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 tumor promoting phorbol diester, 12-O-tetradecanoyl-phorbol-13-acetate, stimulates MDCK cells to deacylate cellular phospholipids and to produce prostaglandins when measured as the release of arachidonic acid and its metabolites into the culture fluid. Indomethacin, at levels of 2.8 x 10(-8) to 2.8 x 10(-6) M, inhibits the release of radioactivity from [3H]arachidonate labeled cells stimulated by 12-O-tetradecanoyl-phorbol-13-acetate treatment in a concentration dependent manner. At these concentrations, the conversion of released [3H]arachidonic acid into prostaglandins E2 and F2alpha and the production of PGE2 measured serologically also is suppressed in a concentration dependent manner. Indomethacin, at these levels, has no effect on the acylation of [3H]arachidonic acid into cellular lipids. The tumor promoting phorbol diester does not stimulate the release of radioactive materials from MDCK cells labeled with [14C]linoleic acid, although prostaglandin production by these cells is stimulated.
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PMID:Tumor promoting phorbol diesters stimulate release of radioactivity from [3H]-arachidonic acid labeled- but not [14C]linoleic acid labeled-cells. Indomethacin inhibits the stimulated release from [3H] arachidonate labeled cells. 73 76

We have developed a sensitive immunoassay for murine calcitonin which can measure the basal concentration of the hormone in peripheral plasma of rats as well as the calcitonin, extracted from rat thyroid tissue. Human calcitonin was used for tracer, standard, and antibody production. Assay methods were devised to minimize artifacts which have been shown to spuriously influence immunoassay performance. The basal plasma concentration of calcitonin in rats was 6 to 75 pg. per milliliter. Infusions of calcium, pentagastrin, and PGE2 produced a 2- to 7-fold increase in plasma calcitonin. Elevated concentrations of calcitonin were demonstrated in tumor specimens obtained from the second and fourth generations of a transplanted rat medullary thyroid carcinoma. Our results demonstrate that calcitonin circulates in the peripheral plasma of rats in the basal state and that hormone concentrations change during functional tests of secretion. This assay will permit studies of calcitonin secretion in physiological and pathophysiological states in the rat.
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PMID:Radioimmunoassay of calcitonin in plasma, normal thyroid, and medullary thyroid carcinoma of the rat. 82 6

In rabbits bearing the prostaglandin-producing VX2 carcinoma, the plasma concentration of 13,14-dihydro-15-keto-PGE2 (PGE2-M) was elevated within one week after tumor implantation and preceded the development of hypercalcemia. Both the rate of rise and magnitude of the increase were greater for the metabolite than for PGE2; at the time of peak hyercalcemia (about 4 to 5 weeks after tumor implantation), the increase over basal in plasma PGE2-M was about 75 fold whereas it was previously shown that the increase in PGE2 was less than 2 fold. Indomethacin, which inhibits PGE2 synthesis in VX2 cells in culture, lowered in parallel plasma calcaium and PGE2-M in tumor-bearing rabbits. Administration of hydrocortisone to rabbits bearing the VX2 tumor prevented the development of hypercalcemia when given at the time of tumor implantation and reversed the elevated plasma calcium in previously untreated animals; the steroid hormone also lowered plasma concentrations of PGE2-M. These findings are consistent with our hypothesis that the hypercalcemic syndrome in VX2 tumor-bearing rabbits is due to the secretion of PGE2 by the tumor.
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PMID:Plasma concentrations of 13,14-dihydro-15-keto-prostaglandin E2 in rabbits bearing the VX2 carcinoma: effects of hydrocortisone and indomethacin. 89 22

Prostaglandin biosynthesis and metabolism were studied in the VX2 carcinoma-bearing rabbit, an animal model of prostaglandin-mediated hypercalcemia. All the identification and quantification of the prostaglandins were done by gas chromatography-mass spectrometry. The tumor incubated in vitro converted exogeneous arachidonic acid principally to PGE2. Biosynthesis from endogenous precursor lipids yields mainly PGE2 and PGF2alpha. The 100,000 x g supernatant fluid of the tumor did not contain any metabolizing enzymes. Significant hypercalcemia developed between the first and second week after tumor implantation. The levels of the major plasma metabolite of PGE2, 15-keto-13,14-dihydro-PGE2, became elevated at one week, had risen 25-fold by the end of the second week, and at the fourth week were elevated to 256 times the pre-incubation levels. The concentration of 15-keto-13,14-dihydro-PGF2alpha in plasma rose in parallell but to a lesser degree. 7alpha-hydroxy-5,11-diketotetranor-prostane-1,16-dioic acid, the major urinary metabolite of the E prostaglandins, was elevated two weeks after tumor implantation and rose until the fifth week. Indomethacin treatment lowered both serum calcium and the plasma level of 15-keto-13,14-dihydro-PGE2.
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PMID:Prostaglandin-mediated hypercalcemia in the VX2 carcinoma-bearing rabbit. 89 23

Mice bearing syngeneic tumors, chemical and virus-induced, became immunologically unresponsive to sheep erythrocytes. The increase in the degree of unresponsiveness with tumor growth suggested a causal relationship. Immunosuppression was in fact caused by the tumor cells because the addition of tumor cells to in vitro cultures of spleen cells and sheep erythrocytes resulted in suppression of antibody response. Suppression was dose dependent with a ratio of 1 to 1000 of tumor cells to spleen cells sufficient to produce significant suppression. Prostaglandins were found to have a role in immunosuppression by tumor cells in that PGE2 was itself immunosuppressive and in that indomethacin and aspirin, inhibitors of prostaglandin synthetases, blocked immunosuppression in vitro and retarded tumor growth in vivo. These findings suggest that tumors, although antigenic, may be able to escape immuno-sureillance by their host by means of subverting the immune system. Thus, success of immunotherapy may well depend on our ability to prevent or block the immunosuppressive activity of tumors.
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PMID:Subversion of immune system by tumor cells and role of prostaglandins. 105 74

Mice bearing a syngeneic tumor become increasingly immunodepressed during growth of the tumor, being unable to develop both cellular and humoral immunity to a histoincompatible tumor allograft and to reject the allograft. This failure to reject a strongly antigenic tumor allograft suggests that immunodepression associated with growth of a weakly antigenic syngeneic tumor provides the syngeneic tumor with an escape mechanism. This immunodepression is also manifest by the suppression of the response of spleen cells to mitogen stimulation by syngeneic tumor cells, both in vivo and in vitro. T cells that are stimulated by PHA, a T-cell mitogen, are the primary targets, and their suppression is the result of the direct subversive activity of the tumor cells. Subversion of T cells by tumor cells seems to be mediated through the prostaglandin pathway, because the prostaglandin PGE2 is itself suppressive, and an antagonist of PGE2 and an inhibitor of prostaglandin synthetases both inhibit the subversive activity of tumor cells. Several tumor cell lines tested, of different etiology and histologic type, all were subversive. This suggests that this subversive activity may be a general property of tumor cells and may be a key element in their ability to thwart the immunological system of the host. For this reason, any therapeutic regimen of cancer, based on immunostimulating drugs, should include drugs that can inhibit active subversion of the immune system by the tumor itself. Antagonists of prostaglandins and inhibitors of prostaglandin synthetases show promise in this regard.
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PMID:Subversive activity of syngeneic tumor cells as an escape mechanism from immune surveillance and the role of prostaglandins. 107 71

The renal prostaglandins PGS2 and PGE2 possess potent antihypertensive and vasodepressor activity. The mechanism of blood pressure lowering effect is through peripheral arteriolar dilation with a fall in total peripheral resistance. PGA unlike PGE escape degradation by the lung and thus could circulate as antihypertensive hormones. Since plasma PGA levels rise in humans on a low sodium intake, it has been postulated that the beneficial effects of a low sodium diet in some hypertensives may be the result of an increase in peripheral vasodilating PGA. Support that plasma PGA may be a regulator of systemic blood pressure is also derived from the fact a PGA-secreting renal tumor was associated with a fall in blood pressure and a rise in plasma PGA in a previously hypertensive woman. The removal of the tumor resulted in a return of blood pressure to elevated levels and a concomitant fall in PGA. Recently, a number of human patients with essential hypertension have been infused with PGA1 and PGA2. It was observed that there was an initial increase in renal blood flow, sodium and water excretion which was associated with no change in the elevated blood pressure. When blood pressure ultimately fell, there was a return of renal blood flow, sodium and water excretion to preinfusion levels. It would appear that PGA compounds act as 'ideal' antihypertensive agents since they favorably effect renal resistance, sodium and water homeostasis, plasma volume, total peripheral resistance, blood pressure and indirectly cardiac output through baroreceptor stimulation, all factors known to be important in etiology in human hypertension.
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PMID:Renal prostaglandins. 110 Oct 92

The paracrine and intracellular mechanisms controlling stromal cell growth in the normal or neoplastic breast are unknown. This in vitro study uses human breast fibroblasts to investigate a potential role for the inflammatory peptide mediator bradykinin (BK) in the regulation of DNA synthesis and signal transduction in these cells. Bradykinin stimulated a dose-dependent increase in inositol lipid hydrolysis and cytosolic Ca2+ levels in serum-starved fibroblasts derived from both normal and breast tumor tissue. Bradykinin also caused a dose-dependent decrease in cell growth and [3H]thymidine incorporation into DNA in breast fibroblasts. Epidermal growth factor (EGF) and insulin-like growth factor 1 both stimulated DNA synthesis in breast fibroblasts. Bradykinin inhibited this mitogenic effect of EGF but not that due to insulin-like growth factor 1. The binding of 125I-labeled EGF to fibroblasts was also inhibited by BK. Prostaglandin E2 also inhibited fibroblast DNA synthesis, and the cyclooxygenase inhibitor indomethacin partially reversed the inhibitory action of BK on DNA synthesis. Studies with BK receptor antagonists and agonists indicate that inositol lipid signalling and arachidonic acid mobilization in response to BK are B2 receptor-mediated pathways, whereas the inhibition of DNA synthesis appears to be via B1 receptors. Although these data support a role for prostaglandins and EGF receptor down-modulation in the inhibitory action of BK on DNA synthesis in breast fibroblasts, a B1 receptor-mediated pathway is also implicated. This study highlights a potential pathophysiological role for BK as a negative regulator of breast stromal cell growth.
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PMID:Inhibition of DNA synthesis and growth in human breast stromal cells by bradykinin: evidence for independent roles of B1 and B2 receptors in the respective control of cell growth and phospholipid hydrolysis. 130 39

The presence of serum immunosuppressive factor has recently been reported in patients with Crohn's disease. We investigated the mechanism of action of this immunosuppressive factor in vitro. The factor in serum fraction from patients with Crohn's disease had an inhibitory activity on the proliferation of phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMCs) from healthy volunteers. The growth of tumor cell lines, however, was not inhibited by the factor. While the factor did not influence the production of interleukin 2 (IL2) or the expression of IL2 receptor of PHA-stimulated PBMCs, it inhibited the expression of transferrin receptor. The effect of the factor on cell cycle of PHA-stimulated PBMCs was examined by flow cytometry analysis. The factor kept the cells in quiescent G0/G1 phase and decreased the number of cells in S phase. Prostaglandin E2, an immunosuppressive substance, may not participate in the inhibitory action of the factor, since indomethacin did not affect the inhibitory activity of the factor. These results suggest that the immunosuppressive factor in serum from patients with Crohn's disease is unique in the mechanism of inhibitory action and further clarification of this factor might contribute to the development of a new diagnostic assay for Crohn's disease and the elucidation of the pathogenesis of this disease.
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PMID:The mechanism of action of serum immunosuppressive factor in Crohn's disease: it blocks the growth of mitogen-stimulated lymphocytes in early G1 phase through an inhibition of transferrin receptor expression. 134 45

Cartilage breakdown, as seen in inflammatory and degenerative joint diseases, can be mediated by proteolytic enzymes, such as the metalloproteinase collagenase, the only enzyme able to digest collagen at neutral pH. In vitro collagenase gene expression can be stimulated by the phorbol ester tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate. We have investigated the effect of prostaglandin E1 (PGE1) on 12-O-tetradecanoyl-phorbol-13-acetate-stimulated collagenase mRNA levels in the rabbit synoviocyte cell line HIG-82. PGE1, but not PGE2 or PGF2 alpha, was able to selectively reduce collagenase mRNA levels in a dose-dependent fashion. PGE1 markedly increased intracellular levels of cAMP, while PGE2 and PGF2 alpha had little or no effect on cAMP production in the HIG-82 synoviocytes. Agents known to increase intracellular cAMP levels, such as the adenyl cyclase activator forskolin and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), mimicked the effect of PGE1, on collagenase mRNA levels. PGE1, forskolin, and IBMX also decreased collagenase mRNA levels in human skin fibroblasts, demonstrating that this observation was not unique to the HIG-82 cell line. Transient transfection experiments carried out in HIG-82 cells using a 1.2-kilobase portion of the 5'-flanking region of the human collagenase gene linked to the reporter gene luciferase demonstrated that PGE1, forskolin, and IBMX exert their inhibitory effect on the promoter region of the collagenase gene.
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PMID:Prostaglandin E1 inhibits collagenase gene expression in rabbit synoviocytes and human fibroblasts. 137 21


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