Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prostaglandins and other eicosanoids have been studied extensively in their physical, biochemical, biophysical and pharmacological aspects. However, studies on their role in tumor progression, especially metastases are relatively recent. Following a brief overview of the history of discovery and metabolism of eicosanoids and other fatty acids, we discuss the functions of these fatty acids (with emphasis on prostacyclin, thromboxane A2, 12-hydroxyeicosatetraenoic acid and 13-hydroxyoctadecadienoic acid) in cell transformation, tumor promotion and particularly in tumor cell metastasis. The relation between these monohydroxy fatty acids and tumor cell metastasis is discussed from three different perspectives, i.e., their effects on tumor cells, on platelets and on endothelial cells. The mechanism of these effects are then addressed at cell adhesion molecule, motility, protease, cell cytoskeleton, protein kinase and eicosanoid receptor levels. Finally, regulation of three key enzymes which generate eicosanoids (phospholipase, prostaglandin endoperoxide synthase and lipoxygenase) is explored.
Cancer Metastasis Rev 1992 Nov
PMID:Fatty acid modulation of tumor cell-platelet-vessel wall interaction. 142 24

Unsaturated fatty acids of the n-6 and n-3 class have been shown to affect tumor growth and metastasis. The very long chain polyunsaturated fatty acids of the n-3 family, e.g. eicosapentaenoic acids (C20:5n-3) and docosahexaenoic acids (C22:5n-3), have an inhibiting effect on tumor growth. Metastasis is promoted by n-6 polyunsaturated fatty acids, e.g. linoleic acid (C18:2n-6) and gamma-linolenic acid (C18:3n-6). The mechanisms of promotion and inhibition are described in the present review. The mechanisms of lipid peroxidation, which appears to be an important factor in the inhibition of tumor growth, are discussed. Lipid peroxidation is induced by polyunsaturated fatty acids involving autoperoxidation a.o. and the enzymes cytochrome P450, cyclooxygenase and lipoxygenase. In tumor cells these enzymes are decreased in activity but at present the reason for this reduction is not known. Lipid peroxidation products such as hydroxyeicosatetraenoic acids (HETES), hydroperoxy eicosatetraenoic acids (HPETES) and malondialdehyde may have a regulating effect on DNA duplication enzymes (e.g. polymerases). Prostaglandin synthesis in tumor cells and macrophages is also affected by polyunsaturated fatty acids. The fish oil fatty acids are known to reduce prostaglandin synthesis by competing with arachidonic acid for the enzyme cyclooxygenase. However, fish oil fatty acids have an antagonistic effect on cyclooxygenase. Polyunsaturated fatty acids also have an effect on the immune system and particularly on macrophages. Macrophages, but also T-cells and B-cells, are inhibited by prostaglandins such as PGE2, while immunosuppressor cells are stimulated by PGE2.
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PMID:Effects of dietary fatty acid composition on tumor growth and metastasis. 144 14

The number of spontaneous lung metastases and the frequency of metastasis formation in the lymph nodes of mice were studied following the induction of tumour growth by injection of tumour cells. A syngeneic transplantable mammary adenocarcinoma, MMT 1, from C3H/He mice, and a cloned strain, MMTV4, obtained by treating MMT1 cells with 5-azacytidine in vitro, were used. No differences between MMT1 and MMTV4 were detected in the number of spontaneous metastases in the lungs of mice. An in vitro cytotoxic test and an adoptive transfer test were used to measure cytotoxic activity and the antimetastatic activity of spleen macrophages. The macrophages from mice bearing the MMT1 tumour exhibited antimetastatic activity in the adoptive transfer test, and specific and nonspecific cytotoxic activity in the in vitro test. Macrophages from mice carrying the MMTV4 tumour possessed nonspecific cytotoxic activity in vitro but did not exhibit antimetastatic activity in the adoptive transfer test. Tumours were surgically removed 13-15 days after their induction. Two weeks after the MMT1 tumour was resected, an abrupt increase in the number of spontaneous metastases in the lungs and in the lymph nodes was observed, whereas after removal of the MMTV4 tumour there were no changes in the number of lung metastases. When mice with the MMT1 tumour were given the cyclooxygenase inhibitor, indomethacin, in their drinking water, there was a significant decrease in the number of spontaneous lung metastases. Spleen macrophages from mice operated on after injection with MMT1 or MMTV4 did not possess specific cytotoxicity in the in vitro test.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Participation of macrophages in the mechanism mediating the enhancement of metastasis formation after tumour resection. 184 24

There is ample evidence to suggest that hematogenous metastasis may be related to the ability of tumor cells to promote aggregation of host platelets. Arachidonic acid metabolism in platelets and vessel walls may also contribute to the metastatic process. Several preliminary trials of platelet inhibitory agents have been performed. Ketoconazole (inhibitor of lipoxygenase and thromboxane synthetase), verapamil (calcium antagonist), forskolin (stimulator of platelet adenylate cyclase), and indomethacin (inhibitor of cyclooxygenase) were examined, alone and in combination, to investigate their effects on platelet aggregation and on hepatic metastases from human pancreatic tumor cells (RWP-2) in nude mice. The tumor cells were injected intrasplenically, and the animals were divided into control, single-drug and combination treatment groups. The agents were administered intraperitoneally 1 hr before and every 24 hr after the tumor cell injections for 6 days. Statistically significant differences were observed between the control and single-treatment groups on the reduction of liver tumor nodules (range P less than 0.001-0.032) and in the liver surface areas occupied by tumor (range P less than 0.001-0.013). Furthermore, when these agents were combined, similar reductions in liver tumor nodules were noted (range P less than 0.001-0.008), while even greater inhibitory effects were seen in the liver surface areas occupied by tumor (P less than 0.001) compared with the single-treatment groups. Also, the combination studies strongly inhibited RWP-2-induced platelet aggregation in human platelet-rich plasma.
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PMID:Effects of antiplatelet agents alone or in combinations on platelet aggregation and on liver metastases from a human pancreatic adenocarcinoma in the nude mouse. 189 Aug 39

We have evaluated in a homologous system the mechanisms of platelet activation by cells isolated from fresh human tumor tissues and the role of thromboxane B2 (TxB2) generation in this process. Thirty-eight of the 46 tumor tissues considered showed a high platelet-aggregating activity, with no particular distribution in any specific tumor type. Apyrase caused a nonsignificant reduction in the aggregation response, hirudin did not change it, while iodoacetic acid or p-hydroxymercuriphenylsulfonate, specific cysteine proteinase inhibitors, significantly reduced the platelet-aggregating capacity of these tumor cells. In 9 colon carcinomas and in 8 breast carcinomas the levels of TxB2 produced by platelets after addition of tumor cells were measured: tumor cell-induced platelet aggregation was accompanied by a significant production of the metabolite; indobufen, a cyclooxygenase inhibitor, significantly reduced aggregation and particularly TxB2 production, while the drug had no effect on both parameters if preincubated with tumor cells only. These data suggest that cells isolated from different human tumor tissues activate platelets through the activity of tumor-associated cysteine proteinase(s); platelet aggregation by tumor cells is largely dependent on arachidonic acid metabolism in platelets, while such metabolism in tumor cells does not play a significant role.
Invasion Metastasis 1991
PMID:Thromboxane production by platelets during tumor cell-induced platelet activation. 191 83

Recent studies have shown that the cyclooxygenase and the 5-lipoxygenase pathways of arachidonic acid, are required for the invasive and metastatic activity of certain tumor cells. We show here that malignant murine melanoma and human fibrosarcoma cells cultured in media supplemented with eicosapentaenoic acid show a dose and time dependent decrease in invasiveness, in collagenase IV production and in the case of the murine cells, a reduced ability to metastasize to the lung after intravenous injection. It was also shown that a metabolite of eicosapentaenoic acid was less potent than the comparable arachidonic acid metabolite in restoring collagenase IV production and invasiveness after inhibition of the lipoxygenase pathway. These studies indicate that such supplements have the potential to reduce the metastasis of certain tumor cells, converting them to benign status.
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PMID:Eicosapentaenoic acid reduces the invasive and metastatic activities of malignant tumor cells. 254 5

Metastatic cancer was treated with interleukin 2 and lymphokine-activated killer cells with the addition of the cyclooxygenase inhibitor ibuprofen in an attempt to reduce side effects in 13 patients (eight male and five female). Twenty-six patients treated with only interleukin 2 and lymphokine-activated killer cells formed the control group. After interleukin 2 administration, a significantly increased number of lymphokine-activated killer cells were transfused in ibuprofen-treated patients. Cytotoxic effects were not significantly different in the treated and untreated groups. With regard to cell phenotype, both groups of patients manifested significant activation of the immune system as measured by T10 and OK1a. Symptom scores were dramatically reduced in patients treated with ibuprofen. Temperature above 37 degrees C were rare. Ibuprofen did not significantly alter rate of response in this immunotherapy trial (38% vs 42%). Ibuprofen is now routinely used in all of our current immunotherapy trials.
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PMID:Ibuprofen causes reduced toxic effects of interleukin 2 administration in patients with metastatic cancer. 278 76

Phorbol ester binding was examined in two lines of murine fibrosarcoma cells. The two cell lines were isolated from the same parent tumor but respond differentially to stimulation with phorbol esters. In one of the lines, these agents stimulate a rapid attachment and spreading response and induce directional migration. The other cell line does not migrate in response to stimulation with phorbol esters and the attachment and spreading response is slow. The cell line which responds actively to phorbol ester stimulation is highly malignant when injected into syngeneic animals while the other line is of low tumorigenicity and is virtually non-metastatic. In spite of these differences, both lines were found in the present study to bind [3H]4 beta-phorbol-12 beta, 13 alpha-dibutyrate in a receptor-mediated fashion. The characteristics of binding were virtually identical between the two cell lines. In additional studies, arachidonic acid metabolism was examined in the same two lines. In the highly responsive line, PMA stimulated a rapid release of [3H]arachidonic acid and its conversion into cyclooxygenase and lipoxygenase products. In the less-responsive line, PMA stimulated a slower release of [3H]arachidonic acid from prelabeled cells. The quantity of arachidonic acid metabolites produced was also much less. These studies suggest that the disparity between the two cell lines in their response to phorbol ester stimulation is not the result of differences in the initial interaction between the cells and ligand but may result from alterations in their signal transductance mechanism. This may be the result of inherent differences in capacity for arachidonic acid metabolism.
Clin Exp Metastasis
PMID:Phorbol ester binding and phorbol ester-induced arachidonic acid metabolism in a highly responsive murine fibrosarcoma cell line and in a less-responsive variant. 308 51

The role of prostaglandin E2 (PGE2) in directly stimulating metastatic spread by Lewis lung carcinoma (LLC) cells was examined with the use of an in vitro migration model for tumor dissemination. The extent to which cloned metastatic and nonmetastatic LLC cells migrated out of glass capillary tubes in vitro reflected their capacity to form pulmonary metastases in vivo. The addition of PGE2 to metastatic LLC cells further stimulated their migration. Other cyclooxygenase products, besides PGE2, did not stimulate the migration of metastatic LLC cells. Nonmetastatic LLC cells did not migrate out of capillary tubes, even in the presence of exogenous PGE2. The amount of PGE2 secreted by cloned LLC cells was quantitated by a radioimmunoassay. Nonmetastatic LLC cells secreted more PGE2 than did the metastatic LLC cells. When the nonmetastatic LLC cells were either mixed with or placed adjacent to cloned metastatic LLC cells, the migration by the metastatic LLC cells was stimulated. The migration-stimulatory capacity of the nonmetastatic LLC cells was minimized in the presence of indomethacin, a prostaglandin synthesis inhibitor. Studies were conducted to relate these in vitro results to tumor metastasis in vivo. Injection of a mixture of metastatic and nonmetastatic LLC cells into mice s.c. resulted in a greater number of lung metastases than did injection of metastatic cells alone. This increase in metastasis formation was prevented by indomethacin. Formation of pulmonary metastases was also augmented when irradiated nonmetastatic LLC cells were injected into metastatic LLC-bearing mice. The results of our studies suggest that nonmetastatic LLC cells, by producing PGE2, can augment in vitro migration and in vivo dissemination of metastatic LLC cells. Thus, the response of tumor cells to PGE2, rather than simply their production of PGE2, appears to be important in regulating tumor dissemination.
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PMID:Effect of prostaglandin E2-producing nonmetastatic Lewis lung carcinoma cells on the migration of prostaglandin E2-responsive metastatic Lewis lung carcinoma cells. 310 29

In recent studies, we have demonstrated that recombinant human tumor necrosis factor (rH TNF), as a single agent, has only minimal therapeutic activity for the treatment of metastatic disease, but when combined with recombinant murine gamma-interferon (rM gamma-IFN), we observed significantly more therapeutic activity than when either agent was administered alone. However, this combination also resulted in increased toxicity. Thus, we undertook a systematic toxicologic study of rH TNF alone or in combination with rM gamma-IFN. Briefly, the toxicity was similar to the generalized Shwartzman's reaction seen during endotoxin shock, with multifocal microthrombi and ischemic necrosis as sequelae. Lesions were observed in the lungs, liver, gastrointestinal tract (preferentially in the duodenum and cecum), testes or uterus, and bone marrow. Our results suggest that TNF (either directly administered or induced in situ) and its induction of arachidonic acid metabolites form one element of toxicity in this model. This conclusion is supported by studies revealing that the toxicity of rH TNF in combination with rM gamma-IFN can be reduced by inhibitors of the cyclooxygenase/lipoxygenase pathway.
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PMID:Toxicity of tumor necrosis factor is synergistic with gamma-interferon and can be reduced with cyclooxygenase inhibitors. 311 9


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