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)

Prostaglandin E2 (PGE2) release from primary cultures of mouse epidermal cells was markedly stimulated by 12-O-tetradecanoylphorbol-13-acetate (TPA), mezerein and 1-oleoyl-2-acetyl-glycerol but not by 4 alpha-phorbol-12,13-di-decanoate in low Ca2+ (50 microM) medium. TPA-evoked PGE2 release was inhibited by mepacrine, indomethacin and H-7 but not by HA1004. These findings suggest that TPA stimulates PGE2 release through activation of protein kinase C, phospholipase A2 and the cyclooxygenase pathway. Of the non-TPA type of tumor promoting agents, i.e. anthralin, chrysarobin, 7-bromomethylbenz[a]anthracene, benzoylperoxide, okadaic acid and palytoxin, only anthralin stimulated PGE2 release. Anthralin-evoked PGE2 release was not inhibited by H-7. In normal Ca2+ (1.8 mM) medium, PGE2 release increased markedly compared to the release in low Ca2+ medium. In normal Ca2+ medium, PGE2 release was stimulated by TPA, anthralin and okadaic acid but not by other tumor promoting agents. In mouse peritoneal macrophages, TPA, palytoxin and okadaic acid stimulated PGE2 release, but other tumor-promoting agents failed to stimulate it. These results suggest that skin tumor promoting agents are not necessarily effective stimulators of prostaglandin production either in macrophages or in epidermal cells, the target cells of skin tumor promotion.
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PMID:Differential effects of various skin tumor-promoting agents on prostaglandin E2 release from primary cultures of mouse epidermal cells. 211 11

We demonstrated recently that the production of tumor necrosis factor (TNF) is induced in normal mice and in the immunosuppressed nude mouse model by the administration of muramyl dipeptide (MDP) derivatives followed by endotoxin (lipopolysaccharide). In the present study, the ability of this treatment to induce the production of TNF in mice receiving cyclophosphamide (CY) was examined. Two days following treatment with high-dose CY (250 mg/kg), mice exhibited leukocytopenia and drastically reduced splenic weight. However, these animals remained capable of producing TNF, albeit at lower levels, when treated with MDP derivatives and lipopolysaccharide (LPS), particularly when the lipophilic analogue MDP-dipalmitoyl glycerol (GDP) was utilized. TNF was also induced by the administration of MDP-GDP and LPS to Meth A sarcoma-bearing mice treated with this dose of CY. Furthermore, in all animals receiving this combination therapy, sarcoma necrosis and complete regression were obtained without any sign of tumor regrowth. A dose of 100 mg/kg CY was not effective for inhibiting tumor regrowth under the same experimental conditions. These results demonstrated that the anti-tumor activity of endogenously induced TNF is potentiated by combined therapy with a high dose of CY.
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PMID:Production and enhanced anti-tumor activity of tumor necrosis factor in mice treated with cyclophosphamide. 212 96

The tumor-promotor phorbol dibutyrate (PDBt) increases the binding of a neoglycoprotein containing mannose 6-phosphate (Man6P) and of insulin-like growth factor II (IGF-II) to the Man6P/IGF-II receptor at the cell surface. This effect is dependent on time and concentration and is also seen with synthetic 1-oleoyl-2-acetyl-sn-glycerol, but not with 4 alpha-phorbol, an inactive tumor-promoter. The increase is due to a 3-4-fold increase in the number of cell-surface, receptors, accompanied by a 1.6-fold increase in ligand-binding affinity. The internalization rate of the Man6P/IGF-II receptor is not affected by PDBt, suggesting that the redistribution of these receptors to the cell surface is due to an accelerated externalization rate. The redistribution of Man6P/IGF-II receptors did not impair the sorting of newly synthesized Man6P-containing ligands while uptake of these ligands is 2-4-fold increased. Inactivation or down regulation of protein kinase C decreased the binding of the Man6P-containing neoglycoprotein to 65% of controls. Incubation of cells with Man6P, IGF-I, IGF-II or epidermal growth factor induces a rapid redistribution of Man6P/IGF-II receptors to the plasma membrane [Braulke, T., Tippmer, S., Neher, E. & von Figura, K. (1989) EMBO J. 8, 681-686]. Incubation with PDBt prevented the effect of growth factors but not that of Man6P on receptor redistribution. Inactivation of protein kinase C did not affect the Man6P/IGF-II receptor redistribution induced by Man6P and growth factors. These data suggest that Man6P, growth factors and activation of protein kinase C by phorbol esters and diacylglycerols modulate Man6P/IGF-II receptor cell-surface binding by at least two independent mechanisms, receptor redistribution as well as an increase of binding affinity, which might be involved in regulation of endocytosis of ligands.
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PMID:Regulation of mannose 6-phosphate/insulin-like growth factor II receptor distribution by activators and inhibitors of protein kinase C. 216 60

Phosphorylations of two proteins (27 KDa, 32 KDa) in oat cells were dependent on phytochrome action. To determine which kinase system(s) for the phosphorylation of these two proteins are controlled by the phytochrome, involvement of the Ca2+/DG dependent protein kinase (protein kinase C) was first investigated. When a protein kinase C inhibitor (1-(5-isoquinoline sulfonyl)-2-methylpiperazine:H-7) or the inositol phospholipid metabolic blocker Li+ was added into the cell suspension, respectively, the phosphorylations of these two proteins were substantially reduced. On the other hand, an addition of 1-oleoyl-2-acetyl-sn-glycerol (OAG:activator of protein kinase C) or phorbol 12-myristate 13-acetate (TPA: tumor promoting phorbol ester) enhanced the phosphorylations of these proteins. These results suggest that phytochrome action is certainly connected with the protein phosphorylation via the activation of protein kinase C or a similar molecule with protein kinase C.
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PMID:Intracellular protein phosphorylation in oat (Avena sativa L.) protoplasts by phytochrome action: involvement of protein kinase C. 216 31

Metabolism of inositol phospholipids and phosphatidylcholine was investigated in tracheobronchial epithelial cells exposed to mitogenic concentrations of crocidolite asbestos. Alterations in levels of diacylglycerol, the endogenous activator of protein kinase C, and inositol polyphosphates, presumed mobilizers of intracellular calcium, were examined. Cultures labeled with [3H]glycerol and exposed to proliferative concentrations of crocidolite asbestos demonstrated significant elevations in [3H]diacylglycerol. In contrast, crocidolite-exposed cells labeled with [3H]myristic acid or [3H]choline did not display elevated production of [3H]diacylglycerol or release of [3H]choline metabolites--i.e., evidence of phosphatidylcholine hydrolysis. The soluble tumor promoter phorbol 12-myristate 13-acetate catalyzed both of these changes. myo-[3H]Inositol-labeled cells exposed as briefly as 10 min to mitogenic concentrations of crocidolite demonstrated elevations in [3H]inositol mono-, tris-, and terakisphosphates, phenomena indicating turnover of inositol phospholipids. The detection of diacylglycerol and inositol phosphates in crocidolite asbestos-exposed cells suggests that this fibrous tumor promoter activates phospholipase C as it stimulates cellular proliferation.
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PMID:Hydrolysis of inositol phospholipids precedes cellular proliferation in asbestos-stimulated tracheobronchial epithelial cells. 217 Sep 75

We evaluated the entrapment of 21 different water-insoluble aglycones or anthracycline antibiotics in multilamellar liposomes composed of dimyristoyl phosphatidyl choline and dimyristoyl phosphatidyl glycerol at a 7:3 molar ratio. The drug:lipid weight ratio was 1:15 to 1:50. The different analogues tested were modified at position 4 in the aglycone portion (4-demethoxy) and/or positions 2' (halo), 3' (hydroxy, acetoxy), or 4' (epi, acetoxy) in the sugar portion. The entrapment efficiency was assessed by measuring the amount of free drug remaining in the supernatant after centrifugation of the liposomes and by direct examination of the pellets by fluorescent microscopy. Optimal entrapment (greater than 98%) was observed with only four compounds: 4-demethoxyadriamycinone; 2'-iododaunorubicin; 4-demethoxydaunorubicin; and 2'-iodo-3'-hydroxy-4'-epi-4-demethoxydoxorubicin (Compound 22). All other compounds showed significant drug precipitation outside the multilamellar vesicles when observed by fluorescent microscopy. Compound 22, entrapped in liposomes, was evaluated in vivo against i.p. L-1210 leukemia by the i.p. route, and liver metastases of M5076 reticulosarcoma by the i.v. route. In both models, liposome-entrapped Compound 22 was more active than doxorubicin at the optimal dose [median survival (given in percentage) of treated to control animals was for L-1210, greater than 600 versus 212; for M5076, 200 versus 133]. 4-Demethoxy and 2'-iodo are structural modifications that markedly enhance the affinity of anthracycline antibiotics for lipid bilayers without compromising biological activity. These findings will serve as a guideline to obtain liposome-anthracycline preparations, with optimal formulation characteristics, enhanced tumor-targeting properties, and non-cross-resistance with doxorubicin.
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PMID:Anthracycline antibiotics with high liposome entrapment: structural features and biological activity. 219 51

Some synthetic alkyl-lysophospholipid analogs have been described as a new class of immunopotentiating and antitumor agents. Among them, 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine has been reported to possess the highest antitumor activity. A new method for the synthesis of this compound and of the ethanolamine- and serine-containing analog is reported. 1-Alkyl-2-methyl-rac-glycerol, prepared from 1,2-isopropylidene-glycerol, is phosphorylated and the intermediate is condensed either with N-t-BOC-protected ethanolamine or with N-t-BOC-protected serine benzhydryl ester. The choline-derivative is obtained by methylation with CH3I of the ethanolamine derivative. The same synthetic sequence has been used also for synthesizing compounds unsaturated at the fatty alkyl chain in position 1 of the glycerol moiety. Preliminary observation are reported on the selective cytolytic action of the compounds on a tumor cell line.
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PMID:Synthesis of 1-O-alkyl-2-O-methyl-glycerophospholipids with potential antitumor activity. 222 22

Whole-body lipolytic rates and the rate of triglyceride-fatty acid cycling (reesterification of fatty acids released during lipolysis) were measured with stable isotopic tracers in the basal state and during beta-adrenergic blockade with propranolol infusion in five cachectic patients with squamous cell carcinoma of the esophagus, five cachectic cancer-free, nutritionally-matched control patients, and 10 healthy volunteers. Resting energy expenditure and plasma catecholamines were normal in all three groups. The basal rate of glycerol appearance in blood in the patients with cancer (2.96 +/- 0.45 mumol.kg-1.min-1) was similar to that in the nutritionally matched controls (3.07 +/- 0.28 mumol.kg-1.min-1), but 48% greater than in the normal-weight volunteers (2.00 +/- 0.16 mumol.kg-1.min-1) (P = 0.028). The antilipolytic effect of propranolol and the rate of triglyceride-fatty acid cycling in the patients with cancer were also similar in the cachectic control group and approximately 50% greater than in the normal-weight volunteers, but the differences were not statistically significant because of the variability in the data. We conclude that the increase in lipolysis and triglyceride-fatty acid cycling in "unstressed" cachectic patients with esophageal cancer is due to alterations in their nutritional status rather than the presence of tumor itself. Increased beta-adrenergic activity may be an important contributor to the stimulation of lipolysis.
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PMID:Whole-body lipolysis and triglyceride-fatty acid cycling in cachectic patients with esophageal cancer. 224 20

Effects of the tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), on expression of pulmonary surfactant proteins, SP-A and SP-B, were determined in a human pulmonary adenocarcinoma cell line (H441-4). TPA decreased cellular SP-A content in association with decreased de novo synthesis of SP-A as assessed by [35S]methionine incorporation. Effects of TPA were time (0-72 h) and dose (IC50 0.5-1.0 nM)-dependent. Phorbol 12,13-dibutyrate (PDBu), and adenosine 5'-O-(3-thiotriphosphate), and 1-oleoyl-2-acetyl-sn-glycerol also decreased SP-A content in these cells. Characteristics of inhibition of SP-A content by PDBu were similar to those of [3H]PDBu binding to H441-4 cells. Inhibitory effects of TPA on SP-A synthesis were associated with concomitant decreases in SP-A mRNA. Expression of a distinct surfactant protein, SP-B, was also markedly decreased after exposure to TPA. SP-A and SP-B mRNA contents decreased more rapidly after treatment with TPA than after actinomycin D. Actinomycin D completely blocked the rapid decrease in SP-A and SP-B mRNAs caused by the phorbol ester, consistent with the concept that the inhibitory effect of TPA on the surfactant protein mRNAs required continued gene transcription and was not mediated solely by changes in SP-A or SP-B transcription. Inhibitory effects of phorbol esters on SP-A and SP-B synthesis support the concept that protein kinase C modulates surfactant protein expression in this cell.
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PMID:Phorbol ester inhibits surfactant protein SP-A and SP-B expression. 224 89

The action of 15 chemicals, being tumor-promoters and/or inhibitors of cell-to-cell communications in vitro upon electric relations between giant cells of salivary gland of the Chironomus tentans larvae are studied. It is shown that out of 11 compounds disturbing the intercellular contacts in this model, 10 chemicals are tumour-promoters (Aroclor 1254, butylated hydroxytoluene, di(ethylhexyl)phthalate, DDT, deoxycholic acid, lithocholic acid, oleic acid, anthralin, iodine-acetate, tween-80) and 1 compound (oleoyl-acetyl-glycerol) is not studied for the promoting activity. At the same time, two other tumor-promoters (phenobarbital and TPA) as well as two nontumor-promoters (phorbol and chlorpromazine) do not influence the electric relations. The possibilities of using the developed test-system for the screening of the tumour-promoters are discussed.
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PMID:[Effects of tumor promoters and related compounds on electric relations between giant cells of the salivary glands of Chironomus tentans larvae]. 229 38


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