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)

Circulating levels of immunoreactive (i) PGE, calcium and parathyroid hormone (iPTH) were examined in 21 patients with neoplasia and 3 patients with primary hyperparathyroidism. Plasma iPGE was elevated in 4 of 11 hypercalcemic cancer patients; all extracts of liver metastases obtained from 3 of these 4 patients had elevated iPGE levels (metastases = 19.43 +/- 3.43, n = 11; normal liver = 2.04 +/- 0.23; ng/g tissue, x +/- SE, P less than .001). In contrast, only one of 10 normocalcemic cancer patients and none of 3 hyperparathyroid patients had elevated plasma iPGE. There were no apparent relationships between the presence of metastases and either hypercalcemia or elevations of plasma iPGE. Serum iPTH levels were undetectable or below the mean of the normal range in 19 of 21 cancer patients; only the three hyperparathyroid patients had elevated levels. Seven hypercalcemic patients were treated with indomethacin; plasma iPGE decreased in 6 (-34 +/- 10% decrement, n = 6, P less than .01). Decreases in serum calcium occurred only in those patients (2 of 6) who had abnormally elevated plasma iPGE prior to the therapy. It is concluded that plasma iPGE elevations are found in some cancer patients, especially those with hypercalcemia, and that this marker may identify those patients who will respond to indomethacin treatment.
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PMID:Plasma prostaglandin E in patients with cancer with and without hypercalcemia. 100 18

Both clinical and experimental breast tumors often synthesize high levels of prostaglandins, most notably prostaglandin E2 (PGE2). We have reported previously that metastatic murine mammary tumor cells also express a high-affinity PGE2 receptor. We have now shown that the receptor plays a functional role in the metastasis of two mammary tumor cell subpopulations, lines 66 and 4526. We showed that three agents, LEO101 (LEO Pharmaceuticals), SC19220 (Searle Co.), and AH6809 (Glaxo Co.), antagonize [3H]PGE2 binding to these cells and block PGE2-mediated elevation of intracellular cyclic AMP. Pretreatment of line 66 cells with nontoxic concentrations of any of the three receptor antagonists prior to i.v. injection results in more experimental lung colonies. As shown previously, and confirmed here, pretreatment of these cells with indomethacin (which inhibits endogenous PGE synthesis and therefore increases detectable PGE receptor) inhibits metastasis. Thus, the tumor cell PGE2 receptor contributes to the ability of murine mammary tumor cells to metastasize.
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PMID:Role of the prostaglandin E2 receptor in mammary tumor metastasis. 184 40

The mechanisms of paraneoplastic hypercalcemic syndromes are heterogeneous. Neoplastic hypercalcemia without bone metastatic disease is caused by parathyroid hormone related protein, whose action is comparable to parathyroid hormone. Growth transforming factors, platelet derived growth factor, tumor necrosis factors and interleukin 1 are also involved in humoral hypercalcemia of malignancy. In addition to these substances, hypercalcemia in bone metastatic disease may be related to PGE. Tumor necrosis factors and interleukin 1 play a major role in multiple myeloma as well as in Adult T cell Leukemia/Lymphoma where overproduction of vit D3 by lymphomatous cells can also be significant.
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PMID:[Hypercalcemia and neoplasms: recent advances in pathogenesis]. 229 Oct 7

Since 1984, an experimental and clinical study on the relation between PGE and gastric carcinoma has been performed by determining PGE content in the bioptic gastric mucosa and plasma. It is found the PGE content in the gastric mucosa and plasma is increased in all patients with gastric cancer, especially with signet ring cell carcinoma. It is higher in the regional lymph node metastasis than in the early cancer, extensive metastases and normal subjects. The PGE content in the plasma is reduced obviously 7-10 days after operation but is increased markedly in recurrent patients. There is no significant difference in extensive metastases, relapse free and normal subjects. The PGE content in the plasma is significantly higher in gastric carcinoma than in chronic atrophic gastritis, but no difference is present between chronic atrophic gastritis and normal subjects.
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PMID:[Prostaglandin E (PGE) and gastric carcinoma]. 303 44

The metastatic murine mammary tumor cell line 410.4 and its nonmetastatic counterpart tumor line 410 were examined for the presence of prostaglandin E2 (PGE2) binding using a 3H-PGE2 ligand binding assay. Inhibition of endogenous prostaglandin synthesis with indomethacin was shown to increase markedly binding of 3H-PGE2. Equilibrium binding data for tumor 410.4 show that specific binding is saturable, reversible by unlabeled PGE2, temperature-dependent and specific. PGE1, PGE2 or 16-16-dimethyl PGE2 compete well with 3H-PGE2 for binding. PGD2 partially inhibits 3H-PGE2 binding, whereas PGA2 does not compete. Scatchard analysis of equilibrium binding data reveals a high affinity (Kd = 3.9 X 10(-9) M) and an average of 33,785 binding sites/cell. In contrast, binding of 3H-PGE2 to nonmetastatic line 410 has a slightly lower affinity (Kd = 8.8 X 10(-9) M) and an average of 368,857 binding sites/cell. 3H-PGE binding to line 410 cells is comparatively nonspecific as PGD2 is nearly as effective as PGE1, PGE2 and an analogue of PGE2 in competing with 3H-PGE2 and PGA2 also inhibits 3H-PGE2 binding.
Invasion Metastasis 1988
PMID:Heterogeneity of prostaglandin E2 binding in murine mammary tumor cells differing in metastatic potential. 342 34

Our earlier work revealed that PGE-mediated inactivation of NK cells in tumor-bearing mice by host macrophages promoted spontaneous lung metastasis that could be prevented or ameliorated by chronic indomethacin therapy. Since PGE was found to suppress the in vitro development and/or activation of a family of tumoricidal lymphocytes such as CTL, NK, and LAK cells by one or both of two mechanisms, that is to say, a down regulation of IL-2-R and an inhibition of IL-2 production, the present study tested whether a combined therapy with indomethacin and IL-2 was more effective than one with indomethacin or IL-2 alone in ameliorating established experimental lung metastasis. B6 mice injected intravenously with 10(6) highly metastatic B16F10 melanoma cells showed profuse micrometastases in the lungs by day 5, and macrometastases by day 10 which were confluent on day 21. Chronic indomethacin therapy by the oral route (14 micrograms/ml in drinking water) starting on day 0 or day 5, or a single round of IL-2 therapy (25,000 U rIL-2, every 8 h for 5 d on days 10-14) reduced the number of metastatic nodules by two-thirds (from a median of 473 in control mice receiving vehicles alone) by day 21. A single round of IL-2 as above, combined with either protocol of indomethacin therapy, completely or nearly completely irradicated the lung metastases, corroborated by a histological examination. An evaluation of splenic killer cell activity measured with a 4-h 51Cr-release assay against NK-sensitive YAC-1 lymphoma and B16F10 melanoma or NK-resistant thymic lymphoma 9705 targets revealed negligible activity in control tumor-bearing mice, and a good restoration of activity against NK-sensitive targets with either protocols of indomethacin therapy. IL-2 alone or a combination of IL-2 and indomethacin given by either protocol generated strong killer activity against all these targets, most marked with the combination therapy. Splenic killer cell phenotype in normal as well as all treated animals was ASGM1+, Thy-1-, and Lyt-2-. The combination therapy resulted in the strongest mononuclear cell infiltration in the lungs, with areas of young granulation tissue suggestive of repair sites of original metastases.
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PMID:Amelioration of B16F10 melanoma lung metastasis in mice by a combination therapy with indomethacin and interleukin 2. 349 67

The immune regulation of phytohemagglutinin (PHA) and concanavalin A (Con A) mitogen responses by prostaglandin (PG)-producing suppressor monocytes was examined in 57 patients with colorectal cancer and 55 normal individuals. The blood lymphocyte responses to either PHA or Con A were significantly depressed in 74% of patients compared to normal controls. The mean PHA response for the patients was significantly lower than that for controls (17,649 versus 25,549 cpm, P = 0.02), while the mean Con A response for the patients was also depressed but not as significantly (13,551 versus 18,623 cpm, P = 0.09). The depression of immune competence was greatest in older patients and those with metastatic disease. The addition of indomethacin (1 microgram/ml) to cell cultures of both patients and normal individuals enhanced the mitogen response, suggesting that PGE-producing suppressor cells were operative in both groups. Among the patient group, however, a differential modulation of the immune response by indomethacin was observed. Thus, the addition of indomethacin restored the PHA response in patients almost to normal levels, while the Con A increase was less pronounced. Even after indomethacin treatment, the Con A proliferative response by lymphocytes was significantly depressed in patients as compared to controls (P = 0.002). To prove that indomethacin was blocking excessive PG production by suppressor monocytes in colon cancer patients, we directly measured PGE2 production by peripheral blood mononuclear cells (PBMCs) using a radioimmunoassay. PBMCs from the patients produced significantly greater amounts of PGE2 compared to controls (10.1 versus 5.1 ng/ml, P = 0.0001). This comparison was still significant after adjustment for age and sex. The increased PGE2 production appeared to be selective, since the levels of two other arachidonic acid metabolites, PGF1 alpha and thromboxane B2, were the same or less than control levels. PG-mediated immune suppression of mitogenesis thus appears to be abnormally increased in colon cancer patients, particularly for the PHA response. This abnormality was partially corrected in vitro by incubation of the PBMCs with indomethacin, a prostaglandin synthetase inhibitor.
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PMID:Prostaglandin E2-mediated suppression of cellular immunity in colon cancer patients. 622 53

Growth and metastasis to the lung of the human breast cancer cell line MDA-MB-435 in nude mice fed a high-fat (20% wt/wt) high-linoleic acid (LA; 12% wt/wt) diet were significantly reduced by the addition of the cyclooxygenase inhibitor indomethacin to the drinking water at a dose of 10 micrograms/ml (approximately 1 mg/kg body wt). No toxicity was observed in these mice; at 20 micrograms/ml indomethacin, gastric ulcerations occurred. After necropsy, tumor eicosanoids were measured by radioimmunoassay in the control and 10 micrograms/ml indomethacin treatment groups. Levels of the cyclooxygenase products prostaglandin (PG) E (PGE), 6-keto-PGF1 alpha, and thromboxane B2 (TxB2) were significantly reduced in indomethacin-treated mice compared with controls; however, the 6-keto-PGF1 alpha-to-TxB2 ratio was significantly increased. Two lipoxygenase products, 5-hydroxyeicosatetraenoic acid (5-HETE) and 15-HETE, were unaffected, but the 12-HETE levels were increased compared with the untreated high-LA-fed group. Metastases to the lungs in mice fed a high-fat low-LA (2% wt/wt) diet were also reduced compared with those in the high-LA-fed control mice, but whereas tumor cyclooxygenase and lipoxygenase product levels were reduced, no change in the 6-keto-PGF1 alpha-to-TxB2 ratio was observed. The use of selective cyclooxygenase inhibitors may prevent LA-mediated progression of breast cancer at several levels of the metastatic cascade, among which may be interference with tumor cell-vascular endothelial cell interaction and with angiogenesis.
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PMID:Dietary linoleic acid-stimulated human breast cancer cell growth and metastasis in nude mice and their suppression by indomethacin, a cyclooxygenase inhibitor. 877 66

Non-steroidal anti-inflammatory drugs (NSAIDs) have been reported to reduce the risk and mortality of colorectal cancer (CRC). Although the exact mechanisms remain unclear, the inhibition of cyclooxygenase (COX) by NSAIDs appears to abort, if not prevent, CRC carcinogenesis or metastatic tumor progression. The aim of our study was to investigate the association between COX-2 expression and CRC tumor cell invasiveness. The differences in immunoblot-detectable COX-2 protein contents in primary CRCs, metastatic hepatic lesions and corresponding normal mucosa from the same individual were evaluated in 17 patients. Three different colon cancer cell lines, SW620, Lovo, HT-29 and a metastatic variant of HT-29, HT-29/Inv3, were employed to evaluate COX-2 expression and prostaglandin E(2) (PGE2) production in relation to their invasive abilities in vitro. The effects of a COX-2-selective inhibitor, etodolac, on cell proliferation and invasive activity were also determined. The results showed that 15 of 17 (88%) metastatic CRC cells from the liver and 14 of 17 (82%) primary CRC tissue exhibited much higher levels of COX-2 than corresponding adjacent normal mucosa from the same patient. Among those patients with relatively high COX-2 expression in the primary tumors, almost all exhibited even higher levels of COX-2 in their hepatic metastases. Among the 4 colon cancer cell lines, HT-29/Inv3 manifested the highest COX-2 expression, PGE2 production and in vitro invasive activity. The selective COX-2 inhibitor, etodolac, could especially exert cytotoxicity and markedly suppress the invasive property and PGE(2) production, although not the COX-2 protein level, in HT-29/Inv3 cells. Our results imply that COX-2 expression may be associated with the invasive and metastatic properties of CRC tumor cells.
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PMID:Tumor invasiveness and liver metastasis of colon cancer cells correlated with cyclooxygenase-2 (COX-2) expression and inhibited by a COX-2-selective inhibitor, etodolac. 1127 97

(89)SrCl(2) is currently used as a systemic radioactive palliative treatment for painful osseous metastases associated with an osteoblastic reaction in bone. However, the biological mechanism by which (89)SrCl(2) mediates pain palliation remains unclear. In this study, attempts were made to elucidate the mechanisms by which (89)SrCl(2) might influence pain at these sites. Both the direct radiotoxic effects of (89)SrCl(2) on cell viability and its influence on cellular biosynthetic activity were investigated. The direct radiotoxic effects of (89)SrCl(2) and X-rays were compared using the prostate carcinoma cell line, PC-3. Comparable effects upon PC-3 cell viability were seen in response to exposure to an equivalent dose given by (89)SrCl(2) and X-rays (2 Gy). Experiments to investigate the indirect action of (89)SrCl(2) exposure employed the MC3T3-E1 cell line and focused on their production of Prostaglandin E(2) (PGE(2)) and interleukin-6 (IL-6). Exposure of the MC3T3-E1 cell line to (89)SrCl(2) resulted in an increased production of PGE(2) in a concentration-dependent manner. No increased PGE(2) production was seen by the MC3T3-E1 cells in response to X-ray exposure either in the presence or absence of SrCl(2). IL-6 was produced by the MC3T3-E1 cells in response to (89)SrCl(2) exposure via a PGE(2)-mediated pathway. This study demonstrates the release of potent biochemical modifiers of bone turnover in response to the systemically applied radiotherapeutic (89)SrCl(2). This strongly suggests the mechanism of pain palliation by (89)SrCl(2) is likely to result from a complex interaction of direct and indirect radiation-induced effects.
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PMID:Biochemical responses in cultured cells following exposure to (89)SrCl(2): potential relevance to the mechanism of action in pain palliation. 1172 Aug 44


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