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)

23 (60%) of 38 human breast carcinomas had significant in-vitro osteolytic activity. All patients presenting with bone metastases or hypercalcaemia had active tumours. Over a subsequent three-year follow-up period, bone metastases did not develop in any of the 15 patients with inactive tumours, and metastases at other sites developed in only 2. Of the 23 patients with active tumours, 7 either had, or have since developed bone metastases; in 4 of these hypercalcaemia also developed. 14 tumours, chosen at random, were tested for in-vitro osteolytic activity in the presence and absence of aspirin, which inhibits prostaglandin synthetase. The activity of 8 of the 9 osteolytically active tumours was significantly, though not completely inhibited by aspirin. Although the number of patients is limited, these results indicate that the in-vitro osteolysis assay may detect substances, perhaps including prostaglandins, produced by breast tumours which affect prognosis and contribute to the subsequent formation of bone metastases.
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PMID:Breast-cancer osteolysis, bone metastases, and anti-osteolytic effect of aspirin. 5 92

Patients with breast cancer and bone destruction were found to have a pattern of calcium metabolism which was broadly similar to that found in other malignancies, but different from that in primary hyperparathyroidism. Thus, they tended to have reduced absorption of calcium from the intestine, elevated endogenous faecal calcium and normal or reduced urinary cyclic AMP excretion. Since prostaglandin synthetase inhibitors have been shown to inhibit breast cancer-induced osteolysis in vitro we have attempted to reduce bone destruction and serum calcium in patients with hypercalcaemia complicating breast cancer using these agents. High doses failed to reduce the serum calcium or the urinary hydroxyproline: creatinine ratio in ten patients with skeletal metastases, four of whom had hypercalcaemia.
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PMID:Calcium metabolism in breast cancer. 87 Sep 1

Therapy should be individualized on the basis of patient symptoms, severity of hypercalcemia, and prospects for inducing a remission in the underlying malignancy. We have found the most effective approach to be vigorous hydration of the patient, usually intravenously with normal saline at a rate of 300 to 500 mL/h. Intravenous furosemide is given as needed to prevent fluid overload. If the patient is volume replete and if hypercalcemia persists after 24 to 48 hours of intravenous hydration, calcitonin, 200 MRC units subcutaneously every 12 hours plus prednisone, 20 mg orally four times daily, are added. In most cases, a response is seen shortly after institution of this therapy. Meanwhile, attempts to treat the malignancy are initiated, including palliative radiation therapy for bony metastases. If the patient is still hypercalcemic and symptomatic after seven days of this therapy, treatment with plicamycin is given unless the patient's condition is clearly terminal. At present, use of prostaglandin synthetase inhibitors is not recommended, and bisphosphonates are available only for investigational use.
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PMID:Hypercalcemia of malignancy: diagnosis and therapy. 294 51

Interleukin-2 (IL-2) production following concanavalin A stimulation and the response of peripheral blood mononuclear cells (PBMC) to both IL-2 alone and IL-2 plus indomethacin, a prostaglandin synthetase inhibitor, were examined in 16 melanoma patients and 12 healthy controls. Mean IL-2 production by PBMC in 11 melanoma patients with metastatic disease (Stage III) was significantly decreased compared with controls and was moderately decreased compared with five patients with resected nodal disease (Stage II). Indomethacin restored IL-2 production in Stage III PBMC to levels equivalent to that produced by control PBMC. The PBMC of stage III patients also produced 40 times more prostaglandin E2 than PBMC from controls or Stage II patients. Indomethacin plus IL-2, but not IL-2 alone, was capable of restoring the low blastogenic response of PBMC of Stage III patients to normal levels. Hence, these data emphasize the importance for using IL-2 along with indomethacin for in vivo immunorestoration in disseminated melanoma.
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PMID:In vitro inhibition of interleukin-2 production by peripheral blood lymphocytes from stage III melanoma patients by prostaglandin E2: enhancement of lymphocyte proliferation by exogenous interleukin-2 plus indomethacin. 348 3

Hypercalcemia is common among patients with cancer and may be due to secretion by tumors of a humoral, calcemic, bone-resorbing factor or, alternatively, to skeletal metastases. In each case, hypercalcemia ultimately results from osteoclastic bone resorption. Therapy should be aimed at (1) reducing or eliminating tumor burden, (2) increasing renal calcium clearance, and (3) inhibiting osteoclastic bone resorption. Hydration with saline infusion and augmentation of calciuresis with furosemide should be the initial modes of therapy in most patients. Oral phosphorus should be used in hypophosphatemic patients. Glucocorticoids, calcitonin, and prostaglandin synthetase inhibitors may be effective in reducing bone resorption in selected patients. Mithramycin reliably induces a fall in serum calcium but long-term use is usually complicated by toxicity. A new class of drugs that inhibit osteoclastic bone resorption, the diphosphonates, is being employed in clinical trials in patients with malignancy-associated hypercalcemia. Results have been particularly promising with dichloromethylene diphosphonate.
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PMID:Therapy of malignancy-associated hypercalcemia: 1983. 621 80

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

Tissue prostaglandin (PG) content and production by human breast cancers were measured in 24 human mammary carcinoma specimens. The 5 compounds studied were PGE1, PGE2, PGF2 alpha, 6-keto-PGF1 alpha, and TXB2. The tissue content of all 5 compounds was higher in neoplastic tissue in comparison with the paired noncancerous breast tissue. However, microsomal PG synthetase activity in vitro in noncancerous and neoplastic breast tissue was comparable. Increased thromboxane formation was associated with three clinical variables--tumour size, axillary lymph node metastases and distant metastasis. A lesion negative for either oestrogen or progesterone receptor content tended to produce more TXB2 but lower PGE2 and 6-keto-PGF1 alpha. Results obtained in this pilot study may provide clues as to what direction future larger studies could take in the search for reliable prognostic indicators for breast cancer.
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PMID:Prostaglandins in breast cancer: relationship to disease stage and hormone status. 641 85

It has been assumed that the rate-limiting step in the ligand-induced synthesis of prostaglandins is the release of arachidonic acid from membrane phospholipid stores as a result of the activation of phospholipase. The assumption has been that the arachidonic acid is converted to PGH2 by the constitutive prostaglandin synthase/cyclooxygenase EC1.14.99.1 (PGS-1) enzyme present in cells. In this model, PGS-1 is proposed to be present in excess, and the production of arachidonic acid is thought to be rate limiting. However, a second prostaglandin synthase gene, PGS-2 has recently been described. The PGS-2 gene is induced by a variety of ligands, in cells as diverse as fibroblasts, monocytes, macrophages, smooth muscle cells, ovarian granulosa cells, epithelial cells, endothelial cells, and neurons. Moreover, PGS-2 induction is inhibited in nearly all contexts by glucocorticoids. It seems likely, therefore, that the regulation of PGS-2 expression plays a critical role in the production of prostanoids, both in normal physiological processes and in pathophysiological processes involving these paracrine mediators. In this review, we consider the regulation of the two genes, PGS-1 and PGS-2, that encode the isoforms of prostaglandin synthase.
Cancer Metastasis Rev 1994 Dec
PMID:Regulation of prostaglandin synthase-1 and prostaglandin synthase-2. 771 87

Despite undergoing a curative resection, many patients with colorectal cancer will develop and die of metastatic disease. It has been shown clinically and experimentally that surgery causes a transient period of immunosuppression, and it is postulated that this may encourage both the implantation of surgically disseminated tumor cells and the growth of existing micrometastases. The present study used natural killer cell cytotoxicity (NKCC) and tumor burden to evaluate perioperative modulation of immunocompetence in a murine model. We measured NKCC and tumor burden responses to a standardized surgical stress (SSS) alone, and to either morphine sulfate (MS) (15 mg/kg subcutaneously x 4 doses), ketorolac (a prostaglandin synthetase--prostaglandin E2--inhibitor) (2.5 mg/kg subcutaneously x 4 doses), or interleukin 2 (2,000 units intraperitoneally x 3 doses) administration with the SSS. In this model, we found that both low-dose interleukin-2 (IL-2) and ketorolac reversed the NKCC suppression associated with surgery, whereas morphine resulted in further depression of NKCC. In addition, IL-2 significantly decreased tumor incidence, whereas continuous MS exposure markedly increased tumor burden after surgery. These data suggest that IL-2 and ketorolac may be effective agents for the restoration of perioperative immune competence, whereas the use of continuous morphine might have significant deleterious effects.
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PMID:Perioperative immunomodulation in cancer surgery. 831 Nov 30

Cyclooxygenase-2 (COX-2), a prostaglandin synthetase, is involved in development of certain tumors. We therefore analyzed COX-2 expression in pancreatic cancer tissues (53 samples) and Panc-1 human pancreatic cancer cells by immunohistochemistry, RT-PCR and western-blotting analyses. Also, immunohistochemistry of proliferating cell nuclear antigen (PCNA) was performed. We found expression of COX-2 was dramatically upregulated in 36 of 53 cases (67.9%) and the expression of COX-2 was associated with the diameter (> 3 cm) of the tumors (p < 0.05), but not with the age, gender, tumor location, differentiation, lymph-node metastases and TNM stage. The positivity rate of PCNA expression in the pancreatic cancer cells of the COX-2 positive group (32.88 +/- 13.26%) was significantly higher than that in the COX-2 negative group (24.56 +/- 11.51%) (p < 0.05). Then we investigated the effect of selective inhibitors of COX-2 (NS398 and celecoxib) on proliferation of Panc-1 cells by 3-(4,5 dimethyl-2-thiazolyl)-2.5-diphenyl-2H-tetrazolium bromide (MTT) assay. Either NS398 or celecoxib suppressed proliferation of Panc-1 cells dose-dependently in vitro. Furthermore, Panc-1 cells were implanted into nude mice, and celecoxib was administrated orally with feed. The volume of the tumor xenografted into nude mice was decreased by 51.6% in the celecoxib group (p < 0.01). In conclusion, the increased expression of COX-2 may be responsible for rapid proliferation of pancreatic cancer, and specific inhibition of COX-2 suppresses proliferation of Panc-1 cells in vitro and in nude mice. The selective inhibitor of COX-2 may be an effectual agent for pancreatic cancer chemoprevention.
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PMID:Selective inhibition of cyclooxygenase-2 suppresses the growth of pancreatic cancer cells in vitro and in vivo. 1857 44


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