Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have studied the relative prostaglandin E (PGE) synthesizing abilities of a number of mammary tumor lines cultured in vitro. These lines differ in a number of biologic characteristics including tumorigenicity, immunogenicity and metastatic potential. They also synthesize different levels of PGE and these levels are in the same relative order as seen in situ. The metastatic tumor lines 4526 and 410.4 synthesize more PGE than does the non-metastatic tumor line 410. Synthetic activity of all lines decreases with time in culture. Relative synthetic capacity is not correlated with cell doubling time as the highest PGE levels are seen with the slowest growing (68H) and fastest growing (4526) cell lines. Indomethacin is able to inhibit the synthesis of PGE in vitro in a dose-dependent manner and the presence of indomethacin results in stimulation of cell division.
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PMID:Effects of indomethacin on the growth of cultured mammary tumors. 669 39

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

After binding a sensitizing tumor antigen, human leukocytes undergo a series of changes that lead to a loss of their glass-adherent properties; a phenomenon called leukocyte adherence inhibition (LAI). After surgery or when patients have a large tumor burden, their test results become negative. This study shows that in vitro incubation of the leukocytes for 5 min with PGE2 converted to positive the negative test, in an immunologically specific manner. The effect was critically dose-dependent, too little or too much did not alter the result. The same effect was achieved with PGE2, PGI2, aminophylline or other drugs that raise intracellular nucleotides, including dibutyryl cyclic AMP and dibutyryl cyclic GMP. Dibutyryl cyclic AMP stimulated a stronger response and 100 times less was needed than of dibutyryl cyclic GMP. Prostaglandins did not mediate LAI since Indomethacin failed to inhibit a positive test. Nonetheless, arachidonate metabolites were critical for the LAI phenomenon since BPB and mepacrine, inhibitors of phospholipase A2, negated the LAI response. Moreover, ETYA, phenidone and NDGA, inhibitors of the lipoxygenase metabolic pathway, all negated the positive LAI response. The positive response was especially sensitive to nullification by ETYA. Although the last-named drugs inhibit other arachidonate metabolic pathways too, conclusive evidence that the metabolites of the lipoxygenase pathway, and leukotrienes in particular, mediate the LAI response was the fact that FPL 55712, a competitive antagonist of SRS, nullified a positive response at levels as low as 10(-13) M. The results imply that prostaglandins were able to modulate the expression of LAI by affecting intracellular nucleotides, but leukotrienes, it seems, were the metabolites that mediated leukocyte nonadherence after monocytes recognized and bound tumor antigen.
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PMID:Modulation of antigen-induced leukocyte adherence inhibition by metabolites of arachidonic acid and intracellular nucleotides. 675 47

Inhibition of prostaglandin synthesis at the time of antigen presentation was used to test the role of prostaglandins in the inductive stage of the in vivo immune response to several antigens. Indomethacin and Ro 20-5720, two prostaglandin synthesis inhibitors, produced a several-fold enhancement of the primary immunoglobulin (Ig) M and IgG anti-sheep red blood cell plaque-forming cell (PFC) response in CAF1 mice. Indomethacin and Ro 20-5720 also enhanced the antibody response to chicken serum albumin (CSA) in buffered saline. However, the antibody response to CSA in Freund's adjuvant was reduced by indomethacin treatment. Indomethacin treatment enhanced the PFC response to a chicken lysozyme-lipopolysaccharide conjugate, and did not greatly affect the PFC response to pneumococcal polysaccharide. The allogeneic cytotoxic response to the El-4 tumor line was delayed by indomethacin treatment and, since this tumor does not synthesize prostaglandins, we speculate that prostaglandin synthesis by the host is important in the generation of a cytotoxic response to this tumor. It is concluded that the role of prostaglandins in the induction of the immune response varies, and can be proinductive or anti-inductive, depending on the eliciting antigen.
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PMID:Effects of prostaglandin synthesis inhibition on the immune response. 679 42

Aspirin and indomethacin, administered systemically by oral route, were found to delay the development of hamster buccal pouch epidermoid carcinomas induced by thrice weekly topical applications of a 0.5 percent solution of 7,12-dimethylbenz(a)anthracene (DMBA) in mineral oil. Forty male and female Syrian hamsters (Mesocricetus auratus) were divided into four equal groups. In Group 1 animals the left buccal pouch was painted thrice weekly with DMBA. Group 2 animals were painted thrice weekly with DMBA and received 12 mg. aspirin daily by oral route. Group 3 animals were painted thrice weekly with DMBA and received 1 mg. indomethacin daily by oral route. Group 4 animals were maintained as untreated controls. Two animals in each of the four groups were killed with ether at 8, 10, 12, 13, and 14 weeks after the start of the experiment. At the time of sacrifice the buccal pouches were photographed and the average number of tumors and the average size of tumors in each group were noted. The left and right buccal pouches were dissected, fixed in 10 percent formalin, sectioned in paraffin, and stained with hematoxylin and eosin. Autopsies were also performed on each animal. Both left and right buccal pouches and major organs were studied histologically. Both aspirin and indomethacin in the dosages used were found to delay DMBA buccal pouch carcinogenesis. A suggested mechanism of action is the inhibition of prostaglandin synthesis by the role of both aspirin and indomethacin as inhibitors of prostaglandin synthetase. Indomethacin appeared to exert a greater tumor-inhibiting effect than aspirin in the dosages used.
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PMID:Delay in hamster buccal pouch carcinogenesis by aspirin and indomethacin. 679 84

Maintenance and regulation of natural killer (NK) cell activity in human bone marrow cultures were studied using K562 leukemia cells as targets. Culture of bone marrow cells in medium supporting long-term generation of myeloid cells resulted in a rapid loss of NK activity in 1-3 days. In contrast, antibody-dependent cytotoxicity to an NK-resistant tumor was maintained for more than 7 weeks. Horse serum, a component of the myelopoietic culture medium, was found to diminish NK cytotoxicity of blood and bone marrow cultures whereas hydrocortisone supplement did not. In addition, an adherent cell is present in bone marrow which greatly inhibits NK activity. Nonadherent bone marrow cells exhibited higher cytotoxicity than unfractionated cells at all days of culture; adherent cells were not cytotoxic to K562. Purified adherent marrow cells inhibited the cytotoxic capacity of nonadherent blood or marrow mononuclear cells during coculture. Indomethacin, an inhibitor of protaglandin synthesis, augmented levels of NK activity in cultures of bone marrow cells, indicating that macrophages may be suppressing this effector function via prostaglandins. Further identification of the adherent suppressor cells came from experiments in which suppression was prevented by treatment of the adherent cells with monoclonal OKM1 antibody plus complement. This study shows that bone marrow-adherent OKM1-positive cells, presumably macrophages, negatively regulate NK activity, and it defines conditions for analysis of the generation and/or positive regulation of NK cells in human bone marrow.
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PMID:Suppression of natural killer activity in human blood and bone marrow cultures by bone marrow-adherent OKM1-positive cells. 683 66

The anti-inflammatory drug indomethacin was tested for antitumor activity against transplantable mouse colon adenocarcinoma 38 (colon 38). Groups of BDF1 mice (C57BL/6 X DBA/2) were given intraperitoneal injections of this drug beginning on the 6th day after subcutaneous implantation of the tumor and continued for 4 to 8 days. In other groups of mice, identical treatment was delayed until the 16th day after implantation of the tumor. The higher antitumor activity against colon 38 was obtained with earlier initiation of treatment, indicated by decreased growth of the tumor and increased life span of the host. The later initiation of the treatment produced less antitumor activity. The antitumor activity was, however, less than that of 5-fluorouracil, which was used as a positive control drug. The two drugs in combination produced few advantages over 5-fluorouracil alone using the dose schedule designed in the present experiment. Indomethacin treatment significantly reduced prostaglandin E and F levels in the tumor tissue, but 5-fluorouracil did not. It seems likely that the inhibition of prostaglandin biosynthesis by indomethacin underlies the antitumor effect of this drug on colon 38.
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PMID:Growth inhibition of transplantable murine colon adenocarcinoma 38 by indomethacin. 688 96

Retinoic acid induced lysozyme activity in mouse myeloid leukemia M1 cells. It also stimulated the synthesis and release of prostaglandins such as prostaglandin F2alpha, E2, and D2 by the cells. The particulate fraction of retinoic acid-treated M1 cells converted arachidonate to prostaglandins, and this conversion was almost completely inhibited by indomethacin. Retinol, retinal and retinyl acetate, but not the pyridyl analog of retinoic acid, also induced lysozyme activity and stimulated synthesis and release of prostaglandins. Indomethacin inhibited the induction of lysozyme activity by retinoic acid. The induction of lysozyme activity and the stimulation of prostaglandin E2 production were dependent on the concentration of retinoic acid. Kinetic studies showed that stimulation of prostaglandin E2 production by retinoic acid was followed by induction of lysozyme activity. The tumor promotor 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and phorbol 12,13-didecanoate inhibited the induction of lysozyme activity by retinoic acid, but 4 alpha-phorbol didecanoate and phorbol did not. TPA and phorbol 12, 13-didecanoate, but not 4 alpha -phorbol didecanoate, also inhibited the stimulation of prostaglandin E2 production by retinoic acid. These results suggest that stimulation by retinoic acid of prostaglandin E2 production in M1 cells is a prerequisite for the induction of lysozyme activity. On the other hand, both retinoic acid and TPA inhibited the induction by dexamethasone of phagocytic activity, which is a typical functional marker of differentiation of M1 cells, without causing significant growth inhibition. Suboptimal concentrations of retinoic acid and TPA had synergistic inhibitory effects on the induction of phagocytic activity of M1 cells by dexamethasone.
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PMID:Stimulation by retinoic acid of prostaglandin production and its inhibition by tumor promoters in mouse myeloid leukemia cells. 694 53

We have investigated the effects of tumor-promoting phorbol esters on the generation of T-killer cells against syngeneic tumor cells in tissue culture. C57BL/6 or BALB/c spleen cells were cultured with irradiated EL-4 or MPC-11 tumor cells, respectively, for 3 to 7 days at responder:stimulator ratios of 25:1 to 200:1. Lysis was measured in a 4-hr 51Cr release assay. During the sensitization phase, 12-O-tetradecanoylphorbol-13-acetate (TPA) at concentrations as low as 10 ng/ml inhibited the response by 90 to 100% at all responder: stimulator ratios and when added on Day 0, 1, 2, or 4 of a 5-day assay. Thus, TPA was able to suppress the response following successful activation of lymphocytes, since cytotoxicity could be detected as early as Day 3. Addition of TPA on Day 0 caused complete suppression of lysis when measured on Day 3, 5, or 7, indicating that the suppression was not due to a change in the kinetics of the cytotoxic response. The degree of suppression caused by five different phorbol compounds was positively correlated with their tumor-promoting activity. TPA was much less suppressive when added at the effector phase. Indomethacin, an inhibitor of prostaglandin synthesis, did not reverse the TPA effect even when added daily, beginning 3 days before the addition of TPA. The data suggest that one mechanism of phorbol ester tumor promotion may be the inhibition of T-cell immunity against tumor cells initiated by carcinogens.
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PMID:Suppression of the cytotoxic response of mouse lymphocytes to syngeneic tumor cells by tumor-promoting phorbol ester. 710 34

The effects of dexamethasone and indomethacin on the growth of androgen-dependent Shionogi carcinoma 115 were studied. When castrated male DS mice were treated with dexamethasone for 2 weeks at daily doses of 1-5 mg/kg starting from 3 days before tumor inoculation, the tumor weight as well as the transplantability was significantly increased. The tumor grown in dexamethasone-treated mice had morphological, biochemical and biological characteristics similar to those of the original Shionogi carcinoma 115. Indomethacin at daily doses of 2-10 mg/kg also stimulated the tumor growth in castrated DS mice, but the effect was less pronounced than that of dexamethasone. In allogeneic male ICR mice, dexamethasone promoted tumor growth, but indomethacin had no effect. These results suggest that tumor growth in the mouse is stimulated not only by androgens but also by glucocorticoids through the suppression of immune responses of the host and direct action on the tumor cells.
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PMID:Stimulatory effects of dexamethasone and indomethacin on growth of androgen-dependent Shionogi carcinoma 115 in the mouse. 715 Oct 46


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