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)

Antibody-dependent cellular cytotoxicity (ADCC) against Raji cells was used as a model system to investigate the polymorphonuclear leukocyte (PMN) mechanisms involved in tumor cell lysis. PMN killed target cells by nonoxidative means, as indicated by the following observations: PMN from patients with chronic granulomatous disease (CGD), defective in their metabolic burst, lysed Raji cells normally; impairment of the oxidative metabolism of normal PMN by phenylbutazone did not affect ADCC. Rosenthal's inhibitor of phospholipase A2 completely prevented the lysis, suggesting the involvement of this enzyme in the target cell damage. The inhibition of the Raji cell glutathione redox cycle by carmustine [1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU)] increased cell susceptibility to PMN-mediated ADCC. This increment of lysis was related to oxidative killing systems. In fact, CGD PMN had an ADCC against BCNU-treated Raji cells lower than that mediated by normal PMN, but comparable to that observed with untreated targets, and phenylbutazone reduced the lysis of BCNU-treated Raji cells by normal PMN to the level observed with the use of untreated targets. The remaining ADCC against BCNU-treated Raji cells mediated by CGD PMN and by normal PMN in the presence of phenylbutazone was suppressed by Rosenthal's inhibitor. Thus PMN killed sensitized BCNU-treated Raji cells by use of both oxidative and nonoxidative means. The results indicate that the interaction of sensitized Raji cells with PMN triggers simultaneously oxidative and non-oxidative potentially lytic systems and the mediator(s) of Raji cell lysis actually operating may depend on the metabolic state of the target cells themselves. Therefore, the lysis of sensitized tumor cells might not reflect the simple effect of PMN tumoricidal systems; rather it should be regarded as a result of an inability of the target cells to escape the various PMN cytolytic mechanisms.
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PMID:Antibody-dependent killing of tumor cells by polymorphonuclear leukocytes. Involvement of oxidative and nonoxidative mechanisms. 620 10

Natural killer (NK) cells in the human are a population of large granular lymphocytes (LGL) with at least one unique surface antigen not expressed on cells of other lineages. NK-target-cell interaction appears to involve carbohydrate recognition and, following binding, the NK cells are induced to generate O2-, transmethylate membrane phospholipids, and activate phospholipase A2. Some or all of these activities trigger a cascade of events which ultimately leads to the secretion of a substance toxic to the target cell. A variety of genes controls various steps in this cytolytic pathway. There is a good deal of evidence in the mouse, and some in the human, that NK cells play a role in host surveillance against tumor development, resistance to viral infections, and, possibly, hematopoietic regulation.
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PMID:The biology of the human natural killer cell. 629 59

Natural killer (NK) cell-mediated cytotoxicity, as measured by the lysis of the human erythroleukemic cell line K562, is inhibited by the glucocorticosteroid dexamethasone (DEX). Kinetic analysis revealed that DEX inhibits an early event(s) in the lytic mechanism and that the inhibition is both transient and readily reversible if DEX is removed. The inhibition is not due to the production of a DEX-induced inhibitory protein or decreased target-cell binding. Attempts to counter the effects of DEX through the addition of inducers of NK activity were unsuccessful. Neither the calcium ionophore A23187 nor exogenous cyclic GMP was able to reverse the inhibition by DEX. The addition of arachidonic acid (AA), a pharmacologically active metabolite of phospholipase A-2 activation, was also unsuccessful in reversing the effects of DEX. In fact, AA itself inhibited NK activity in a dose-dependent fashion. This inhibition was not due to reduced target binding and was observed even in the presence of indomethacin. It is concluded that DEX blocks an early membrane-signaling event necessary to activate the lytic mechanism and that inhibition was not through some alternative mechanism. Inhibition of NK activity by arachidonic acid is not yet understood but most likely is not a result of enhanced prostaglandin synthesis. Hence, the study of DEX and AA inhibition provides a new approach to unravel some of the intricacies surrounding NK-mediated tumor target destruction.
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PMID:Studies on the mechanism of human natural killer cell-mediated cytolysis. I. Modulation by dexamethasone and arachidonic acid. 630 3

PGE2 overproduction by a nephroblastoma associated with hypercalcemia was clearly demonstrated in a 2-month-old girl. Compared with normal tissue, tumor showed greater phospholipase A2 and PGE2 synthetase activities but metabolized PGE2 at a faster rate. Of the enzymes involved in PGE2 synthesis, those which transform arachidonic acid into PGE2 seem to be more active.
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PMID:Synthesis and catabolism of PGE2 by a nephroblastoma associated with hypercalcemia without bone metastases. 633 25

Phospholipase A2 was localized with peroxidase anti-peroxidase (PAP)-technique in pancreatic tissue resected from normal portions of tumor-bearing glands of 4 patients and from pancreases of 16 patients suffering from either acute or chronic pancreatitis. In acute pancreatitis the enzyme immunoreactivity was detected in the apical zymogen granule portion of acinar cells and in ductal secretory material similarly as in normal tissue. At the border of necrotic and non-necrotic exocrine parenchyma the staining reaction was evenly dispersed throughout the cytoplasm or localized in small cell fragments. There was no reaction in necrotic acinar cell remnants. Some dilated acinar lumina contained intensively stained plugs. Fat necroses were stained but surrounding neutrophil leukocytes were unstained. Thrombosed small vessels were also unstained. In chronic pancreatitis, diminished staining characterized small acinar cells at the border of lobules. Some macrophages stained positively. It was concluded that during acute inflammation in pancreas, localization of phospholipase A2 in pancreatic tissue is abnormal, and that phospholipases A2 of neutrophil leukocytes and platelets are not crossreactive with the secretory enzyme.
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PMID:Immunohistochemical localization of phospholipase A2 in human pancreas in acute and chronic pancreatitis. 634 33

Cells of a mouse macrophage-like tumor cell line, J774.2, were incubated with 0.6 microM radiolabeled mono- and di-hydroxyfatty acids. Monohydroxyfatty acid products of the neutrophil and platelet lipoxygenase pathways (5-HETE, 15-HETE, and 12-HETE) were rapidly taken up (42-64% of the counts cell associated at 1 min) and esterified into triglycerides and phospholipids. 5-HETE and 12-HETE were found in triglycerides and distributed among phospholipid classes while 50% of added 15-HETE was esterified into phosphatidyl inositol. Treatment of phospholipids from cells incubated with 5-HETE, 12-HETE, and 15-HETE with phospholipase A2 resulted in release of the respective monohydroxyfatty acid. HHT, a monohydroxyfatty acid product of the cyclooxygenase pathway, was taken up and esterified more slowly than the lipoxygenase products. In addition, HHT was not released when the phospholipids from cells incubated with HHT were treated with phospholipase A2. LTB4, a dihydroxyfatty acid product of neutrophil lipoxygenase, was not taken up by J774.2 cells. The unique patterns of uptake and intracellular distribution of the different monohydroxyfatty acids suggests that the enzymes involved in the esterification of these compounds have substrate specificity and may also relate to the specific biologic effects of these compounds.
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PMID:Esterification of monohydroxyfatty acids into the lipids of a macrophage cell line. 641 29

A tumor promoter teleocidin induced insulin secretion from isolated pancreatic islets in a concentration-dependent manner. The teleocidin-induced secretion was inhibited by p-bromophenacyl bromide, nordihydroguaiaretic acid, 3-amino-1-(3-trifluoromethylphenyl)-2-pyrazoline and 2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone, but not by indomethacin. Insulinotropic concentrations of teleocidin stimulated 6-keto-prostaglandin F1 alpha release from pancreatic islets. These results suggest that phospholipase A2 activation and lipoxygenase product(s) are involved in the mechanism of teleocidin-induced insulin secretion.
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PMID:Insulinotropic effect of the tumor promoter teleocidin in isolated pancreatic islets. 641 38

The action of the tumor promoter, phorbol 12,13-dibutyrate (PDBu), on rabbit peritoneal and human neutrophils is associated with stimulation of 14C-arachidonic acid incorporation into phospholipids within 1-2 min. Stimulated 14C-arachidonate incorporation was relatively selective for phosphatidylinositol (PI) in rabbit neutrophils. In contrast, the secretory response of human neutrophils to PDBu coincided with stimulated label incorporation into phosphatidylserine (PS), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidic acid (PA) and PI. Significant increases in label incorporation were observed with PDBu concentrations as low as 2 nM, and the dose response of stimulated label incorporation paralleled that of evoked lysozyme secretion. A parallel, but partial, inhibition of PDBu-stimulated PI labeling and enzyme release was observed after exposing rabbit neutrophils to calcium-deprived medium, whereas calcium deprivation failed to significantly depress either of these stimulant actions of PDBu in human neutrophils. Further, in rabbit neutrophils PDBu elicited an increase in cell associated 45Ca. However, PDBu was unable to promote the incorporation of 32P orthophosphate into PI or enhance phospholipase A2 activity in broken cells. These findings suggest that one expression of the interaction between phorbol esters and their receptors on neutrophils involves the turnover of arachidonic acid in phospholipids. This stimulated turnover of arachidonate may be a critical step in the cascade of events associated with neutrophil activation.
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PMID:Regulation of phosphatidylinositol turnover, calcium metabolism and enzyme secretion by phorbol dibutyrate in neutrophils. 642 67

PMNs upon stimulation by a chemoattractant adhere to a substratum and then in amoeboid fashion migrate toward the source of the attractant. We have studied molecular events in both adherence and migration and have arrived at the following conclusions: 1) PMNs, like other motile cells such as highly metastatic tumor cells, can use laminin to attach to Type IV basement membrane collagen. PMNs may use this anchoring mechanism in their emigration from the vasculature. 2) Attached cells may be stimulated to migrate as a result of the chemo-attractant-induced inactivation of lipomodulin, a natural inhibitor of phospholipase A2, an enzyme that may be essential for chemotaxis. 3) The substrate for this enzyme is generated by both the CDP-choline and transmethylation pathways. These pathways may be regulated by another enzyme, transglutaminase (TGase). 4) Natural substrates of TGase, such as uteroglobin, inhibit leukocyte chemotaxis, again suggesting a regulatory role for TGase in chemotaxis. 5) Tumor cells also produce inhibitors of chemotaxis. In addition to protecting the tumor from the host's phagocytes, these inhibitors may be related to normal modulators of cell motility. Therefore, determination of their mode of action could increase our understanding of this type of cell behavior.
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PMID:Adherence and regulation of leukotaxis. 657 14

After binding a sensitizing tumor antigen, human leukocytes undergo a series of changes that lead to a loss of their glass-adherent properties; a phenomenon called leukocyte adherence inhibition (LAI). After surgery or when patients have a large tumor burden, their test results become negative. This study shows that in vitro incubation of the leukocytes for 5 min with PGE2 converted to positive the negative test, in an immunologically specific manner. The effect was critically dose-dependent, too little or too much did not alter the result. The same effect was achieved with PGE2, PGI2, aminophylline or other drugs that raise intracellular nucleotides, including dibutyryl cyclic AMP and dibutyryl cyclic GMP. Dibutyryl cyclic AMP stimulated a stronger response and 100 times less was needed than of dibutyryl cyclic GMP. Prostaglandins did not mediate LAI since Indomethacin failed to inhibit a positive test. Nonetheless, arachidonate metabolites were critical for the LAI phenomenon since BPB and mepacrine, inhibitors of phospholipase A2, negated the LAI response. Moreover, ETYA, phenidone and NDGA, inhibitors of the lipoxygenase metabolic pathway, all negated the positive LAI response. The positive response was especially sensitive to nullification by ETYA. Although the last-named drugs inhibit other arachidonate metabolic pathways too, conclusive evidence that the metabolites of the lipoxygenase pathway, and leukotrienes in particular, mediate the LAI response was the fact that FPL 55712, a competitive antagonist of SRS, nullified a positive response at levels as low as 10(-13) M. The results imply that prostaglandins were able to modulate the expression of LAI by affecting intracellular nucleotides, but leukotrienes, it seems, were the metabolites that mediated leukocyte nonadherence after monocytes recognized and bound tumor antigen.
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PMID:Modulation of antigen-induced leukocyte adherence inhibition by metabolites of arachidonic acid and intracellular nucleotides. 675 47


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