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)

Rabbits were injected with VX2 cancer cells into the left thigh or tibia, and given indomethacin 1-16 mg/kg daily starting on the day before tumour implantation or 7, 14 or 21 days after implantation. Indomethacin at 2 mg/kg and above from before tumour implantation reduced osteoclast proliferation and the amount of prostaglandin-like material extracted from homogenates of excised tumours, but the inhibition of bone destruction in vivo was significant only with indomethacin at 4 mg/kg and above. Indomethacin at 8 mg/kg reduced osteoclast proliferation and bone destruction, but the effect was statistically significant only when given within 7 days of inoculation with the tumour. The place of indomethacin and other inhibitors of prostaglandin synthesis has not yet been established in the management of patients with skeletal metastases. Drug administration might need to be started at the time of diagnosis and removal of the primary tumour, rather than when skeletal metastases are evident.
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PMID:Timing of indomethacin in the control of prostaglandins, osteoclasts and bone destruction produced by VX2 carcinoma in rabbits. 50 64

Prostaglandin synthetase inhibitors have, in the past, been shown to inhibit osteolysis caused by breast carcinoma tissue in vitro. We therefore assessed the effect of Indomethacin and aspirin on some parameters of calcium metabolism in patients with breast cancer. Neither drug reduced the serum calcium in pateints with hypercalcemia, nor reduced skeletal destruction as measured by the urinary hydroxy proline: creatinine ratio and urinary calcium in normocalcemic or hypercalcemic patients with osteolytic metastases. A possible reason for the discrepancy between results obtained in vitro and in vivo is that there are two phases of bone destruction in breast cancer; the early phase dependent and the late phase independent of prostaglandin synthesis.
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PMID:Failure of indomethacin to reduce hypercalcemia in patients with breast cancer. 100 35

Preclinical models of advanced melanoma have shown that chronic indomethacin therapy combined with interleukin 2 (IL-2) can eradicate experimental metastases. A phase II trial was done in patients with advanced melanoma. Indomethacin and ranitidine were begun at least one week before IL-2. Of the objective responses in 3 patients, 2 were achieved on ranitidine and indomethacin alone, before start of IL-2. Indomethacin and ranitidine may be responsible for some responses in melanoma patients previously attributed to IL-2.
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PMID:Effect of indomethacin plus ranitidine in advanced melanoma patients on high-dose interleukin-2. 135 39

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

The in vivo effect of indomethacin therapy in head and neck cancer was tested using rats (Fisher 344) with implanted epithelial palatal carcinoma. Indomethacin was then given to half of the rats in their drinking water, starting two weeks after tumor implantation. The animals were then killed at four weeks and the tumor volumes were measured. It was found that four (21%) of the 19 rats were complete responders and eight (42%) of the 19 rats were partial responders. The control group showed increased tumor growth in all animals. The experimental group also demonstrated five (26%) of the 19 regional metastases. No metastases were seen in the control group. Indomethacin seems to inhibit local tumor growth, perhaps through its effects on cellular and humoral immunity and its effects on the host-tissue stroma. It also may increase tumor spread through the regional lymphatics or hematogenously. Further animal studies need to be carried out to determine the effect on cancer on a cellular and biochemical level before using it for treatment of cancer in humans.
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PMID:The effect of indomethacin on the growth of epidermoid carcinoma of the palate in rats. 663 38

Indomethacin treatment to rats bearing dimethylhydrazine-induced colonic cancer resulted in increased mortality (p less than 0.01) and a greater incidence of metastases compared to untreated animals with the same stage of disease. It is postulated that indomethacin might have a promotional effect on the spread of autochthonous experimental colon cancer.
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PMID:Enhancement of colonic cancer by indomethacin treatment in dimethylhydrazine pretreated rats. 669 45

The in vivo administration of a prostaglandin-synthetase inhibitor inhibited or reduced tumor growth in cancer patients and experimental animals. Indomethacin, a prostaglandin-synthetase inhibitor and nonsteroidal anti-inflammatory agent commonly used in the management of arthritic patients, acted as an immune adjuvant by decreasing the production of prostaglandins. Seven cases demonstrated that indomethacin taken in the usually recommended dosages causes regression and stabilization of head and neck cancer. The following factors were also considered in this study: prostaglandin production, a survey of other reports of solid neoplasm response to prostaglandin-synthetase inhibitor administration, drug toxicity, irradiation therapy and metastases, the need for tumor biopsy, and the role that reduction in inflammation plays in tumor shrinkage.
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PMID:Regression of head and neck carcinoma with a prostaglandin-synthesis inhibitor. 729 59

Prostaglandin E2 (PGE2) is known to downregulate the generation of lymphokine-activated killer (LAK) cell activity. Indomethacin, an inhibitor of cyclooxygenase catalyzing the biosynthesis of PGE2, has been shown to augment LAK cell activities generated from peripheral blood mononuclear cells of normal healthy individuals. This study was undertaken to examine whether or not this augmentation is also a common phenomenon in cancer patients. LAK cell activities generated in the presence and the absence of indomethacin were examined in 15 normal healthy individuals and in 83 cancer patients. Paired data analysis revealed that indomethacin exhibited a significant augmentation of LAK activity generated from healthy individuals. Indomethacin enhanced LAK activity in patients with no distant metastases (TxNxM0); but depressed LAK activity in patients with distant metastases (TxNxM1). In patients without distant metastases, indomethacin showed an upregulating effect on LAK activity in those with an early T stage (T1-2NxM0), and no such effect was detected in those with a late T stage (T3-4NxM0). Indomethacin also significantly enhanced LAK cell generation in cancer patients with an ECOG performance status of 1, but significantly inhibited LAK cell generation in patients with a performance status of 4. These results indicated that indomethacin inhibited generation of LAK cell activity in cancer patients with a poor performance status or with distant metastatic disease, who normally would be the subjects of adoptive immunotherapy. Further, PGE2 production in cultured LAK cell medium was suppressed by indomethacin in all 20 cancer patients that were examined, suggesting that other yet to be identified factors or mechanisms may be responsible for the paradoxical effects of indomethacin on LAK cell activity.
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PMID:Effects of indomethacin on lymphokine-activated killer cell activities in cancer patients. 760 4

Sulindac is useful in regression of adenomatous polyps. In addition to orally administered sulindac, rectal preparations also appear to be efficacious [32]. However, further studies are necessary to determine whether regression of adenomas, the precursor of colorectal cancer, will cause decrease in colorectal cancer risk in both FAP and non FAP patients. Moreover, clinical studies are needed to test the application of this potential chemopreventative drug in several other patient populations. Several interesting observations have been made concerning the use of sulindac. Indomethacin, a related NSAID to sulindac, did not cause polyp regression. Also, upper gastrointestinal tract polyps in the stomach and duodenum appear not to be affected by sulindac therapy. These observations might be explained by the metabolism of sulindac in which the pharmacologically active sulfide metabolite is generated and distributed in the large intestine. Also, investigators noted that after discontinuation of sulindac adenomas recurred. Sulindac treatment was well tolerated at the usual clinical doses. Although some investigators have speculated on the effect of prostaglandin inhibition sulindac on cAMP-dependent mechanisms which control cellular proliferation [33], the cause of adenoma regression is unknown. There is evidence that colorectal endogenous prostaglandin levels decrease with sulindac. Evaluation of colorectal mucosal cellular proliferation in patients treated with sulindac has revealed a decrease in labelling index by bromodeoxyuridine labeling in one study [28] but no change in labelling index by [3H]thymidine incorporation in another investigation [34]. Also, ki 67 labelling index, another measure of cellular proliferation, was not affected in the colorectal mucosa of patients taking sulindac.(ABSTRACT TRUNCATED AT 250 WORDS)
Cancer Metastasis Rev 1994 Dec
PMID:Sulindac and polyp regression. 771 90

Tumor cells in bone metastases are thought to induce bone resorption primarily by releasing paracrine factors. Parathyroid hormone related protein (PTHrp) has been proposed to mediate osteolytic activity of many tumors. PTHrp is produced by 40% to 60% of breast tumors and is elevated in the serum of up to 50% of patients with breast cancer metastases to bone. Most biologic processes in humans are heterogeneous in nature, so the purpose of this study was to investigate the hypothesis that paracrine factors other than PTHrp could mediate bone resorption by breast tumor cells. Serum-free conditioned medium (CM) was collected from five human breast tumor cell lines and tested for bone resorption-stimulating activity (BRSA) in mouse calvaria organ cultures. CM from all tumor cells studied produced significant bone resorption, comparable to that produced by 10 nM PTH. Small amounts of immunoreactive PTHrp (1.4-12.5 pM) were produced by all breast tumor cell lines. When tested in vitro, equivalent amounts of human PTHrp [1-36] did not produce significant bone resorption. Indomethacin (1 microM) significantly blocked BRSA by CM from all cell lines but did not decrease BRSA by PTHrp. In contrast PTHrp antibody (130 micrograms/ml) completely blocked BRSA by 1 nM PTHrp but did not modify BRSA by CM of breast tumor cells. The results of this study support the hypothesis that breast cancer cells release paracrine factors in vitro that stimulate bone resorption by a mechanism that is partially dependent on prostaglandin synthesis and at least in part different from that of PTHrp.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Parathyroid hormone-related protein: primary osteolytic factor produced by breast tumor cells in vitro? 775 38


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