UMLS:C0027651 - FACTA Search

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Query: UMLS:C0027651 (tumor)
685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interferons have been shown to be potential anti-cancer agents and to inhibit tumor cell growth in culture. The in vivo mechanism of the anti-proliferative effect may be direct or indirect through the immune system; however, in vitro a primary mechanism of cytotoxicity is through the depletion of tryptophan. In particular, interferon-gamma (IFN-gamma) induces an enzyme of tryptophan catabolism, indoleamine 2,3-dioxygenase (IDO), which is responsible for conversion of tryptophan and other indole derivatives to kynurenine. The inhibitory effect of interferon on many intracellular parasites such as Toxoplasma gondii and Chlamydia trachomatis is by the same mechanism. Elevated kynurenine levels have been found in humans in a number of diseases and after interferon treatment, and the enzyme is induced in rodents after administration of interferon inducers, or influenza virus. IDO induction also occurs in vivo during rejection of allogeneic tumors, indicating a possible role for this enzyme in the tumor rejection process. The gene for IDO has been cloned and shown to be differentially regulated by IFN-alpha and IFN-gamma. IDO induction has been correlated with induction of GTP-cyclohydrolase, the key enzyme in pteridine biosynthesis. A direct role for IDO in pteridine synthesis has not been shown, and this parallel induction may reflect coordinate regulation of genes induced by IFN-gamma. A possible role for IDO in O2-radical scavenging and in inflammation is discussed.
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PMID:Relationship between interferon-gamma, indoleamine 2,3-dioxygenase, and tryptophan catabolism. 175 66

The depletion of an essential amino acid (aa), tryptophan, caused by interferon-gamma (IFN-gamma)-mediated induction of indoleamine 2,3-dioxygenase (IDO) in mouse allografted tumor cells, has been suggested as a reason for the allograft rejection. To elucidate the mechanism of this IDO induction, attempts were made to isolate cDNA clones encoding mouse IDO. In seven of 25 mouse cell lines, IDO was induced by IFN-gamma, and the highest IDO induction was observed in the case of rectal cancer (CMT-93) cells, which were further stimulated two- to threefold by the simultaneous addition of dibutyryl cyclic AMP (Bt2cAMP). A cDNA library was prepared from poly(A)+ RNA isolated from CMT-93 cells treated with IFN-gamma/Bt2cAMP. The cDNA clones were isolated using the cDNA encoding human IDO as a probe. The mouse IDO cDNA encodes a 407-aa protein with an Mr of 45,639. The deduced aa sequence agreed with partial aa sequences derived from endopeptidase digestion of purified mouse IDO and revealed 61% homology with that of human IDO. Transient expression of the mouse IDO cDNA in COS-7 cells yielded a high level of IDO activity in the cells. Northern hybridization analysis of RNA in CMT-93 cells indicated that IFN-gamma induced the IDO mRNA, and that the level of RNA was increased by simultaneous addition of Bt2cAMP, while Bt2cAMP itself had no effect on mRNA induction.
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PMID:Cloning and expression of a cDNA encoding mouse indoleamine 2,3-dioxygenase. 193 18

A monomoprhic monoclonal antibody (LA45 antibody) reactive with "a new activation-induced surface structure on human T lymphocytes" (LA45 antigen) that resembled free class I heavy chains has recently been described (Schnabl, E., H. Stockinger, O. Majdic, H. Gaugitsch, I.J.D. Lindley, D. Maurer, A. Hajek-Rosenmayr, and W. Knapp. 1990. J. Exp. Med. 171:1431). This antibody was used to clone a class I-like heavy chain (LA45 gene) from the HUT 102 tumor cell, which paradoxically did not give rise to the LA45 antigen on transfection into monkey COS cells. We show here that the LA45 gene is HLA-Aw66.2, a previously uncharacterized allele of the HLA-A locus. The previously determined LA45 sequence differs from that of HLA-Aw66.2, from HUT 102, and the CR-B B cell line derived from the same individual as HUT 102 by substitution of tryptophan for serine at position 4 in the alpha 1 domain. Transfection of HLA-Aw66.2, and of a mutant of this gene with serine 4 substituted for tryptophan, into a human B cell line (C1R) both resulted in expression of the LA45 epitope. Furthermore, we find expression of the LA45 epitope on Epstein Barr virus-transformed B cell lines as well as lectin-activated T cells, but not on long-term T cell lines or unstimulated peripheral blood T cells. The specificity of the LA45 antibody is polymorphic and the presence of the LA45 epitope is precisely correlated with the sequence arginine, asparagine (RN) at residues 62 and 63 of the helix of the alpha 1 domain. The LA45 epitope is broadly distributed, being associated with half the alleles of both HLA-A and -B loci but none of the HLA-C locus. All the results are consistent with the presence of pools of free HLA-A and -B heavy chains at the surfaces of certain cell types but not others. Such molecules are probably responsible for the HLA-associated class I alloantigens of lectin-activated T cells. We hypothesize the free heavy chains result from dissociation of beta 2-microglobulin from subpopulations of empty HLA-A,B molecules, or molecules with weakly bound peptides, that vary in size depending on cellular activation and peptide supply.
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PMID:Molecular definition of a polymorphic antigen (LA45) of free HLA-A and -B heavy chains found on the surfaces of activated B and T cells. 194 Jul 90

The depletion of an essential amino acid, tryptophan, caused by induction of indoleamine 2,3-dioxygenase (IDO), has been shown to be a mechanism involving self-defense against inhaled microorganisms and tumor growth. We recently reported that the IDO is dramatically (approximately 50-fold) induced in allografted tumor (3-methylcholanthrene-induced ascites type tumor cells) cells undergoing rejection, and that the enzyme is induced by factor(s) released through the interaction of allografted tumor cells with infiltrating leukocytes. The culture supernatant of infiltrating leukocytes, which were harvested on day 7 after tumor transplantation, induced the highest IDO activity in the tumor cells. The inducer activity was completely neutralized by the addition of antibody to IFN-gamma but not by antibody to IFN-alpha/beta. Approximately 6 U/ml of IFN-gamma was detected by an ELISA assay in the 12-h culture supernatant with 2 x 10(6) leukocytes/ml, and rIFN-gamma at 6 U/ml induced IDO in 3-methylcholanthrene-induced ascites type tumor cells to the same extent as IFN-gamma in the culture supernatant. Moreover, i.p. administration of antibody to IFN-gamma almost completely inhibited the induction of IDO in the allografted tumor cells. These observations indicate that the factor responsible for IDO induction in the allografted tumor cells is IFN-gamma.
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PMID:IFN-gamma is the inducer of indoleamine 2,3-dioxygenase in allografted tumor cells undergoing rejection. 211 80

Groups of 15 female Syrian golden hamsters with N-nitrosobis(2-oxopropyl)amine-induced pancreatic cancers were treated for 2 mo with microcapsules of the luteinizing hormone-releasing hormone (LH-RH) antagonist [Ac-D-Nal(2)1-D-Phe(4Cl)2-D-Pal(3)3,D-Cit6,D-Ala10] LH-RH (SB-75) releasing 8 micrograms/day or with the microcapsules of the LH-RH agonist D-tryptophan-6-luteinizing hormone-releasing hormone (D-Trp-6-LH-RH) releasing 8 micrograms/day or 25 micrograms/day. Chronic treatment with SB-75 resulted in 70% inhibition of pancreatic tumor weight; D-Trp-6-LH-RH in doses of 8 micrograms/day and 25 micrograms/day produced 66% and 62% inhibition, respectively. The number of animals with pancreatic tumors was reduced by about 50% in each treated group. Tumorous ascites were found in seven control hamsters and in one hamster in each group treated with D-Trp-6-LH-RH but not in the group given SB-75. Reduction in serum luteinizing hormone levels and ovarian as well as uterine weights indicated that an inhibition of the pituitary-gonadal axis occurred during chronic SB-75 and D-Trp-6-LH-RH treatment. Membrane receptor assays showed a significant decrease of the concentration of binding sites for LH-RH in tumor cells after SB-75 or D-Trp-6-LH-RH treatment. Insulin-like growth factor I receptors, but not epidermal growth factor receptors, were down-regulated by D-Trp-6-LH-RH. SB-75 did not influence the concentration or the binding capacity of insulin-like growth factor I and epidermal growth factor receptors in the tumor cells. The inhibitory effect of chronic treatment with SB-75 and D-Trp-6-LH-RH on tumor growth was mediated by enhanced apoptosis (programmed cell death) induced by the change in hormonal environment. Apoptosis was also produced in hamsters with N-nitrosobis(2-oxopropyl)amine-induced pancreatic cancers by acute treatment (3 to 6 days) with high doses of D-Trp-6-LH-RH or SB-75. In view of its potency and an immediate powerful inhibitory effect, the LH-RH antagonist SB-75 might be considered as a possible new hormonal agent for the treatment of exocrine pancreatic cancer.
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PMID:Regression of nitrosamine-induced pancreatic cancers in hamsters treated with luteinizing hormone-releasing hormone antagonists or agonists. 216 Mar 23

The interferon (IFN)-gamma-mediated induction of indoleamine 2,3-dioxygenase (IDO) enzyme, which converts tryptophan into N-formylkynurenine, has been implicated in the inhibition of intracellular pathogens, e.g. Toxoplasma gondii and Chlamydia psittaci, and in the antiproliferative effect of IFN-gamma on tumor cells. The IDO activity is induced strongly in many cell types by IFN-gamma but rather poorly by IFN-alpha or -beta. A genomic DNA clone containing part of the transcribed region of the IDO gene and approximately 13 kilobases (kb) of the 5'-upstream DNA sequence was isolated and analyzed. An approximately 1.4-kb fragment of this clone, containing 329 nucleotides of the transcribed sequence and approximately 1.1 kb of the 5'-upstream sequence, when ligated to chloramphenicol acetyltransferase (CAT) structural gene made its expression inducible by IFN-gamma, but this construct responded poorly, if at all, to IFN-alpha 2. Deletion constructs derived from this plasmid narrowed down the IFN-gamma-responsive region to a 151-nucleotide segment (-495/-344) which also contained a 14-nucleotide sequence (GGTTTCAGTTTTCC) highly homologous to the IFN(alpha)-stimulated response element (ISRE) that has been found so far in all cellular genes inducible with IFN-alpha or -beta. Expression of CAT activity was stimulated by IFN-gamma more effectively than by IFN-alpha 2 when a 155-nucleotide fragment (-495/-340) containing the 151-nucleotide segment required for IFN-gamma response was inserted before herpes simplex virus thymidine kinase promoter linked to CAT structural gene. The results indicate that despite the presence of an ISRE, the control region of the IDO gene can distinguish between IFN-gamma and IFN-alpha. This may account for the differential activation of IDO gene expression by IFN-gamma as against IFN-alpha or -beta in intact cells, and suggests that the response of ISRE to IFN-alpha or -beta may be governed by other features in the upstream control region of this gene.
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PMID:Regulation of indoleamine 2,3-dioxygenase gene expression in human fibroblasts by interferon-gamma. Upstream control region discriminates between interferon-gamma and interferon-alpha. 217 56

Functional gastrin-containing tumor cells were maintained for up to 8 wk without fibroblastoid cell overgrowth. Short-term cultures consisted mainly of colonies composed of small polygonal cells, 70%-90% of which stained positive for immunoreactive gastrin. Cultures exhibited limited growth but viability remained high for 2-3 wk. Culture medium contained component I, and gastrin 34, 17, and 14. With time the major C-terminal gastrin species in medium changed from gastrin 17 at 3 days to gastrin 34 at 5 wk. Extracts of cultured cells contained gastrin 34, 17, and 14; gastrin 17 was the major form detected at all times. Ultrastructurally, cultured tumor cells retained morphological integrity for several weeks; however, with time changes in the appearance of the secretory granules accompanied by evidence of cellular retrodifferentiation were gradually observed. Secretin, gastrin-releasing peptide, 8-bromoadenosine 3':5'-cyclic monophosphate, and phorbol, 12-myristate, 13-acetate stimulated the release of gastrin from cultured cells in a time-dependent fashion. Secretin, bombesin, gastrin-releasing peptide, L-tryptophan, and ethylamine stimulated gastrin release in a dose-dependent fashion. Somatostatin 14 inhibited secretin, bombesin, and gastrin-releasing peptide stimulated gastrin release but did not alter basal release. Cultured cells demonstrated de novo gastrin synthesis, evidenced by their ability to incorporate radiolabeled amino acids into immunoadsorbable gastrinlike material. Primary cultures of gastrin-containing tumor cells free from stromal contamination offer unique advantages for studies of factors that regulate the synthesis and secretion of gastrin and may prove of potential value for studies on cell differentiation and growth.
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PMID:Gastrinoma in vitro: morphological and physiological studies of primary cell cultures. 217 34

Rat alpha-fetoprotein (AFP) contains one binding site for estradiol with an association constant, Ka = 1 X 10(8) M-1. This site overlaps with a high affinity arachidonic acid binding site (Ka = 1 X 10(7) M-1) and with a tryptophan methyl ester binding site, AFP also possesses a second site able to bind retinoids with a Ka = 1 X 10(6) M-1, and a third site for the binding of bilirubin (Ka = 1 X 10(6) M-1). These two sites presented no interaction and do not overlap with the estrogen or fatty acid binding site. It is suggested that these three binding sites reflect the three-domain structure of the rat AFP molecule deduced from the studies on the nucleotide sequence of AFPmRNA and AFPcDNA segments.
Tumour Biol 1985
PMID:Presence of three different binding sites for retinoids, bilirubin and estrogen or arachidonic acid on rat alpha-fetoprotein. 241 17

Human Y79 retinoblastoma cells are capable of synthesizing the putative retinal neurotransmitters dopamine and serotonin. Separation of the catecholamines and indolamines by high performance liquid chromatography combined with electrochemical detection showed that the cells readily convert tyrosine to 3,4-dihydroxyphenylalanine (DOPA) and, to a lesser extent, dopamine. When DOPA was added, a large quantity of dopamine was produced, as well as norepinephrine, epinephrine, and 3,4-dihydroxyphenylacetic acid. Exogenous tryptophan added to the cells was partially converted to 5-hydroxytryptophan and serotonin. A larger quantity of serotonin was produced when 5-hydroxytryptophan was added. Y79 cells have a high- and low-affinity uptake system for dopamine and serotonin. The K'm and V'max for the high-affinity uptake of dopamine and serotonin are 2.34 +/- 0.64 and 3.63 +/- 1.15 microM and 4.77 +/- 1.12 and 3.20 +/- 1.20 pmol min-1 mg protein-1, respectively. These kinetic parameters are similar to those reported for other retinal preparations where dopamine and serotonin have been suggested to function as neurotransmitters. Tyrosine and tryptophan, the physiologic precursors of dopamine and serotonin, respectively, and phenylalanine are also taken up by high- and low-affinity transport systems. The kinetic parameters for their high-affinity uptake systems are all very similar, suggesting that they may be taken up by the same transporter. These studies show that a tumor cell line derived from the human retina synthesizes dopamine and serotonin and has high-affinity uptake systems for these compounds and their precursors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Synthesis and high affinity uptake of serotonin and dopamine by human Y79 retinoblastoma cells. 244 11

Effects of temperature and pH on the spatial structures of trophoblast-specific beta 1-glycoprotein (TSG) and its various derivatives and fragments have been studied by circular dichroic spectroscopy. The spatial organization of the protein portion of TSG derivatives, as revealed by the spectroscopic evidence, has been discussed with respect to the antigenic activity of the species studied. We concluded that the TSG protein portion consists mainly of a beta-structural type. The antigenic determinants were shown to be topographic, and are preferentially localized in the protein portion; only about 15% of the TSG antigenic activity failed to bear a direct relation to the spatial structure. The antigenic determinants seemed to include a tryptophan residue.
Tumour Biol 1988
PMID:Trophoblast-specific beta 1-glycoprotein: its spatial structure and localization of antigenic determinants. 246 78

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