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)

TPA (12-O-tetradecanoylphorbol-13-acetate) is an effective tumor promoter that affects a variety of ion transport processes. To examine the relationship between effects on transport and growth and differentiation, we have been studying the actions of TPA on frog skin, a particularly well-characterized epithelium. We have reported that high concentrations of TPA stimulate base-line short-circuit current (ISC) and inhibit the subsequent natriferic action of vasopressin. The current study of 89 preparations extends those findings. The Km of the stimulatory effect of TPA is approximately 3 nM; this high affinity indicates that the transport phenomenon does not simply reflect a nonspecific interaction of phorbol ester with the plasma membranes. TPA acts largely or entirely at the mucosal surface of both split and whole skins; thus the sidedness of the effect does not arise from adsorption onto the underlying connective tissue when TPA is applied to the serosal surface of whole skin. Amiloride, an inhibitor of apical Na+ entry, abolishes ISC across frog skins pretreated with TPA. The phorbol ester also increases ISC across split skins, preparations which do not produce net Cl-transport. Indomethacin (1 microM) blocks PGE1 release, but does not alter the response to TPA at a fivefold lower concentration than previously used. NDGA (nordihydroguaretic acid, 10 microM), an inhibitor of the lipoxygenase pathway, partially inhibited the responses of ISC to 8 nM TPA. The present results indicate that frog skin is highly responsive to TPA at concentrations known to activate protein kinase C in broken-cell preparations.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of TPA on short-circuit current across frog skin. 310 64

NMRI and SENCAR, two stocks of mice commonly used in multistage skin carcinogenesis studies, were compared with respect to the effects of inhibitors of arachidonic acid metabolism for the following 12-O-tetra-decanoylphorbol-13-acetate (TPA)-elicited events: tumor promotion, DNA synthesis in vivo and in vitro, ornithine decarboxylase induction, and prostaglandin (PG) E2 synthesis. Previous work had shown that the cyclooxygenase inhibitor indomethacin enhanced TPA promotion in SENCAR mice. We report here that over the same dose range (50 to 200 micrograms) indomethacin caused a dose-dependent inhibition of promotion in NMRI mice. Significant reversal of this inhibition was achieved with concomitant application of 10 micrograms PGF2 alpha but not PGE2. DNA synthesis studies showed that low doses of indomethacin and flurbiprofen increased TPA-stimulated DNA synthesis in primary cultures from SENCAR mice; indomethacin suppressed this response in NMRI cultures. In vivo DNA synthesis studies showed the same pattern: indomethacin enhanced TPA-stimulated DNA synthesis in SENCAR mice but inhibited in NMRI mice. Other classes of inhibitors of arachidonate metabolism (i.e., the cyclooxygenase-lipoxygenase inhibitors 5,8,11,14-eicosatetraynoic acid and phenidone and the phospholipase A2 inhibitor dibromoacetophenone) had inhibitory activity in vitro and in vivo in both stocks of mice. Indomethacin was found to inhibit TPA-induced ornithine decarboxylase activity to the same extent in both mice. Indomethacin was also very effective in inhibiting TPA-induced PGE2 synthesis in both stocks of mice. 5,8,11,14-Eicosatetraynoic acid and phenidone were likewise suppressive in both stocks of mice. It is concluded that the NMRI and SENCAR mice respond similarly to TPA with respect to promotion, DNA synthesis, ornithine decarboxylase induction, and PG synthesis. The difference appears to be in the degree of involvement of the lipoxygenase pathway.
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PMID:Events associated with mouse skin tumor promotion with respect to arachidonic acid metabolism: a comparison between SENCAR and NMRI mice. 310 6

Tumors were allowed to develop in the cheek pouches in two groups of hamsters following topical application three times per week of a 0.5% solution of 7, 12-dimethylbenz(alpha)anthracene (DMBA) in liquid paraffin administered for 10 weeks. Two control groups received no DMBA treatment. After carcinogen application, the animals in one DMBA-treated group and those in one of the control groups were given indomethacin daily; this was administered through the oral route for an additional 10 weeks. At this time, all of the animals were killed and their cheek pouches, the draining cervical lymph nodes, and other organs were removed for examination. The number and size of tumors in each pouch were recorded, and each pouch was weighed. Indomethacin, in the dosage administered, was not found to cause regression of established tumors. The effects of prostaglandins, indomethacin, and other prostaglandin-synthesis inhibitors in tumor tissue are discussed. It is suggested that more knowledge is needed about the role of prostaglandins, and the related products of AA metabolism, in squamous cell cancer before indomethacin is used therapeutically.
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PMID:The effect of indomethacin on tumor regression in DMBA-induced epithelial neoplasia of hamster cheek pouch mucosa. 310 42

The murine subrenal capsule assay is an in vivo method for determining the responsiveness of solid tumor xenografts to chemotherapeutic agents. It was used in this study for the purposes of constructing growth curves of squamous cell carcinoma of the head and neck and collecting pilot data on the effects that indomethacin and cisplatin have on this malignant condition. Nine of the ten assays performed were evaluable. Indomethacin, cisplatin, or both were used as treatment drugs in each assay. One-millimeter fragments of viable tumor, from patients with head and neck squamous cell carcinoma, were implanted beneath the renal capsules of normal immunocompetent mice. Baseline and posttreatment measurements were made of the xenografts, and response to treatment was determined by comparing changes in tumor sizes of the test and control groups. Results indicated that reduction in tumor sizes occurred in indomethacin-treated mice in four assays and in cisplatin-treated mice in six assays. In addition, two separate growth curves were calculated by plotting the mean change in tumor size in five mice per day on days 3 through 7. In conclusion, the subrenal capsule assay is a relatively rapid and inexpensive assay in which squamous cell carcinoma remains viable and therapeutic agents can be tested. However, clinical trials that use this assay to choose treatment drugs are needed in order to correlate assay results with clinical responses.
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PMID:Subrenal capsule assay for squamous cell carcinoma of the head and neck. 310 55

The mechanism of the anti-promoting effect of the prostaglandin (PG) synthesis inhibitor indomethacin in colon carcinogenesis was investigated. Male Sprague-Dawley rats received 0.002% water solution of indomethacin as drinking water freely for 3 days, then a subcutaneous injection of various doses of PGE2 and/or an intrarectal instillation of 12 mumol of sodium deoxycholate as a colon tumor promoter. Ornithine decarboxylase (ODC), a marker of tumor promotion, in the distal colonic mucosa was assayed at 4 hr after deoxycholate instillation. Indomethacin significantly suppressed the deoxycholate-augmented increase of ODC activity, while exogenous PGE2 restored or further increased the augmented ODC activity. The amount of PGE2 and the level of ODC activity were well correlated. However, PGE2 alone without deoxycholate did not increase the activity. Deoxycholate markedly increased colonic mucosal PGE2 at 1 hr after the instillation, and indomethacin decreased it. The results indicate that PGE2, the production of which is stimulated in the colonic mucosa by deoxycholate, is involved in the induction of colonic mucosal ODC. This is probably why PG synthesis inhibitors may inhibit the tumor promotion and prevent cancer development in the colon.
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PMID:Involvement of prostaglandin E2 in bile acid-caused promotion of colon carcinogenesis and anti-promotion by the cyclooxygenase inhibitor indomethacin. 311 24

The effects of lipoxygenase and cyclooxygenase inhibitors on ornithine decarboxylase (ODC) induction by a potent tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA) were examined in vitro in isolated mouse epidermal cells. Lipoxygenase inhibitors such as quercetin, nordihydroguaiaretic acid (NDGA), 3,4,2',4'-tetrahydroxychalcone, 3-amino-1-(3-trifluoromethylphenyl)-2-pyrazoline (BW755C) inhibited the TPA-caused ODC induction. Indomethacin, a selective cyclooxygenase inhibitor, failed to inhibit it. These results suggest that the lipoxygenase inhibitors inhibit TPA-caused epidermal ODC induction in mouse skin at least in part by acting directly on epidermal cells while cyclooxygenase inhibitor inhibits it indirectly by acting on cells other than epidermal cells, e.g. cells which are involved in the prostaglandin-dependent inflammatory process.
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PMID:The induction of ornithine decarboxylase caused by 12-O-tetradecanoylphorbol-13-acetate in isolated epidermal cells is inhibited by lipoxygenase inhibitors but not by cyclooxygenase inhibitors. 312 55

We investigated whether there is a relationship between the production of eicosanoids by murine solid tumors and their response to the prostaglandin H (PGH) synthase inhibitor indomethacin. Three sarcomas, designated FSA, NFSA, and SA-NH, and two carcinomas, designated MCA-K and HCA-I, syngeneic to C3Hf/Kam mice were used. In general, FSA and NFSA produced more PGH synthase products than lipoxygenase products, whereas HCA-I produced both types of metabolites in large quantities. All three tumors responded well to indomethacin treatment by slowing their growth. In contrast, MCA-K and SA-NH tumors produced insignificant quantities of PGH synthase products, but substantial amounts of lipoxygenase products. Their growth was not affected by treatment with indomethacin. Indomethacin did not influence tumor cell survival either in vitro or in vivo, but it reduced the proportion of S-phase cells in the tumors. The antitumor effect of indomethacin was not reduced by immunosuppression of the tumor host and was independent of tumor immunogenicity, implying that indomethacin acted through nonimmunological mechanisms. Thus, the effectiveness of indomethacin was directly related to the ability of tumors to produce PGs. Consequently, the eicosanoid profile of tumors could serve as a valuable way to select patients likely to respond to indomethacin and other PGH synthase inhibiting agents.
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PMID:Prostaglandin production by murine tumors as a predictor for therapeutic response to indomethacin. 313 Jan 82

The spleens of mice with large M-1 fibrosarcomas contain two populations of suppressor cells with the properties of macrophages and T cells. In this study, we tested the effect of indomethacin on suppressor cell activation and effector function. Neither the activation nor the effector function of the suppressor macrophages was inhibited by indomethacin, and the activity of suppressor macrophages correlated with the tumor size. In contrast, the treatment of tumor-bearing mice with indomethacin from the day of injection of tumor cells completely blocked the in vivo activation of suppressor T cells. Indomethacin did not, however, depress suppressor T cell activity if mice were treated only during the third week of tumor growth. The effector function of the suppressor T cells, as assessed in mixing assays, was partially blocked by indomethacin, while selective suppression by low-molecular-weight factors was completely blocked if indomethacin was present in the cultures. Furthermore, the in vitro activation of suppressor cells by soluble factors secreted by tumor-bearer spleen cells was completely blocked by indomethacin, and this inhibition was reversed by prostaglandin E1. These data are consistent with the hypothesis that prostaglandins are involved in the activation, but not the effector function, of tumor-activated suppressor T cells.
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PMID:The effect of indomethacin on the activation and effector function of suppressor cells from tumor-bearing mice. 315 36

Our earlier studies revealed that a rapid and progressive loss of splenic NK activity in mice during the development of a number of transplanted tumors as well as of spontaneous tumors was due to an inactivation of natural killer (NK) lineage cells rather than to their disappearance. The mechanism of this inactivation have now been explored in CBA/J mice receiving transplanted Ehrlich ascites tumors and in C3H/HeJ mice bearing spontaneous mammary tumors or receiving transplants of syngeneic mammary tumor lines of recent origin. A poor activation state or maturation arrest of NK lineage cells due to a low interferon level in vivo was ruled out, since the host NK activity could not be restored after administration of either an interferon inducer poly(I:C) or interferon-alpha, although such treatments enhanced the activity in tumor-free mice by four- to eightfold. Possible presence of host suppressor cells acting on the effector or preeffector stage of NK cells was explored by mixing spleen cells from tumor bearers with normal spleen cells either during the NK assay, or for a 20-hr period of in vitro short-term culture prior to the NK assay. Mixing during the NK assay led to a reduction of NK activity explicable by a simple dilution of active NK cell concentration rather a suppression of active NK cells. On the other hand, a 20-hr coculture of the mixed population at various ratios led to a complete abrogation of the NK activity, indicating that the suppressor cells acted on the preeffector stage of the NK Lineage. A further characterization of suppressor cells revealed that they were (1) contained in the adherent fraction of the spleen of tumor bearers, (2) of monocyte/macrophage morphology, (3) capable of phagocytosing latex particles, and (4) positive for surface Mac-1 antigen, as noted from a radioautographic binding of 125I-labeled monoclonal anti-Mac-1 antibody. The mechanism of the suppression was identified, at least in part, as being mediated by prostaglandin-like molecules, since the presence of indomethacin, a prostaglandin-inhibitor, during the 20-hr coculture period completely abrogated the suppression. Indomethacin exerted no direct effect on the recruitment or killer activity of NK lineage cells in vitro. NK cell suppression may be another normal immunoregulatory mechanism which alters the host-tumor balance in favor of the tumor rather than the host.
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PMID:Changes in the host natural killer cell population in mice during tumor development. 2. The mechanism of suppression of NK activity. 315 80

The authors recently measured the Interleukin-1 (IL-1) and Prostaglandin E (PGE) activity of the monocyte-macrophage system (M phi) in vitro. The results indicated that immunodeficiency in cancer patients is closely associated with reduced IL-1 activity and increased PGE activity of M phi. Immunosuppressive factors in the serum of cancer patients seem to play some role in the mechanism of such change. Therefore, when potentiating M phi in nonspecific immunotherapy, it seems important to suppress secretion of PGE (a suppressor factor of M phi origin which is secreted simultaneously) to make this therapy more effective in advanced cancer cases. Based on these results, an animal experiment was carried out in which tumor-bearing mice were treated with OK-432 and Indomethacin (Ind.) (a PG inhibitor). The results of this experiment suggested that this combination therapy reinforces the M phi-mediated immunopotentiation, resulting in a stronger antitumor effect of OK-432. When we used this combination therapy in advanced cancer cases, the changes observed in immunological parameters also indicated an immunopotentiating effect, i.e., an antitumor effect. These results indicate that the optimum application of BRM therapy should be decided on the basis of an understanding of the immunological factors in the patient.
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PMID:Immunomodulating capacity of the monocyte-macrophage system in patients with uterine cervical cancer. 326 Feb 61


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