Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Spleen cells removed from C57Bl/6J mice bearing a methylcholanthrene-induced fibrosarcoma (MC-16) demonstrate suppressed responsiveness of phytohemagglutinin (PHA) and bacterial lipopolysaccharide (LPS) induced mitogenesis as compared to non-tumorous mice. A similar depression of PHA-induced mitogenesis was observed with spleen cells from C3H/HeJ mice bearing syngeneic mammary adenocarcinomas (C3HBA). The administration of indomethacin, a non-competitive irreversible prostaglandin (Pg) synthesis inhibitor, (75 or 100 mug/mouse, IP) on an alternate day basis to groups of tumor-bearing mice of both strains, significantly enhanced immune cell responsiveness to mitogenic stimulation. The addition of indomethacin (10 mug/ml) to cultures of spleen cells from these tumor-bearing mice, as well as to DBA/1J mice bearing the Cloudman S-91 melanoma, enhanced spleen-cell responsiveness to mitogen-induced DNA synthesis by as much as 156%. Indomethacin administration in vivo or in vitro had no significant effect on mitogen-induced DNA synthesis of spleen cells from non-tumor-bearing animals. It is hypothesized that tumors, or tumor-cell antigens, increase Pg production of a population of spleen cells, and that the increased Pg content of the spleen may be important in controlling immune responsiveness in mice.
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PMID:Indomethacin enhancement of spleen-cell responsiveness to mitogen stimulation in tumorous mice. 18 13

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

Therapeutic responses to systemic administration of interferon-beta (IFN-beta) were studied in 13 patients with malignant melanoma. Of 4 patients with stage IV malignant melanoma receiving systemic IFN-beta therapy alone, none showed any effective result (1MR, 3NC). Treatment with IFN-beta combined with chemotherapy, e.g. DTIC, produced a clinical improvement in 2 of 5 patients with malignant melanoma (1CR, 1PR, 2NC and 1PD). IFN-beta therapy has been performed by intravenous drip infusion concomitantly with chemotherapy before or after surgery, for prevention of metastasis in 4 cases of malignant melanoma (stage Ib, 1 case; stage II, 2 cases; stage III, 1 case). Three patients with stage Ib to II have been progressing favorably without metastasis over the past 3 years and 2 months. Patients receiving indomethacin suppositories for fever associated with IFN-beta therapy were examined for plasma and urinary IFN-beta activity levels. No significant difference was observed whether indomethacin was administered or not. Indomethacin is therefore considered to have no appreciable influence on IFN-beta therapy.
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PMID:[Therapeutic response of interferon-beta in malignant melanoma]. 242 45

alpha-Interferon has antitumor activity in a variety of malignancies but is frequently associated with unacceptable toxic side-effects. The routine use of agents potentially capable of reducing these side-effects has not been recommended out of concern for possible reductions in the therapeutic activity of interferon. We conducted a prospective randomized trial of alpha-interferon given with or without indomethacin to patients with malignant melanoma to determine what effect, if any, indomethacin might have on the toxic, immunomodulatory, and therapeutic properties of interferon in this disease. 53 patients were stratified according to performance status and randomized to receive alpha 2b-interferon, 20 million units per m2 i.v., 5 days per week for 4 weeks followed by 10 million units per m2 s.c. three times per week, either with or without indomethacin, 25 mg orally three times a day. The overall major response rate was 13% (three complete responders and three partial responders among 47 evaluable patients) and was the same on both arms. The mean maximal temperature elevation induced by interferon was significantly reduced (from 102.1 to 100.7, P = 0.0002) by indomethacin, but the incidence and severity of interferon-related fatigue, reduction in performance status, headache, depression, confusion, elevations in liver function tests, and myelosuppression were no different in either arm of the study. Indomethacin did not reduce the frequency of dose reductions for toxic side-effects and did not permit the administration of higher interferon doses. Peripheral blood natural killer activity was significantly enhanced in patients during maintenance therapy whether or not they received indomethacin. Indomethacin appeared to inhibit augmentation of natural killer activity during high dose induction therapy. Immunological changes did not correlate with response status. We conclude that indomethacin can reduce the fever associated with interferon therapy in patients with malignant melanoma without interfering with its therapeutic or chronic immunomodulatory activities. Since fever is rarely the dose-limiting toxicity of interferon, indomethacin is of marginal benefit to patients with malignant melanoma receiving interferon at the doses outlined in this study.
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PMID:Randomized trial of recombinant alpha 2b-interferon with or without indomethacin in patients with metastatic malignant melanoma. 264 94

Treatment of BALB/c, C57Bl/6 or C3H/HeJ mice with non-toxic concentrations of indomethacin (75-100 micrograms/day) led to a depression of plasma neutral proteinase activity as determined with an (125I)-caseinolytic assay. Lower concentrations of indomethacin (50 micrograms/day), aspirin (1 mg/day), LiCl (3 meq/kg/day), Sulindac (100 micrograms/day), indomethacin analogs (MK-410, MK-555) or lipopolysaccharide (100 micrograms) did not induce depression in proteinase activity. Indomethacin did not directly inhibit the proteinase activity of normal plasma in vitro. The in vivo effects of indomethacin were reversible and plasma proteinase activity returned to normal values within 8 days of cessation of treatment. These results indicate that indomethacin can uniquely alter plasma proteinase homeostasis in normal mice. While effective in depressing the plasma proteinase activity of normal mice, treatment of mice bearing either the BCL1 leukemia or the B16-F10 melanoma with indomethacin did not depress the elevated plasma proteinase levels detected in tumor-bearing animals. Thus the elevation in proteinases detected in tumor-bearing animals may not be the result of increased prostaglandin synthesis and plasma proteinase activity in such disease states may be regulated differently than in normal mice. However, the ability of this potent anti-inflammatory agent to alter proteinase metabolism may contribute to its therapeutic efficacy in the management of inflammatory disease.
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PMID:Indomethacin induces the suppression of plasma neutral proteinase activity in mice: possible relationship to efficacy as an anti-inflammatory drug and induction of alterations in the immune system. 302 Feb 55

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

Mononuclear blood cells from 40 healthy donors, 25 patients with melanoma and 35 patients with lung cancer were tested for suppressor cell activity and response to phytohemagglutinin (PHA). The suppressor cell activity was measured by determining the ability of Mitomycin C (MMC)-treated mononuclear cells from patients and controls to suppress the in vitro response of responder cells to PHA. Mononuclear cells from one healthy donor were stored in liquid nitrogen for use as responder cells. Indomethacin-sensitive suppression was also measured. In both groups of patients the mean values of suppressor cell activity in co-culture were higher than those in control group. When patients were subdivided in groups according to the clinical stage, the level of suppressor cell activity increased with the stage. Indomethacin-sensitive suppression was detected in some patients but the differences between patient and control groups were not statistically proved. An inverse relationship was observed between indomethacin-sensitive suppression and the PHA response.
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PMID:Suppressor cells in melanoma and lung cancer: correlation with the clinical stage. 622 Nov 96

Indomethacin significantly enhances the depressed levels of lymphocyte proliferation to the mitogens phytohemagglutinin and concanavalin A in melanoma patients. We postulated that these results were related to an abnormality in prostaglandin E2 (PGE2)-mediated suppression, since this mechanism has previously has previously been demonstrated in patients with Hodgkin's lymphoma and with head and neck carcinoma. However, the results of three experimental approaches did not support this hypothesis. First, in vitro PGE2 production by cultured blood mononuclear cells was the same in 16 melanoma patients as in 45 normal controls (4.9 versus 4.7 ng/ml). Second, lymphocyte sensitivity to PGE2 for melanoma patients was essentially the same as that for normal controls, since exogenous doses of PGE2 inhibited the mitogen responses to the same degree. Third, another prostaglandin synthetase inhibitor (RO-205720), which is structurally unrelated to indomethacin, did not augment the mitogen response in these patients. Thus PGE2 cannot be implicated as a mediator of immunosuppression in melanoma patients. To further examine the immunomodulatory mechanism of indomethacin, we preincubated the drug with purified populations of either lymphocytes or monocytes, which were then recombined and tested for mitogen response. The results suggested that indomethacin had a direct effect on the responding T lymphocytes rather than an indirect effect on monocytes. These are the first studies demonstrating that indomethacin can act directly as a modulator of cellular immune function, independent of PGE2-mediated suppression.
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PMID:Immune modulatory effects of indomethacin in melanoma patients are not related to prostaglandin E2-mediated suppression. 628 58

Indomethacin is a non-steroidal anti-inflammatory agent that inhibits prostaglandin synthesis. Administration of indomethacin, in doses which were non-toxic to normal BALB/c mice, to mice bearing the BCL1 leukemia resulted in increased mortality of these animals. This effect was only observed if the indomethacin was administered to animals with advanced disease (splenomegaly, hepatomegaly and leukemia). If indomethacin treatment was initiated prior to transplantation of the tumor or 2 weeks post-transplantation, and continued throughout the disease process, there was no effect on either the course of the disease or mortality. Injection of similar doses of indomethacin into mice bearing advanced B16 melanoma tumors did not result in increased mortality. Therefore, metabolic changes which occur in the leukemic animals may uniquely alter host sensitivity to this non-steroidal anti-inflammatory agent. The BCL1 leukemia may be a useful animal model to provide insights into the biochemical basis for the adverse reactions experienced by some Hodgkin's disease patients when they are treated with anti-inflammatory agents such as indomethacin.
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PMID:Increased sensitivity to indomethacin of mice bearing the BCL1-leukemia. 674 40

The potential interaction between cyclooxygenase (Cox) and NO metabolic pathways in the control of local tumor growth was evaluated. Mice bearing either a sarcoma-derived tumor (C57B1; MCG 101) or a malignant melanoma (C3H/HeN; K1735-M2) were used. These models were principally different because they demonstrate, in tumor hosts, conditions with and without cancer cachexia, seemingly related to high and low production of prostanoids, respectively. Cox inhibitors (Cox-1 and Cox-2) decreased tumor growth by 35-40% in MCG 101-bearing mice but had no such effect on melanoma-bearing mice, despite the expression of the Cox-2 protein in melanoma cells. Indomethacin reduced prostanoid production in both tumor (MCG 101) and host tissues and reduced tumor cell proliferation, mainly in vivo. Nitric oxide synthase (NOS) inhibitors (N(omega)-nitro-L-arginine methyl ester and N(omega)-nitro-L-arginine) reduced tumor growth in vivo by approximately 50% in both tumor models. Tumor growth reduction, related to NOS inhibition, was unrelated to prostanoid production and was an in vivo phenomenon in both tumor models. Specific inhibitors of inducible NOS activity, unexpectedly, had no effect in any tumor model, although inducible NOS protein was present in tumor tissues in large amounts. A combination of Cox and NOS inhibitors had no additive effect on tumor growth (MCG 101). Cox inhibition increased tumor tissue (MCG 101) expression of cNOS mRNA but had no significant effect on tumor tissue expression of the transferrin receptor, vascular endothelial growth factor, or basic fibroblast growth factor. NOS inhibition increased tumor tissue content of cNOS mRNA but showed as well a trend to increase mRNA content of the transferrin receptor and vascular endothelial growth factor. Our results suggest that NOS inhibitors can decrease the local growth of tumors that are either responsive or unresponsive to Cox inhibition. This effect may reflect cross-talk between Cox and NOS pathways within or among tumor cells, or it may represent unrelated effects on tumor and host cells. Whether NO inhibition may be used therapeutically in clinical tumors that are unresponsive to eicosanoid intervention remains to be evaluated.
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PMID:Effect of cyclooxygenase and nitric oxide synthase inhibitors on tumor growth in mouse tumor models with and without cancer cachexia related to prostanoids. 1074 48


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