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)

The administration of murine monoclonal antibodies (MAbs) induces, in many patients, an immunological response represented by the development of human anti-mouse antibodies (HAMA). HAMA have been previously shown to interfere in some assays for the detection of CEA, as well as other non tumor related analytes. The present study was performed to determine whether the CA 72-4 assay is affected by the presence of HAMA, and to establish conditions capable of overcoming this artifact. Serum samples obtained from 8/9 patients entered into a therapeutic protocol using 131I-labeled MAb B72.3 showed the development of apparently high levels of TAG-72 during the clinical follow-up concurrent with the appearance of elevated titers of HAMA. Heat treatment at 90 degrees C at pH 5.0 sodium acetate, previously reported as a method of abolishing HAMA interference without affecting CEA levels, resulted in a considerable loss of detectable TAG-72. However, treatment of these samples at 90 degrees C in pH 6.5 Bis Tris abolished the artifact due to HAMA and resulted in the reversion of reported TAG-72 levels to those observed prior to any MAb administration. As the use of murine MAbs, for both diagnostic and therapeutic applications continues to expand, the identification of this artifactual increase in reported antigen levels due to the development of HAMA has become an important factor in the use of tumor markers, e.g. TAG-72 and CEA, in the follow-up of carcinoma patients.
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PMID:Potential for artifacts in monitoring for the detection of tumor associated antigens (TAG-72 and CEA) in serum from patients undergoing MAb-based diagnostic and therapeutic protocols. 209 32

ATP and ADP, in concentrations ranging from 1-100 microM, increased the release of [3H]choline and [3H]phosphorylcholine (P-choline) from bovine aortic endothelial cells (BAEC) prelabelled with [3H]choline. This action was detectable within 5 minutes and was maintained for at least 40 minutes. ATP and ADP were equiactive, and their action was mimicked by their phosphorothioate analogs (ATP gamma S and ADP beta S) and adenosine 5'-(beta, gamma imido) triphosphate (APPNP), but not by AMP, adenosine, and adenosine 5'-(alpha, beta methylene)triphosphate (APCPP): these results are consistent with the involvement of P2Y receptors. ATP also induced an intracellular accumulation of [3H]choline: the intracellular level of [3H]choline was increased 30 seconds after ATP addition and remained elevated for a least 20 minutes. The action of ATP on the release of choline metabolites was reproduced by bradykinin (1 microM), the tumor promoter phorbol 12-myristate 13-acetate (PMA, 50 nM), and the calcium ionophore A23187 (0.5 microM). Down-regulation of protein kinase C, following a 24-hour exposure of endothelial cells to PMA, abolished the effects of PMA and ATP on the release of choline and P-choline, whereas the response to A23187 was maintained. These results suggest that in aortic endothelial cells, ATP produces a sustained activation of a phospholipase D hydrolyzing phosphatidylcholine. The resulting accumulation of phosphatidic acid might have an important role in the modulation of endothelial cell function by adenine nucleotides. Stimulation of phospholipase D appears to involve protein kinase C, activated following the release of diacylglycerol from phosphatidylinositol bisphosphate by a phospholipase C coupled to the P2Y receptors (Pirotton et al., 1987a).
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PMID:Adenine nucleotides modulate phosphatidylcholine metabolism in aortic endothelial cells. 210 83

PMA causes rapid down-modulation of CD4 molecules on murine immature thymocytes, human PBL, and CD4-positive human tumor cell lines, but not on murine peripheral lymphocytes. The mechanisms of phorbol ester-induced down modulation of CD4 molecules, however, have not been elucidated. To determine how PMA down-modulates CD4 expression by T lymphocytes, we studied the ability of inhibitors of protein kinase C, calmodulin, actin, and tubulin to block PMA-induced modulation of CD4 in several murine and human cell types. We also tested the ability of intracellular and extracellular calcium chelators to block CD4 internalization. There was marked variability in the degree of PMA-induced down-modulation of CD4 among various cell types. The effects of PMA on CD4 expression were greater for murine thymocytes, for human PBL, and for the human lymphoblastic leukemia cell line, MOLT-3, than for any of the other cell types studied. The protein kinase C inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine, blocked phosphorylation but not internalization of CD4 molecules induced by PMA. Therefore, phosphorylation of CD4 molecules by protein kinase C is not required for the internalization of the molecules. Internalization was blocked by both inhibitors of calmodulin, N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide, and trifluoperazine. PMA-induced internalization of CD4 was blocked by Quin-2 AM, which chelates intracellular calcium. EGTA, which chelates extracellular calcium, did not block internalization. Inhibitors of actin or tubulin did not block internalization. These results suggest that PMA-induced modulation of CD4 can occur in the absence of phosphorylation of the CD4 molecules and is calmodulin and intracellular calcium dependent.
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PMID:Phorbol myristate acetate-induced down-modulation of CD4 is dependent on calmodulin and intracellular calcium. 210 10

The murine macrophage tumor lines, P388D1 and J774A.1 were stimulated with LPS, IL-6, IL-1 alpha, TNF-alpha, IFN-gamma, PMA, or combinations of these reagents to induce the production of IL-6, IL-1, and TNF-alpha. Using Northern blot analysis and bioassays for the detection of cytokine production, it was noted that identical stimuli induced all three inflammatory mediators. However, unlike fibroblasts or endothelial cells, neither P388D1 nor J774A.1 macrophages respond to IL-1 alpha or TNF-alpha by producing IL-6. The results imply that these cytokines are not autoregulatory for macrophages and may be tissue-specific in their stimulatory effects. IFN-gamma and PMA synergize with LPS in the production of IL-6 as well as IL-1 and TNF-alpha. These observations suggest that IFN-gamma may mediate amplification pathways important in the production of inflammatory mediators. Kinetic studies on the transcription of mRNA and secretion of IL-6, IL-1, and TNF-alpha revealed that TNF-alpha mRNA transcription and cytokine production occur very rapidly. TNF-alpha mRNA accumulation peaked 1-2 hr after stimulation and maximum concentrations of cytokine are found in supernatants collected after 2-4 hr of culture. IL-6 and IL-1 alpha mRNA accumulation peaked simultaneously after 4-8 hr. However, IL-6 bioactivity peaks between 8 and 12 hr whereas maximum concentrations of IL-1 bioactivity are not detected in supernatants from stimulated cells collected prior to 12 hr of culture. Thus even though TNF-alpha production precedes that of IL-1 and IL-6, and stimulates IL-6 production in fibroblasts, there is no evidence that TNF-alpha acts to amplify the production of IL-6 or IL-1 by murine macrophage cell lines. The results suggest differential regulation of IL-6 expression between fibroblasts and macrophages.
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PMID:Interleukin-6 production by murine macrophage cell lines P388D1 and J774A.1: stimulation requirements and kinetics. 211 31

Macrophages in varying states of activation differ in their ability to perform antibody-dependent cellular cytotoxicity (ADCC). To define further the activation requirements for macrophages to perform cytolytic functions, we stimulated peptone-elicited peritoneal macrophages, which exhibit only a low level of ADCC, with a panel of cytokines and then assayed for the macrophages capacity to effect the rapid and slow forms of ADCC, to bind antibody-coated tumor cells, and to secrete H2O2 in response to immune complex or PMA. All four cytokine preparations, at optimal conditions, enhanced both forms of ADCC, but did not appreciably increase tumor cell binding. Three of the four cytokine preparations (Il-4, TNF and IFN-alpha/beta), however, increased the macrophages capacity to secrete H2O2 in response to either immune complex or PMA, IFN-gamma alone did not affect H2O2 secretion.
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PMID:Cytokine stimulation of antibody-dependent cellular cytotoxicity (ADCC) enhances cytolytic but not binding capacity of peritoneal macrophages. 211 20

The level of Ca2+, phospholipid-dependent, protein kinase C (PKC) activity in murine peritoneal macrophages treated with swainsonine, an indolizidine alkaloid, has been investigated. The present studies are based on our recent report that murine peritoneal macrophages are activated by swainsonine (Grzegorzewski, K.; Newton, S.A.; Akiyama, S.K.; Sharrow, S.; Olden, K.; White, S.L., Cancer Commun. 1:373-379, 1989). Presently, we have demonstrated that macrophages treated with swainsonine exhibited a substantial increase in PKC activity. The activity was enhanced as much as 4- to 5-fold over that obtained in untreated macrophages and was inhibited by H-7 (1-[5-isoquinoline sulphonyl]-2-methylpiperazine), D-sphingosine, or a monoclonal antibody specific for the active site of PKC. This represents the first report to demonstrate an effect of swainsonine on a second messenger system known to be involved in tumor promotion and macrophage activation. Elevation of PKC activity occurred much more slowly in swainsonine-treated cells than in cells treated with agents known to activate PKC directly, e.g., PMA (4-beta-phorbol-12-beta-myristate-13-gamma-acetate) or gamma-interferon (IFN-gamma). Furthermore the increase in PKC activity was inhibited by alpha-amanitine and cycloheximide, inhibitors of RNA and protein synthesis, respectively. These results suggest that swainsonine enhancement of PKC activity occurred by an indirect and possibly protein-synthesis-dependent mechanism. Whatever its precise mechanism of action, swainsonine provides a potentially important new probe to evaluate PKC mediated events. Selective enhancement of PKC activity may be important not only in elucidating the role of PKC in tumor promotion or macrophage activation but, also, in contributing to development of therapeutic regimens.
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PMID:Swainsonine modulation of protein kinase C activity in murine peritoneal macrophages. 211 76

Ornithine decarboxylase (ODC) activity increases by 2 times in the process of progesterone-induced Bufo oocyte maturation (Table 1). Tumor promotor phorbol ester (PMA) is unable to affect both basal and stimulated ODC activity (Fig. 5) although it is capable of elevating the rate of steroid-induced maturation (Fig. 4). Spermine can inhibit significantly ODC activity of oocytes (Fig. 3). Hormone-stimulated ODC activity falls by 17% when Bufo oocytes are cultured in the alkaline Ringer's solution containing 5 mM spermine (pH 11.6) (Fig. 2). The period, however, is shortened by more than 50% during which the oocytes undergo GVBD (Fig. 1). Otherwise, spermine is found to repress ODC activity in dose dependent manner when microinjected in Bufo oocytes (Fig. 3). But oocytes undergo GVBD with a frequency of more than 80% when progesterone-induced increment of the enzyme activity is totally inhibited in the oocytes injected with approximately 50 nl 4.0 mM spermine. The conclusion may emerge from the above-stated results that increased ornithine decarboxylase activity is not essential for progesterone-induced Bufo oocyte maturation. In addition, ODC activity begins to increase rapidly when endogenous spermine level has been lowered to the largest extent in the maturation process. Therefore the endogenous spermine probably acts as a physiologically negative regulator of ODC activity since exogenous spermine inhibits seriously ODC activity of Bufo oocytes.
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PMID:[Increased ornithine decarboxylase activity is not essential for progesterone-induced Bufo oocyte maturation]. 212 37

CD43 is a constitutively phosphorylated 115-kDa sialoglycoprotein expressed on a variety of blood cells including lymphocytes and monocytes. L10, a mAb directed against CD43, triggers T cell activation and enhances hydrogen peroxide production in monocytes. Activation of mononuclear cells by L10 initiates phosphoinositides hydrolysis, C2+ mobilization, and protein kinase C (PKC) activation. In turn, activated PKC hyperphosphorylates CD43, suggesting a potential role for PKC in the regulation of signaling via CD43. To address this issue, we have analyzed the effect of PKC activation by the tumor promoter PMA on L10-triggered rise in intracellular free Ca2+ concentrations ([Ca2+]i). Treatment of mononuclear cells with PMA profoundly inhibited the increase in [Ca2+]i induced by L10. The inhibition of CD43-mediated signaling by PMA was due, in part, to uncoupling of CD43 from the signal-transducing G protein. This was evidenced by the comparatively modest inhibition by PMA of the increase in [Ca2+]i induced by the direct G protein activator AlF4-. PMA treatment did not affect the surface expression of CD43. However, it induced the hyperphosphorylation of CD43, the extent of which correlated with the inhibition of CD43-mediated increase in [Ca2+]i. Staurosporine, a potent inhibitor of PKC, abrogated the hyperphosphorylation of CD43 and normalized CD43-mediated signaling in PMA-treated cells. Significantly, in the absence of PMA, staurosporine enhanced the rise in [Ca2+]i triggered by L10, suggesting that engagement of CD43 by activating ligands results in feedback inhibition by PKC. It is concluded that activation of PKC inhibits signaling via CD43 by mechanisms involving phosphorylation and uncoupling of CD43 from the signal-transducing apparatus and by distal, post-receptor events.
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PMID:Signal transduction via leukocyte antigen CD43 (sialophorin). Feedback regulation by protein kinase C. 213 93

The GL183 mAb was obtained by immunizing BALB/c mice with the E57 clone (CD7+CD2+CD3-CD16+CD56+) derived from human peripheral blood NK cells. In human peripheral blood, GL183-reactive cells ranged between 2 and 12% (mean 6.5%) in 10 different donors. Double fluorescence and FACS analysis showed that GL183+ cells were consistently included in the CD56+ or CD16+ cell populations. Moreover, since only a fraction of CD56+ or CD16+ cells (approximately 40%) coexpressed GL183 surface antigen, reactivity with GL183 mAb appears to define two subsets within the CD3- lymphocyte population expressing NK cell markers. Although, the majority of GL183+ cells were CD3-, approximately 1% expressed CD3 surface antigens. As shown by clonal analysis, these infrequent CD3+GL183+ cells coexpressed CD56 and CD16 antigens. Cloning of CD3-GL183+ or CD3-GL183- cell populations under limiting dilution conditions yielded clonal progenies that maintained their original surface phenotype. Therefore, expression or lack of expression of GL183 surface antigens represents a stable phenotypic property of a subset of human CD3- NK cells. Immunoprecipitation experiments and two-dimensional PAGE analysis indicated that GL183-reactive molecules were represented in different clones either by a single 58-kD chain or, more frequently, by two chains of approximately 55 and approximately 58 kD, respectively. Analysis of GL183+ or GL183- NK clones for their ability to lyse human (IGROV I) or murine (P815) tumor target cells indicated that GL183- clones were, on average, fivefold more efficient in inducing target cell lysis. GL183+ and GL183- clones produced comparable levels of TNF-alpha in response to PHA plus PMA or anti-CD16 mAb plus PMA. Importantly, production of TNF-alpha was also induced by stimulation of GL183+ clones with GL183 mAb plus PMA. These data indicated that GL183 antigen could mediate cell triggering. This concept was confirmed by the analysis of Ca2+ mobilization, as GL183 mAb induced (in GL183+ clones) increments of [Ca2+]i comparable with those induced by PHA. Moreover, GL183 mAb, or its F(ab')2 fragments, strongly enhanced the cytolytic activity of GL183+ clones against a panel of human tumor target cells, including U937, Raji, IGROV I, M14, and A549. In contrast, GL183 mAb, but not the F(ab')2 fragments, sharply inhibited the cytolytic activity of the same clones against P815, M12, and P3U1 murine target cells. In this case, the effect of GL183 mAb (inhibition) was opposite that of PHA or of stimulatory anti-CD2 or anti-CD16 mAbs, which consistently enhanced the target cell lysis.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:A novel surface antigen expressed by a subset of human CD3- CD16+ natural killer cells. Role in cell activation and regulation of cytolytic function. 213 55

T cell lines with a novel phenotype (CD3+ TCR-alpha/beta+ CD4- CD8-) were developed from the peripheral blood of a patient with a combined immunodeficiency and tissue injury resembling graft-vs-host disease. One of these IL-2-dependent T cell lines demonstrated non-MHC-restricted cytolytic function against tumor targets, syngeneic and allogeneic fibroblasts, and PHA blasts from allogeneic donors. The other cell line only became cytotoxic in the presence of lectin or anti-CD3 antibody. The two cell lines also differed in their expression of the T-200 gene products CD45RO (gp180) and CD45RA (gp220). Both cell lines produced tumor necrosis factor-alpha and -beta and IFN-gamma activity when activated with mitogens or PMA and IL-1. The in vitro functions of these T-cell lines suggest a potential role for alpha/beta double-negative T lymphocytes in tissue injury resembling graft-vs-host disease.
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PMID:Double-negative (CD4- CD8-) T cells with an alpha/beta T cell receptor. Non-MHC-restricted cytolytic activity and lymphokine production. 214 Oct 37


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