Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sphingosine (SPN) has been claimed to be a negative modulator of transmembrane signaling through protein kinase C (PK-C) or some yet unidentified mechanism [for review see Y. A. Hannun and R. M. Bell, Science (Washington DC), 243: 500-507, 1989]. N,N-Dimethylsphingosine (DMS) was recently found to be a physiological cellular component and, in comparison to SPN, to show a stronger and stereospecific inhibitory effect on PK-C activity of A431 cells (for review see Y. Igarashi, Trends Glycosci. Glycotechnol., 2: 319-332, 1990; and S. Hakomori, J. Biol. Chem., 265: 18713-18716, 1990). (4E)-N,N,N-Trimethyl-D-erythro-sphingenine (TMS) is not detectable as a normal cellular component; however, it is expected to exhibit potent activity because of its quaternary ammonium ion structure, and in fact it showed much stronger inhibitory effect than DMS or SPN on PK-C activity (which plays an important role in cell growth regulation) in vitro. In view of these findings, we investigated the effects of SPN, DMS, and TMS on in vitro growth of various human carcinoma cell lines and on in vivo tumor growth in athymic nu/nu mice. Both DMS and TMS showed similar in vitro and in vivo growth inhibitory effects on tumor cells, despite the fact that TMS showed a much stronger inhibitory effect than DMS on PK-C activity of A431 cells. In contrast, SPN showed only a weak effect on in vitro cell growth and no effect on in vivo tumor growth. Tumor growth following s.c. inoculation of mice with human gastric carcinoma cell line MKN74 was inhibited in a dose-dependent manner by DMS, and tumor size was decreased after three or four consecutive daily injections of 0.5-mg doses of DMS or TMS. Increased tumor growth occurred after administration of these compounds was stopped; however, size of tumor remained significantly smaller than in groups treated with SPN or control saline. The effect of DMS or TMS on in vitro or in vivo MKN74 cell growth was stronger than that of 8-chloro-adenosine-cyclic 3':5'-monophosphate dihydrate, the most promising agent currently being used in clinical trials for inhibition of tumor growth by induction of differentiation. These results suggest that DMS or TMS could be useful anticancer agents through modification of transmembrane signaling related to cancer cell growth.
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PMID:Cell membrane signaling as target in cancer therapy: inhibitory effect of N,N-dimethyl and N,N,N-trimethyl sphingosine derivatives on in vitro and in vivo growth of human tumor cells in nude mice. 199 52

Chemical and biological studies are presented for a new series of platinum(II) antitumor agents that violate the classical structure-activity relationships established for platinum complexes. These new agents, which have demonstrated activity against murine and human tumor systems, are cis-[Pt(NH3)2(Am)Cl]+ cations, in which Am is a derivative of pyridine, pyrimidine, purine, or aniline. Members from this series block simian virus 40 DNA replication in vitro and inhibit the action of DNA polymerases at individual guanine residues in replication mapping experiments. Monoclonal antibodies that bind selectively to cisplatin lesions on calf thymus DNA were used in a competitive enzyme-linked immunosorbent assay study to show that the platinum-triamine complexes do not produce the type of intrastrand cross-links on DNA that are characteristics of cisplatin and analogues with the general formula cis-[Pt(amine)2X2]. These results indicate that cis-[Pt(NH3)2(Am)Cl]+ cations form monofunctional adducts on DNA rather than eliminate NH3 or Am to afford bifunctional lesions. This conclusion is further supported by nuclear magnetic resonance spectroscopic and enzymatic digestion analyses of the products of the reactions of these triamine complexes with d(GpG) and dG, which also reveal monofunctional binding. When cis-[Pt(NH3)2(4-Br-pyridine)Cl]+ was allowed to stand in phosphate-buffered saline at 37 degrees C for 14 days, however, NH4+ was released and trans-[Pt(NH3)(4-Br-pyridine)Cl2] formed concomitantly. This compound was characterized by a single crystal X-ray diffraction study, the details of which are reported. The fact that trans-[Pt(NH3)(4-Br-pyridine)Cl2] displays no anticancer activity, however, indicates that its formation from cis-[Pt(NH3)2(4-Br-pyridine)Cl]+ is not a significant component of the mechanism of action of this platinum-triamine complex. Taken together, these findings indicate that the cytotoxicity of cis-[Pt(NH3)2(Am)Cl]+ complexes most likely arises from the formation of monofunctional adducts. The DNA binding properties associated with this new class of antitumor agents suggest that they may display an activity profile different from that of cisplatin and related analogues.
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PMID:Mechanistic studies of a novel class of trisubstituted platinum(II) antitumor agents. 200 70

Human Sertoli cells in vitro secrete a factor that stimulates steroid biosynthesis in purified human and rat Leydig cells as well as in the MA-10 mouse tumor Leydig cell line. MA-10 cells were used as a bioassay system to follow the characterization and purification of the active principle in the conditioned medium of human Sertoli cells. The Leydig cell stimulatory factor is a thermo-labile and trypsin-sensitive protein retained onto 10,000 mol wt (MW) cut-off filters. The following scheme was used to purify the active protein: concentration by ammonium sulfate (80%) precipitation, followed by dialysis using molecularporous membrane tubing of MW cut-off 12,000-14,000, heparin-agarose, Concanavalin-A-Sepharose, and immobilized reactive textile dye affinity chromatography. Yellow 86 and green 19 dyes immobilized on agarose matrix were used. This procedure resulted in the rapid (less than 24-h) purification of a 79,000 +/- 6,082 (n = 3; under denaturating conditions) MW protein which stimulated Leydig cell steroid biosynthesis 25-fold at picomolar concentrations. The MW of the biologically active protein was further confirmed to be around 80,000 by gel filtration chromatography. This 80,000 MW human Sertoli cell-secreted protein (hSCSP-80) was shown to be different from human transferrin, human serum albumin, and rat testibumin. hSCSP-80, by modulating Leydig cell steroid biosynthesis, may play a significant role in the regulation of testicular function.
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PMID:Identification and purification of a human Sertoli cell-secreted protein (hSCSP-80) stimulating Leydig cell steroid biosynthesis. 202 54

The in vivo 14N nuclear magnetic resonance spectra of s.c. implanted murine radiation induced fibrosarcomas (RIF-1) display narrow resonances assignable to betaine and other trimethylamines and broad resonances due to amino acids and peptides. In 19 of the 41 tumors studied a distinct resonance from the ammonium ion is detectable. The accumulation of ammonium in the tumor to nuclear magnetic resonance detectable levels may result from glutaminolysis (a possible pathway for energy production in the tumor), from the degradation of peptides and proteins, or from the deamination of adenine nucleotides. Estimates of the tissue ammonium concentration were obtained from the in vivo tumor spectrum and the spectrum of the nonlabile trimethylamines in the perchloric acid extract. In the extract, the 14N resonances of betaine, carnitine, choline, phosphorylcholine, and glycerophosphorylcholine were resolved, and a relatively high level of tissue urea was observed. Spin-lattice relaxation times were obtained for the 14N nucleus of each of these metabolites in phosphate buffer.
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PMID:In vivo 14N nuclear magnetic resonance spectroscopy of tumors: detection of ammonium and trimethylamine metabolites in the murine radiation induced fibrosarcoma 1. 205 77

The aim of this study was to determine the suitability of a ribosome-inactivating protein (RIP) from barley endosperm for use as an immunotoxin. This barley RIP is identical with the 30-kDa protein first reported by Coleman and Roberts [(1982) Biochim. Biophys. Acta 696, 239] and sequenced by Asano and co-workers [(1986) Carlsberg Res. Commun. 51, 75]. Use of the terms barley toxin I, II, and III is proposed to describe the three isoforms resolved by cation-exchange chromatography. An improved procedure for isolating the protein involving the steps of aqueous extraction, ammonium sulfate precipitation, and cation-exchange HPLC is described. Barley toxin II retained activity after exposure to ca. 40% acetonitrile and 0.1% trifluoroacetic acid or lyophilization. In a comparative study using the rabbit reticulocyte lysate assay, the protein was about 68% and 30% as potent as gelonin and ricin A-chain (RTA), respectively. Introduction of SH groups with 2-iminothiolane resulted in a substantial loss of activity as the number of thiol groups approached four. Therefore, it was necessary to limit thiolation to an average of one to two SH groups per toxin molecule. Anti-transferrin receptor-based immunotoxins constructed with RTA, gelonin, and barley toxin II exhibited comparable cytotoxicity against a human colon tumor cell line. We conclude that the availability of raw material, ease of purification, and stability of barley toxin II to lyophilization and denaturing conditions render it a suitable protein for the construction of immunotoxins.
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PMID:Immunotoxin construction with a ribosome-inactivating protein from barley. 209 10

Engelbreth-Holm-Swarm (EHS) tumor cells were utilized as a model for investigating the production of basement membrane components. These cells contain two immunologically distinct NADPH-dependent reductases, aldose reductase (EC 1.1.1.21) and aldehyde reductase (EC 1.1.1.2), which were purified to apparent homogeneity by a combination of procedures which included ammonium sulfate fractionation, Sephadex G-75 gel filtration, Matrex Gel Orange A affinity chromatography, and chromatofocusing on Pharmacia Mono P. The molecular weights of aldose and aldehyde reductases were estimated to be 38K and 40K, respectively, by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Substrate specificity studies showed that both enzymes were capable of reducing a variety of aldehydes to their respective alcohols; however, only aldehyde reductase oxidized L-gulonic acid. Surprisingly, both enzymes showed similar reactivities with D-glucose and D-galactose, suggesting that both aldose and aldehyde reductases may contribute to sorbitol production in the EHS tumor cell. The activities of both enzymes were increased by the presence of sulfate ion, but chloride ion decreased the activity of aldose reductase. Both aldose and aldehyde reductases were inhibited by a series of structurally diverse aldose reductase inhibitors.
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PMID:Purification and properties of aldose reductase and aldehyde reductase from EHS tumor cells. 210 20

A two-step chromatographic procedure, based on a specific ligand-binding approach, for the purification of tumor NAD(P)(+)-dependent malic enzyme is described. The enzyme was purified to near homogeneity by extraction from mitochondria, negative cellulose phosphate chromatography, ammonium sulfate precipitation, and application of specific elution from a malate-agarose column. The rationale for the use of the affinity column is also described.
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PMID:Purification of tumor mitochondrial malic enzyme by specific ligand affinity chromatography. 213 36

The early events in the infection of human rectal tumor cells by bovine coronavirus were investigated by colloidal gold-mediated immunoelectron microscopy and by analysis of the effect of lysosomotropic weak bases on virus yield. Electron microscopic studies revealed sites of fusion between the virus envelope and the plasmalemma but fusion events along intracellular membranes were not observed despite extensive searches. Virion-antibody-colloidal gold complexes were, in fact, endocytosed by synchronously infected cells. These complexes were apparently non-infectious, and they accumulated in vacuoles that resembled secondary lysosomes. Exposure of cells to ammonium chloride or to methylamine during the first hour of infection had little inhibitory effect on the production of infectious virus. Chloroquine treatments were inhibitory but this effect depended on relatively late events in the infectious process. The chloroquine inhibitory step blocked infection of virus absorbed to cells that were exposed to buffers in the pH range of 4.4 to 8.4. These findings indicate that BCV penetrates its host cell by direct fusion with the plasmalemma and does not require an acidic intracellular compartment for infectious entry.
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PMID:Initial events in bovine coronavirus infection: analysis through immunogold probes and lysosomotropic inhibitors. 217 24

Immune complexes (ICs) were recovered from the ascites of a patient with stage IV endometrioid ovarian cancer by sequential precipitation with 33% saturated ammonium sulfate and 2.5% polyethylene glycol 6000 (PEG 6000), followed by affinity chromatography on protein A-Sepharose CL-4B. The IgG-containing ICs were dissociated using 8 M urea, separated by ion-exchange chromatography on Sephadex QAE-50, and subsequently analyzed for purity by immunoelectrophoresis (IEP) and radial immunodiffusion (RID). Recovered antibody was tested for reactivity by immunohistologic techniques against paraffin-embedded tumor tissue and acetone-fixed cell suspensions of epithelial tumors. The antibody which demonstrated ovarian cancer-associated activity was absorbed with antigen extracts of breast, colon, and lung cancers as well as keratin to reduce cross-reactivity. The absorbed endometrioid ovarian cancer-associated antibody (OCAAb) was used to produce an immunoadsorbent column for the recovery of tumor-associated antigens. A mouse monoclonal antibody designated FEN-1 was produced using this antigen-containing fraction, and preliminary screening has demonstrated ovarian tumor-associated reactivity. The use of autologous ICs as reagents for preparing tumor antigen-rich immunogens may provide a valuable tool in the search for tumor-associated antigens.
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PMID:Ovarian cancer-associated antibodies recovered from ascites: their use for the isolation of ovarian cancer-associated antigen to produce monoclonal antibodies. 218 6

It has long been known that complex interactions occur between tumors and normal host immune cells. The human melanoma cell line A375 has been used previously as an indicator cell for tumor cell cytotoxicity mediated by monocytes. During other studies on this tumor cell line, we noted that the conditioned media harvested from A375 cultures induced both the human monocytoid cell line U937 and human blood monocytes to release the cytokine tumor necrosis factor (TNF). We characterized this tumor factor which induced TNF release by monocytic cells. Purification was performed using ammonium sulfate precipitation, ion exchange (DEAE) chromatography, gel filtration, and reversed-phase high performance liquid chromatography. The factor copurified with granulocyte-macrophage colony-stimulating factor (GM-CSF). The purified material caused the release of TNF by U937 cells and stimulated formation of granulocyte-macrophage colonies in methyl cellulose. TNF release by U937 cells in response to A375-conditioned medium was inhibited by neutralizing antibodies to GM-CSF. The TNF-inducing activity in A375-conditioned medium was completely removed by an anti-GM-CSF affinity column. Western blotting using antibodies to GM-CSF confirmed a single Mr27,000 band in A375-conditioned medium. We found that recombinant human GM-CSF stimulated TNF production by the same cells as the tumor-conditioned medium. These data show that A375 human melanoma cells produce GM-CSF, which in turn causes TNF production by cells in the monocyte lineage. The combination of GM-CSF production by the tumor and TNF production by immune cells may influence not only tumor growth but also some of the paraneoplastic syndromes associated with malignancy such as hypercalcemia, cachexia and leukocytosis.
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PMID:Stimulation of tumor necrosis factor release from monocytic cells by the A375 human melanoma via granulocyte-macrophage colony-stimulating factor. 218 30


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