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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ability of macrophages to secrete reactive oxygen intermediates, such as superoxide or hydrogen peroxide, correlates closely with their capacity to kill trypanosoma, toxoplasma, leishmania, and candida. In this sense, secretion of oxygen intermediates is a biochemical marker of macrophage activation. The close correlation between oxidative metabolism and antimicrobial activity appears to stem from the direct involvement of oxygen intermediates in the killing of the same parasites by the macrophages. Similarly, there seem to be at least three experimental settings in which oxygen intermediates play a major role in nonphagocytic lysis of tumor cells by macrophages: in the presence of phorbol myristate acetate, of antitumor antibody, or of a peroxidase derived from eosinophils. These findings direct attention to antioxidant defenses in tumor cells and parasites. The oxidation-reduction cycle of glutathione is one major pathway used by tumor cells to limit oxidative injury by macrophages and granulocytes. Thus, cytotoxicity is augmented by inhibition of glutathione reductase or glutathione peroxidase, by interruption of glutathione synthesis, or by diversion of glutathione into another pathway. On the other hand, catalase appears to play a prominent role in limiting macrophage effector function against toxoplasma.
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PMID:Secretion of oxygen intermediates: role in effector functions of activated macrophages. 628 Oct 78

Glutathione content and the activity of glutathione reductase were examined in ventral prostate and chemically induced 11095 squamous-cell prostatic carcinoma in rats. Castration produced a significant reduction in the levels of reduced (GSH) and oxidized (GSSG) glutathione and glutathione reductase activity in the prostate. Replacement of testosterone (50 mg/kg) daily for 7 days to castrated animals elevated the reduced glutathione level and the activity of glutathione reductase almost to normal limits. Squamous-cell carcinoma was implanted in castrated and intact animals. Tumor growth in normal rats produced a decrease of almost 30% in the weight of the ventral prostate at 21 days post-implantation, although the glutathione levels remained unaffected. Much greater activity of glutathione reductase was detected in the tumor in comparison to the values noted for the normal tissue. The tumor also showed significantly higher values for the GSH/GSSG ratio. No apparent difference could be found in the rate of the growth of tumors whether implanted in normal or castrated animals. The levels of reduced and oxidized glutathione and glutathione reductase activity also seemed identical in tumors obtained from both groups of animals. Administration of testosterone (50 mg/kg) or beta-estradiol (2 mg/kg) daily for 11 days to tumor-bearing castrated animals did not alter the levels of glutathione and glutathione reductase activity. A significantly higher level of blood reduced glutathione was found in tumor-bearing rats in comparison to that seen for the normal subjects. Our results demonstrate that androgen depletion and replacement therapy influence the metabolism of glutathione in rat ventral prostate. Squamous-cell carcinoma of the prostate appears to differ from the normal tissue with respect to the observed androgen effects. There is dissimilarity in the metabolism of glutathione in the two tissues since greater activity of glutathione reductase and lower values of reduced glutathione were seen in the tumor as compared to those of the ventral prostate. Treatment with beta-estradiol, an antiprostatic agent, does not seem to influence the growth or glutathione metabolism of squamous-cell carcinoma of the prostate. The observed changes in blood glutathione levels might prove to be useful as an index of rapid growth of the neoplastic tissue.
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PMID:Studies on glutathione metabolism in ventral prostate and chemically induced prostatic carcinoma in rats. 686 Jul 82

Each of 11 tumors tested produced a factor that markedly suppressed the ability of macrophages to release H2O2 or O.2- in response to phorbol myristate acetate or zymosan. Four of seven normal cell types produced a similar activity, which was 3.5-7 times lower in titer than that in tumor cell-conditioned medium (TCM), and which was much more rapidly reversible in its effects. TCM caused 50% inhibition of H2O2 release when it was present in the medium for 48 h at a concentration of 13%, or when 100% TCM was present in the medium for 18 h. The H2O2-releasing capacity of macrophages incubated in TCM only returned to control levels by 6 d after its removal. TCM prevented augmentation of H2O2-releasing capacity by lymphokines. The titer of suppressive activity in TCM depended on both the concentration of tumor cells and the duration of their incubation. TCM did not augment the activity of catalase, myeloperoxidase, glutathione peroxidase, or glutathione reductase or the content of glutathione within macrophages, suggesting that decreased synthesis rather than increased catabolism was responsible for reduced secretion of H2O2. Suppression of the release of H2O2 or O.2- by TCM appeared to be a relatively specific effect, in that TCM increased macrophage spreading and adherence to glass while exerting little influence on rates of phagocytosis, synthesis of protein, or secretion of lysozyme, plasminogen activator, or arachidonic acid and its metabolites. Thus, tumor cells and some normal cells can secrete a factor that selectively deactivates macrophage oxidative metabolism.
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PMID:Suppression of macrophage oxidative metabolism by products of malignant and nonmalignant cells. 715 14

The basis of resistance to oxidative injury was studied in six murine tumor cell lines that differed 54-fold in their resistance to enzymatically generated H(2)0(2). The tumors varied 56.7-fold in their specific activity of catalase, 5.3-fold in glutathione peroxidase (GPO), 3.3-fold in glutathione reductase (GR), and 2.7-fold in glutathione. There was no correlation among the levels of the three enzymes, and tumor cell resistance to lysis by H(2)0(2). However, the logarithm of the flux of H(2)0(2) necessary to cause 50 percent lysis of the tumor cells correlated with their content of glutathione (r = 0.91). The protective role of glutathione was analyzed by blocking GR and GPO, the catalysts of the glutathione redox cycle. This was facilitated by the demonstration that the anti-neoplastic agent 1,3-bis-(2- chloroethyl)-l-nitrosourea (BCNU) was a potent inhibitor of GR in intact tumor cells. BCNU inactivated tumor cell GR with a 50 percent inhibitory dose of 11 muM and a t(l/2) of inhibition of 30 s. Complete inhibition of GR was attained with no effect on GPO or catalase. Tumor cells whose GR was inactivated by BCNU could be lysed by fluxes of H(2)0(2) to which they were otherwise completely resistant. They could be killed by phorbol myristate acetate (PMA)-stimulated, bacilli Calmette-Guerin-activated macrophages in numbers which were otherwise insufficient, and by nonactivated macrophages, which otherwise were ineffective. BCNU-treated target cells were also much more sensitive to antibody-dependent, macrophage-mediated cytolysis. However, such tumor cells were no more sensitive than controls to lysis by alloreactive T cells or by antibody plus complement. Next, we deprived tumor cells of selenium by passage in selenium-deficient mice. GPO was inhibited 85 percent in such cells, with no effect on GR or catalase. Tumor cells with reduced GPO activity were markedly sensitized to lysis by small fluxes of H(2)0(2) or by PMA-stimulated macrophages or granulocytes. In contrast, inhibition of catalase with aminotriazole had no effect on the sensitivity of three tumors to peroxide-mediated lysis, and had modest effects with two others. Thus, the oxidation-reduction cycle of glutathione serves as one of the major defense mechanisms of tumor cells against three related forms of oxidant injury: lysis by fluxes of H(2)0(2), by PMA-triggered macrophages, and by macrophages in the presence of anti-tumor antibody.
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PMID:Tumor cell anti-oxidant defenses. Inhibition of the glutathione redox cycle enhances macrophage-mediated cytolysis. 725 13

Glucose oxidase, covalently coupled to polystyrene microspheres (GOL), produced H(2)0(2) at an average rate of 3.6 nmol/min per 10(9) beads under standard assay conditions. Injection of 1.3 x 10(10) to 1.1 x 10(11) GOL i.p. prolonged the survival of mice by 27 percent after injection of 10(6) P388 lymphoma cells in the same site, consistent with destruction of 97.6 percent of the tumor cells. Placing mice for several hours in 100 percent O(2), the probable rate-limiting substrate for GOL, afforded a 42 percent prolongation of survival from P388 lymphoma, consistent with destruction of 99.6 percent of the tumor cells. When the P388 inoculum was 10(5), 10(4), or 10(3) cells, GOL led to long-term survival (presumed cure) of 23 percent, 77 percent, and 92 percent of the mice, respectively, consistent with reduction of the injected tumor dose to less than 10 cells. Subcutaneous growth of 10(5) P388 cells (approximately 300 lethal dose to 50 percent of mice) was suppressed in 83 percent of mice by admixture of GOL with the tumor cell inoculum. GOL alone had no effect against a more peroxide-resistant tumor, P815 mastocytoma. However, P815 cell glutathione reductase could be inhibited in vivo by well-tolerated doses of the antitumor agent, 1,3-bis(2-chloroethyl)- 1-nitrosourea (BCNU). BCNU alone cured few mice with P815. Together, BCNU and GOL apparently cured 86 percent of mice injected with 10(6) P815 cells i.p. The protective effect of GOL was abolished by boiling it to inactivate the enzyme, by co-injection of catalase coupled to latex beads, or by delaying the injection of tumor cells for 3 h, by which time the beads had formed aggregates. Soluble glucose oxidase, in doses threefold higher than that bound to GOL, had no detectable antitumor effect. A single injection of preformed H(2)0(2) readily killed P388 cells in the peritoneal cavity, but only at doses nearly lethal to the mice. In contrast, GOL had very little toxicity, as judged by the normal appearance of the mice for over 400 d, gross and microscopic findings at autopsy, and various blood tests. GOL injected i.p. remained in the peritoneal cavity, where it was gradually organized into granulomata by macrophages, without generalized inflammation. Thus, an H(2)0(2)-generating system confined to the tumor bed exerted clear- cut antitumor effects with little toxicity to the host.
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PMID:Antitumor effects of hydrogen peroxide in vivo. 729 47

Glutathione-dependent defense against xenobiotic toxicity is a multifaceted phenomenon that has been well characterized in mammals. This study undertakes a comparison of two benthic fish species, the channel catfish and brown bullhead, in terms of characteristics of the glutathione system. The channel catfish, a species that has seldom been observed to express pollutant-mediated neoplasia in field studies, was observed to have significantly higher constitutive levels of hepatic total glutathione and reduced glutatione (GSH). Brown bullhead, a species that is often observed to express neoplasia in contaminated systems, had significantly higher hepatic levels of glutathione disulfide. Furthermore, catfish expressed higher levels of activity of the enzymes gamma-glutamylcysteine synthetase (GCS), glutathione reductase (GR), and glutathione S-transferase, whereas bullhead expressed higher hepatic glutathione peroxidase (GPOX) activity. Both species responded to treatment with the redox active quinone, menadione, by expressing elevated hepatic content of total glutathione. However, the induction response was more rapid and more extensive in catfish compared to that in bullhead. This is attributable to the observed interspecific difference in GCS activity. Following treatment with the organic peroxide, tert-butyl hydroperoxide (t-BOOH), bullhead hepatic glutathione was depleted up to 4 hr post-treatment, whereas catfish demonstrated no significant depletion of glutathione in response to t-BOOH. The differing responses to t-BOOH are attributable to interspecific differences in hepatic GPOX and GR activity. Bullhead, therefore, appear to be more susceptible to the effects of GSH arylators and oxidants based upon constitutive levels of glutathione, related enzyme activities, and the response of this system to model xenobiotics.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Glutathione-dependent defense in channel catfish (Ictalurus punctatus) and brown bullhead (Ameriurus nebulosus). 752 70

Fe-NTA is a known renal carcinogen. However, little is known about its carcinogenic potential in liver. In this study we for the first time show that Fe-NTA is a potent hepatic tumor promoter. Fe-NTA administration induced dose dependently the hepatic ornithine decarboxylase (ODC) activity several folds as compared to its activity in the saline-treated rats. Similarly, hepatic DNA synthesis which is measured as [3H]thymidine incorporation in DNA is also increased following Fe-NTA treatment. The effects of Fe-NTA were similar to other tumor promoters not only with respect to inducing ODC activity and [3H]thymidine incorporation in DNA but also in depleting antioxidant armory of the tissue. Fe-NTA depleted levels of glutathione to about 35% of the saline-treated control and activities of antioxidant enzymes catalase, glutathione peroxidase, glutathione reductase and glucose 6-phosphate dehydrogenase decreased significantly (45-55% of saline-treated control). Concomitant with the depletion in antioxidant armory, Fe-NTA augmented hepatic microsomal lipid peroxidation more than three folds. The pretreatment of rats with antioxidants BHA or BHT diminished the observed effects of Fe-NTA. Our data indicate that Fe-NTA is a potent hepatic tumor promoter and acts through a mechanism involving oxidative stress.
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PMID:Ferric nitrilotriacetate (Fe-NTA) is a potent hepatic tumor promoter and acts through the generation of oxidative stress. 762 70

A very potent competitive inhibitor of mammalian glyoxalase II activity, N,S-bis-fluorenylmethoxycarbonylglutathione (DiFMOC-G) has been synthesized and characterized. The Ki value for inhibition of glyoxalase II purified from calf liver is 0.08 microM. The Ki values for glyoxalase I inhibitions range from 285 to 500 fold higher than the values obtained for glyoxalase II inhibitions, depending on the source of the enzyme. Among other enzymes involved in glutathione metabolism, such as glutathione S-transferase, glutathione reductase, and glutathione peroxidase, only glutathione S-transferase is inhibited to a small extent by DiFMOC-G. Diesters of DiFMOC-G were prepared in order to improve transport of DiFMOC-G into mammalian tumor cells (rat adrenal pheochromocytoma, PC-12) in culture. Among the diesters synthesized, diisopropyl DiFMOC-G was found to be the most inhibitory to cell viability, with a [I]0.5 value of 3 microM.
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PMID:N,S-bis-fluorenylmethoxycarbonylglutathione: a new, very potent inhibitor of mammalian glyoxalase II. 762 27

In this work comprehensive data of antioxidant enzymes are reviewed and their role in carcinogenesis is discussed. When compared to their normal tissue counterparts, more of the tumor tissues were low in Cu, Zn-SOD and catalase activity and in some cases in Mn-SOD. It is probably characteristic for tumor tissues. Glutathione peroxidase, and glutathione reductase and glucose-6-phosphate dehydrogenase activities are highly variable. The reason why cancerous cells exhibit abnormal levels and activities of antioxidant enzymes is unknown. It was hypothesized, that during formation of the tumor, by certain obscure mechanism, cells with imbalance of antioxidant enzymes profile were selected over normal cells. It is not known whether the changes in antioxidant defence observed in cancerous tissues play a role in carcinogenesis, or are formed as a results of the disease.
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PMID:[Activity of antioxidant enzymes in cancer diseases]. 763 95

In this study, the activity of the glutathione related enzymes, namely glutathione S-transferase (GST), glutathione reductase (GSSG-R), Selenium-dependent and -independent glutathione peroxidase (GPX) of various TGC tumors (n = 18) obtained from untreated patients, was compared to that of the corresponding enzymes of normal testicular tissues (n = 5). The enzymes of all tumorous tissues except teratomas were significantly less active, than the corresponding enzymes of nontumorous tissues. The GST was in seminomas 4.3-20-, in embryonal carcinomas 47-, and in mixed tumors 13-47-fold less active than in the normal testes. The GST activity of teratomas was about half of that of the normal tissues. The Se-independent GPX, component of GST alfa class, comprised about 90 percent of the total GPX activity in normal testis; however it was absent or barely detectable in all TGC tumors except teratomas. The latter had about the same GPX activity as the tumor-free testicular tissues. Apart from the teratoma, the GSSG-R activity of all TGC tumors was also suppressed to about one third of that of the normal testis. The insufficient function of glutathione related enzymes of TGC tumors may contribute to their sensitivity against treatment. The poorer prognosis of teratomas, however, may be explained by the relatively higher activity of their detoxifying enzymes.
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PMID:Glutathione related enzymes in human testicular germ cell tumors and normal testes. 765 23


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