, pH-insensitive system with a Km of 0.079 mM. Lysine transport is relatively unaffected by the addition of 100-fold excess cold alpha-(methylamino)isobutyric acid, 2-aminobicyclo[2,2,1]heptane-2-carboxylic acid and the anionic amino acids, L-glutamate and L-aspartate. A partial inhibition of lysine transport was observed with L-threonine and L-leucine while L-arginine and L-histidine radically decreased lysine transport. Lysine appears to be transported by a system similar to the system y+ seen in cultured human fibroblasts, Ehrlich ascites cells, and hepatoma cell lines.
 ...
PMID:Further studies on amino acid transport in murine P388 leukemia cells in vitro. Presence of system y+. 310 85

A 93-kDa tyrosine protein kinase (p93) identified previously as the gene product of the c-fes proto-oncogene, is highly expressed in HL-60 leukemia cells induced to differentiate to the granulocyte or monocyte phenotype. We have now studied the relationship of p93 to the differentiation process by using a dimethyl sulfoxide (DMSO)-resistant subline of HL-60 cells (HL-60/DMSO) or the parental cell line treated with peptide or protein substrates of p93. Treatment of HL-60/DMSO cells with DMSO induced neither differentiation nor the expression of p93; however, cotreatment with IFN-alpha and DMSO resulted in partial differentiation and the concomitant induction of p93 activity. Treatment of wild-type HL-60 cells by the coaddition of the p93 substrates poly(Glu,Tyr)1:1, poly(Glu,Tyr)4:1, poly(Glu,Ala,Tyr)6:3:1, angiotensin II or vasoactive intestinal peptide with DMSO or IFN-tau partially blocked differentiation and concurrently diminished the induction of p93 activity. The inhibitory concentrations of the p93 substrates were related to their Km values. These results indicate that there is an obligatory association between the expression of p93 and granulocyte/monocyte differentiation in this cell line.
 ...
PMID:Association of p93c-fes tyrosine protein kinase with granulocytic/monocytic differentiation and resistance to differentiating agents in HL-60 leukemia cells. 316 57

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.
 ...
PMID:N-(Retinoyl)amino acids. Synthesis and chemopreventive activity in vitro. 333 18

An attempt has been made at defining the secondary structural requirement for phosphorylation of substrates of a protein tyrosine kinase from the leukemia virus-transformed LSTRA cell line. An examination of the sites of phosphorylation of substrates of protein tyrosine kinases indicated a relatively high probability of the beta-turn as the secondary structural feature at these sites. We have, therefore, synthesized three tyrosine peptides: Ala-Pro-Tyr-Gly-NHCH3, Leu-Pro-Tyr-Ala-NHCH3, and Pro-Gly-Ala-Tyr-NH2, of which the first two peptides, but not the third, would be expected to contain the tyrosine residue in a beta-turn. Circular dichroism and infrared spectral data on the peptides confirmed this expectation. Phosphorylation data on the peptides by the tyrosine kinase showed that the two beta-turn peptides were phosphorylated with Vmax and Km values comparable to those of the 13-residue-long arginine-containing synthetic peptide substrate having a sequence homologous to the autophosphorylation site of the LSTRA kinase. The peptides used here contain the shortest sequence length among the reported synthetic peptide substrates for protein tyrosine kinases. Their preference for the beta-turn indicated that this conformation may serve as the recognition site for tyrosine phosphorylation.
 ...
PMID:Synthetic beta-turn peptides as substrates for a tyrosine protein kinase. 335 78


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