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)

Tumor cells injected into Balb/c mice together with heat-killed 48-h P. acnes cells were rendered nontumorigenic as early as 12 h after injection, as determined by the inability of the tumor cells to give rise to tumors when transferred to a new host. Determination of tumor cell antigen levels by ELISA indicated that the tumour antigens had virtually disappeared by 24 h after injection of tumor cells and P. acnes. In contrast, in control animals injected with tumor cells only, there was an initial drop in tumor antigen levels at 12 h, after which the level rose steadily and tumors developed in 7-10 days. Since the cellular exudate at 12 h was almost entirely composed of polymorphonuclear leukocytes (PMN), we tested the ability of PMN, stimulated by phagocytosis of 48-h P. acnes cells, to produce substances toxic to tumor cells. Results indicated that the supernatant fluid from a phagocytosis mixture of PMN and P. acnes contained material toxic to tumor cells and also to Chinese hamster ovary cells. Tests with scavengers and inhibitors of oxygen-derived radicals suggested that the toxic material is either hydrogen peroxide (H2O2) or hydroxyl radicals (OH). Suspensions of 12-h P. acnes, P. acnes cells walls, P. freudenreichii, or latex beads were ineffective in preventing tumor growth, and induced little toxicity when phagocytosed. We conclude that in this test system 48-h P. acnes prevents tumor growth by stimulating the production of toxic oxygen metabolites during phagocytosis by PMN.
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PMID:Role of respiratory-burst products from polymorphonuclear leukocytes in the antitumor activity of Propionibacterium acnes vaccine. 270 41

Analogues of staurosporine were synthesized and their ability to inhibit protein kinases was examined. Staurosporine is a potent but non-selective inhibitor of in vitro protein kinase C(PKC) activity (IC50 6.0 nM). The derivative CGP 41 251 had reduced PKC activity with an IC50 of 50 nM but showed a high degree of selectivity when assayed for inhibition of cyclic AMP-dependent protein kinase (IC50 2.4 microM), S6 kinase (IC50 5.0 microM) and tyrosine-kinase-specific activity of epidermal growth factor receptor (IC50 3.0 microM). Staurosporine and CGP 41 251 exerted growth inhibition in the human bladder carcinoma line T-24, human promyelocytic leukemia line HL-60 and bovine corneal endothelial cells at concentrations which correlated well with in vitro PKC inhibition. In addition, both compounds inhibited the release of H2O2 from human monocytes pre-treated with 12-O-tetradecanoyl-phorbol-13-acetate at non-toxic concentrations. In vivo anti-tumor activity was examined in T-24 human bladder carcinoma xenografts in athymic nude mice. Tumor growth inhibition tests revealed significant anti-tumor activity (2p less than 0.001) at 1/10 of the maximum tolerated doses for both compounds. By contrast, a closely related derivative of staurosporine (CGP 42 700) was inactive at concentrations of over 100 microM in all in vitro enzyme and anti-proliferative assays as well as in animal tumor models. Our data suggest an association between PKC inhibition and anti-proliferative and anti-tumor activity.
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PMID:A derivative of staurosporine (CGP 41 251) shows selectivity for protein kinase C inhibition and in vitro anti-proliferative as well as in vivo anti-tumor activity. 1033 43

Serum ferritin levels are often elevated in patients with certain cancers and these elevations are, in part, derived from the tumors. In such patients, the increased levels of serum ferritin are associated with a poor prognosis. This association may be explained in part by biological effects of ferritin on lymphocytes: inhibition of E-rosette formation, masking of cell surfaces and suppression of lymphocytes' response to mitogens in vitro. The authors hypothesized that ferritins from tumor tissues also exert adverse effects on human granulocytes that are involved in tumoricidal activity. Three granulocyte functions were tested: nitroblue tetrazolium test, phagocytosis, and production of hydrogen peroxide. The results supported the authors' hypothesis: NBT reduction and phagocytosis are decreased in granulocytes exposed to ferritins, more so with tumor ferritins, than normal ferritin, and H2O2 production is less in granulocytes previously exposed to ferritins from tumor and nontumor tissues than cells not exposed to ferritins. However, the inhibitory effects of ferritins on H2O2 production can be reversed if granulocytes are further stimulated by phorbol myristate acetate (a membrane stimulant). If the elevated serum ferritin in cancer patients impairs granulocyte functions, in vivo, then it may increase the risk of infection, decrease tumoricidal host responses, and, thereby, contribute to the poor prognosis of these individuals.
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PMID:Effects of isoferritins on human granulocytes. 272 May 99

Reactive oxygen species have been shown in several systems to have a role in tumor promotion and carcinogenesis, although the exact mechanisms are yet to be elucidated. To investigate this further, the effect of hydrogen peroxide was studied in a hamster tracheal organ explant epithelial model. Hydrogen peroxide was added exogenously to tracheal explants maintained in defined serum free media at concentrations of 50, 100, 500 or 1000 microM daily for 1 h for a period of two weeks. The explants were then examined using scanning electron microscopy for evidence of morphologic alteration and for the development of squamous metaplasia. Control tracheal explants maintained in serum free media exhibited normal morphology (except for some decrease in the number of ciliated cells) and developed minimal squamous metaplasia after four weeks in culture. At concentrations of 500 and 1000 microM, hydrogen peroxide was toxic to the epithelium, resulting in complete necrosis of the epithelium within seven days. At concentrations of 50 and 100 microM, hydrogen peroxide treatment resulted within three weeks in the development of a significant degree of squamous metaplasia (covering 52 and 48.7%, respectively, of the surface epithelium). This effect could be negated by the exogenous addition of catalase. This model should be useful in the study of the early cellular events following oxidant injury that contribute to the development of squamous metaplasia.
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PMID:Hydrogen peroxide induces squamous metaplasia in a hamster tracheal organ explant culture model. 279 Dec 9

Mezerein, the most active antitumor compound isolated from the daphne species of plants, has a structural similarity to phorbol myristate acetate (PMA), the major active compound isolated from croton oil. PMA is known to have tumor promoting activity and is a potent inflammatory agent. Mezerein has similarly been reported to have potent inflammatory properties but appears to be a weaker tumor promoter than PMA. While the effect of PMA on the function and metabolism of human blood cells has been extensively studied, there is little similar information concerning mezerein. Therefore, in these studies, we have compared the capacities of mezerein and PMA to activate the cytotoxic capacity and oxidative metabolism of human granulocyte (PMNs), monocyte, lymphocyte, and mononuclear cell (lymphocytes and monocytes) cultures in vitro. Mezerein stimulated the oxidative metabolism of PMNs in an identical manner to PMA as indicated by a burst in the activity of the HMPS pathway, the production of H2O2, hydroxyl radical and stable oxidants. Mezerein also stimulated the release of thromboxane B2 from PMNs. Both compounds activated the oxidative metabolism of monocytes but not the oxidative metabolism of lymphocytes. The enhanced oxidative metabolism of the phagocytic cells was associated with an increased cytotoxicity against human red cells which are sensitive to oxidant damage but not against the NK resistant Raji lymphoblast cell line or the SW1116 colon tumor cell line. Of interest is that mezerein did not augment significantly the minimal cytotoxic capacity (NK activity) of mononuclear cells, monocytes or freshly isolated lymphocyte cultures against the tumor cell targets used in our experiments. However, lymphocyte cultures preincubated for 15 hours with mezerein had a marked enhancement of cytotoxicity against the tumor targets. This activation was not observed in similarly treated mononuclear cell cultures suggesting a suppressor activity of the monocytes. Our data suggest that the potent inflammatory activity of mezerein similar to PMA, may be related to its capacity to activate the oxidative and arachidonic metabolism of phagocytic cells. In addition, the capacity of mezerein to activate the cytotoxic capacity of lymphocytes may relate to its reported in vivo antitumor activity.
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PMID:The effects of the anti-tumor agent mezerein on the cytotoxic capacity and oxidative metabolism of human blood cells. 279 70

We have shown previously that macrophages are mutagenic to bacteria (A. M. Fulton et al., Cancer Res., 44: 4308-4311, 1984) and can induce the appearance of drug-resistant variants of murine mammary tumor cells (K. Yamashina et al., Cancer Res., 46: 2396-2401, 1986). The present study asks whether inflammatory macrophages can induce lesions in the DNA of cocultured tumor cells and seeks to determine the mediators of this damage. We quantitated the induction of DNA strand breaks using the technique of fluorometric analysis of DNA unwinding. We report that inflammatory macrophages coincubated with a mammary tumor cell line for 60 min at a 1:1 ratio result in significant numbers of strand breaks in the tumor cell DNA. The degree of damage is equivalent to 300 to 1200 rads of gamma-irradiation. Resident (unstimulated) peritoneal macrophages also induce tumor cell DNA strand breaks. However, inhibitor studies reveal quantitative and qualitative differences in strand breaks induced by inflammatory (elicited) versus resident peritoneal macrophages. Resident macrophages require a longer induction period (60 min) before significant breaks are detected, but induce more breaks than do elicited macrophages, which require only a 5-min coincubation period to induce significant damage. The enzyme catalase, which removes H2O2, protects tumor cells from both macrophage effector populations as does the prostaglandin synthase inhibitor, indomethacin. The superoxide anion scavenger, superoxide dismutase, and the lipoxygenase inhibitor, nordihydroguaiaretic acid, are protective against resident macrophage effects only. The metal chelator, o-phenanthroline, provides limited protection for elicited macrophages but induces total DNA breakage in the presence of resident macrophages. Taken together, our data indicate that the degree of strand breakage is greater for the macrophage population with high arachidonate metabolism and low oxidative metabolism (resident macrophages) and less for the macrophage population with high oxidative and low arachidonate metabolism (MVE-2 elicited macrophages). Inhibitor studies implicate both metabolites of reactive oxygen and arachidonate as mediators of this tumor cell DNA damage, with the relevant mediator dependent upon the particular macrophage population under study.
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PMID:Macrophage-mediated induction of DNA strand breaks in target tumor cells. 281 15

Possible cytolytic interactions between hydrogen peroxide (H2O2) and neutrophil granule proteins were studied. Preliminary experiments demonstrated synergistic cytolysis when erythro-leukemia targets were exposed to H2O2 combined with a low molecular weight (approximately 3900) granule extract that was predominantly composed of peptide defensins. The synergistic interaction was confirmed when sublytic concentrations of H2O2 were combined with defensin preparations that had been purified to homogeneity. Synergy was concentration dependent in regard to both molecules and could not be explained by trace contamination of defensin preparations with myeloperoxidase. Sequential addition experiments suggested that synergistic lysis required a simultaneous exposure to both cytotoxins. In the presence of sublytic concentrations of H2O2, the binding of iodinated defensin to targets was significantly increased, providing a possible explanation for the observed synergy. Since both molecules are concurrently secreted by activated neutrophils, this interaction may be important during leukocyte-mediated anti-tumor effects or inflammatory tissue injury.
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PMID:Synergistic cytolysis mediated by hydrogen peroxide combined with peptide defensins. 283 69

The mechanism of neutrophil-mediated lysis of tumor targets was investigated. Tumor lysis was directly related to the concentration of phorbol myristate acetate (PMA) used to stimulate PMNs. Lysis increased as the PMA concentration increased between 10(-7) and 10(-4) M. In contrast, the production of H2O2 plateaued between concentrations of 10(-5) and 10(-4) M. The K562 erythroleukemia cell, the target used in this study, was found to be relatively resistant to preformed H2O2, with an LD50 of 8.3 X 10(-3) M. Myeloperoxidase was not capable of enhancing K562 lysis. Although resistant to preformed H2O2, K562 lysis mediated by PMNs stimulated with 10(-7) M PMA was oxidative in nature. It was sensitive to inhibition by catalase and was not significant when PMNs from patients with chronic granulomatous disease were used. In contrast, PMN lysis stimulated by 10(-4) M PMA was nonoxidative in nature. The inhibitors catalase and superoxide dismutase had no effect on lysis, lysis was significant when the assay was performed in an anaerobic atmosphere, and PMNs from patients with chronic granulomatous disease were comparable to control PMNs in tumor lysis. A single-cell conjugate and cytotoxicity assay demonstrated that PMA was both able to increase the ability of PMNs to bind to tumor targets and to enhance their lysis of bound targets. These data indicate that PMNs are capable of achieving tumor lysis by nonoxidative pathways under certain conditions. The high-dose PMA model may be valuable as a tool for investigating these alternative mechanisms of tumor lysis.
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PMID:Neutrophil-mediated nonoxidative tumor lysis stimulated by high concentrations of phorbol myristate acetate. 283 17

We have measured the capacity of highly-purified, paraffin oil-elicited neutrophils to induce DNA single-strand breaks in a newly established plasmacytoma cell line, RIMPC 2304, which was induced by a retrovirus containing the c-myc and V-Ha-ras oncogenes. This cell line effectively repairs DNA damage induced by gamma-irradiation. DNA damage induced by neutrophils was correlated with the oxidative burst of the neutrophils. The levels of superoxide anion, H2O2, and HOCl produced after stimulation of the neutrophils (6 X 10(5)/cm3) with the tumor promoter phorbol myristate acetate (100 nM) were 33.8 microM, 12.8 microM and 1.7 microM respectively in 15 min, and 98 microM, 20 microM and 8.7 microM respectively in 90 min. The results of alkaline elution experiments revealed that when the same concentration of neutrophils was co-incubated for 15 min in serum-free medium with an equal number of radioactively labeled RIMPC 2304 cells, the latter incurred a level of damage that approximated that caused by 300 rad equivalents of gamma-irradiation or by a 1-min treatment with 20 microM H2O2 at 37 degrees C. Damage from neutrophils was coincident with the oxidative burst; it was induced rapidly (within 5 min) but remained high for more than 90 min. The level of damage achieved was dependent upon the ratio of neutrophils: target cells and was clearly detectable at ratios as low as 0.25:1. Induction of single-strand breaks was completely inhibited by catalase and partially inhibited by superoxide dismutase, mannitol, and reduced glutathione but not by Na azide. Addition of the non-steroidal anti-inflammatory drug indomethacin either enhanced (at 50 microM) or had no effect (at 2 microM) on the damage detected. Finally, repair of strand breaks induced by neutrophils was significantly slower (half-time approximately 10 min) than that observed for repair of similar levels of damage induced by H2O2 or gamma-irradiation (half-times approximately 3 min, each). The results indicate that neutrophils cause prolonged DNA damage in neighboring cells. Moreover, they indicate that although H2O2 produced in the oxidative burst is an essential mediator of the damage observed, additional reactive oxygen intermediates including the superoxide anion are also implicated. The data are discussed in relation to the possible role of neutrophils in chronic inflammation and in pristane-induced plasmacytoma formation in mice.
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PMID:Activated neutrophils induce prolonged DNA damage in neighboring cells. 284 79

Xanthine/xanthine oxidase and H2O2 stimulated sugar transport. Application of superoxide dismutase and catalase to the cells showed an inhibitory effect on these agent-stimulated sugar transports. Addition of amiloride and 4-acetamide-4'-isothiocyanostilbene-2,2'-disulfonic acid (SITS), which abolish the cytoplasmic alkalinization, inhibited the stimulation of sugar transport by xanthine/xanthine oxidase in the presence of catalase. The calmodulin antagonists, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) and trifluoperazine inhibited H2O2-stimulated sugar transport. These results suggest that O2- stimulates sugar transport in an intracellular pH-dependent manner and that H2O2 stimulates sugar transport in a calcium-calmodulin-dependent manner. These mechanisms may be involved in sugar-transport stimulation in mouse fibroblast BALB/3T3 cells by the tumor-promoting phorbol ester phorbol-12,13-dibutyrate and insulin, since the stimulatory effects of these agents were inhibited by scavengers of oxygen radicals.
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PMID:Mechanism of O2- (-) and H2O2-induced stimulation of sugar transport in mouse fibroblast BALB/3T3 cells. 284 89


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