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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pharmacokinetic studies of five biological response modifiers (BRMs) show diverse regulator functions on effector cell responses and a capacity to cause the secretion of specific soluble factors. Of the five BRMs tested, MVE-2, Poly ICLC, OK-432, and alpha beta IFN were capable of stimulating both natural killer (NK) cell and macrophage (M phi) tumoricidal activity, whereas BM 41-332 augmented only NK cells. Following one treatment with the aforementioned BRMs, M phi activity remained elevated for a longer period (10-14 days) than did NK cell activity (6-9 days). Of particular interest, multiple treatment with BRMs led to a downregulation of NK cell activity (hyporesponsiveness). Three soluble secretory products were induced by these BRMs (colony stimulating factor, CSF; prostaglandin E, PGE; and interferon, IFN). Treatment with MVE-2 and Poly ICLC led to a significant increase in bone marrow cellularity and GM-CFV-C. Results of studies with the cyclo-oxygense-inhibited indomethacin indicate that CSF and PGE are produced and/or secreted by different cellular mechanisms. The depression of effector cells (NK, bone marrow, and GM-CFU-C), as the result of cyto-reductive treatment with cyclophosphamide, could be reversed by treatment with MVE-2. A significantly earlier time to recovery of these effector cells was achieved following MVE-treatment. When MVE-2 was used as an adjuvant to initial tumor cyto-reductive chemotherapy, more successful antitumor response was achieved, indicating that MVE-2 functioned to elevate a substantial effector cell response as well as reconstituting bone marrow cellularity.
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PMID:Biological response modifiers: regulators of the cellular immune system and adjuvants in antitumor therapy. 348 34

Our earlier work revealed that PGE-mediated inactivation of NK cells in tumor-bearing mice by host macrophages promoted spontaneous lung metastasis that could be prevented or ameliorated by chronic indomethacin therapy. Since PGE was found to suppress the in vitro development and/or activation of a family of tumoricidal lymphocytes such as CTL, NK, and LAK cells by one or both of two mechanisms, that is to say, a down regulation of IL-2-R and an inhibition of IL-2 production, the present study tested whether a combined therapy with indomethacin and IL-2 was more effective than one with indomethacin or IL-2 alone in ameliorating established experimental lung metastasis. B6 mice injected intravenously with 10(6) highly metastatic B16F10 melanoma cells showed profuse micrometastases in the lungs by day 5, and macrometastases by day 10 which were confluent on day 21. Chronic indomethacin therapy by the oral route (14 micrograms/ml in drinking water) starting on day 0 or day 5, or a single round of IL-2 therapy (25,000 U rIL-2, every 8 h for 5 d on days 10-14) reduced the number of metastatic nodules by two-thirds (from a median of 473 in control mice receiving vehicles alone) by day 21. A single round of IL-2 as above, combined with either protocol of indomethacin therapy, completely or nearly completely irradicated the lung metastases, corroborated by a histological examination. An evaluation of splenic killer cell activity measured with a 4-h 51Cr-release assay against NK-sensitive YAC-1 lymphoma and B16F10 melanoma or NK-resistant thymic lymphoma 9705 targets revealed negligible activity in control tumor-bearing mice, and a good restoration of activity against NK-sensitive targets with either protocols of indomethacin therapy. IL-2 alone or a combination of IL-2 and indomethacin given by either protocol generated strong killer activity against all these targets, most marked with the combination therapy. Splenic killer cell phenotype in normal as well as all treated animals was ASGM1+, Thy-1-, and Lyt-2-. The combination therapy resulted in the strongest mononuclear cell infiltration in the lungs, with areas of young granulation tissue suggestive of repair sites of original metastases.
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PMID:Amelioration of B16F10 melanoma lung metastasis in mice by a combination therapy with indomethacin and interleukin 2. 349 67

Human seminal plasma (SP) was found to contain a potent suppressor of human natural killer (NK) cell cytotoxic activity against the K562 erythroleukemia target in vitro. Pooled and filter-sterilized SP reduced the NK cell activity of normal blood donors in a concentration-dependent manner; strong reduction of target cell lysis was observed at a final dilution of 1/400. Possible toxic effects of SP on NK cells were ruled out, because donor leukocytes incubated in a final SP dilution of 1/100 remained greater than 99 percent viable as determined by trypan blue exclusion. SP did not affect the lysability of the tumor targets, but suppressed the cytotoxic activity of the effector leukocytes, an effect that was reversed after washing the leukocytes free of the SP. The suppressive action of SP was retained after heating to 95 degrees C for 10 min, but was removed after adsorption with activated charcoal (Norit-A). Lipids extracted from SP were tested for suppression of NK cell cytotoxic activity, and the active principle was identified with the acidic lipid fraction. Components of the acidic lipid fraction of a single freshly obtained SP sample were separated by high pressure liquid chromatography, and suppression of NK cell cytotoxic activity was found to be associated with the predominant prostaglandins (PG) in this fraction, 19-OH-PGE1 and 19-OH-PGE2. Suppression of cellular immune functions by SP has been described; however, the identity of the suppressor factor (or factors) is unknown. The 19-OH-PGE are present in high concentration in primate semen, and may minimize immunologic sensitization to sperm in females after insemination. In addition, these compounds may suppress NK cell antitumor and antiviral activities in the vagina, as well as in their tissues of origin.
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PMID:Suppression of natural killer cell activity by human seminal plasma in vitro: identification of 19-OH-PGE as the suppressor factor. 375 69

In response to inflammatory stimuli, macrophages synthesize and secrete prostaglandins (PGE) along with other potent inflammatory mediators. We have studied the effect of hyperthermia on the production of PGE by murine mononuclear phagocytes. Exposure to high temperature induced PGE production by cultured C3H/HeJ exudate macrophages in a time- and temperature-dependent manner. Increase in PGE production was detected when macrophages were treated at 41 degrees C and above for 1 h with a much greater increase at 42 and 43 degrees C. The secretion of PGE into culture supernatants by heat-treated macrophages reached a maximum approximately 24 h after heat treatment. The production of PGE by macrophages after hyperthermia was inhibited either by the addition of 5 X 10(-7) M indomethacin or by the subsequent incubation at 4 degrees C, suggesting that the elevated PGE production by macrophages is mediated through the activation of cyclooxygenase. Heat treatment under the same conditions failed to stimulate the production of PGE by either a human monocyte-like tumor cell line (U-937) or a mouse fibroblast cell line (L-929).
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PMID:Induction of prostaglandin production by hyperthermia in murine peritoneal exudate macrophages. 379 Nov 96

Human peripheral blood monocytes from normal donors obtained by separation on a Percoll gradient showed considerable cytotoxicity against tumor cells when preincubated in vitro for 24 hr with human monocyte-derived interleukin 1 (IL 1). In contrast, monocytes after pretreatment in medium alone had low cytotoxic activity. All the IL 1 preparations, including IL 1 which was purified by high-performance liquid column chromatography (HPLC), as well as crude culture supernatant from human monocytes promoted monocyte-mediated cytotoxicity in the same dose-dependent manner as the thymocyte growth-promoting activity. There was no endotoxin or interferon (IFN) activity in the highly purified IL 1, suggesting that IL 1 itself was the active moiety. The effect of IL 1 on monocyte-mediated cytotoxicity was partially inhibited by indomethacin, whereas pretreatment of monocytes with prostaglandin (PG) E1 or E2 rather than IL 1 also resulted in substantial monocyte cytotoxicity. Thus, the effect of IL 1 on monocyte-mediated cytotoxicity is presumably mediated by PGE. Since fresh monocytes that were not preincubated exhibited levels of spontaneous cytotoxic activity similar to that of monocytes preincubated with IL 1, it seemed likely that the effect of IL 1 was to maintain the spontaneous level of activity rather than to induce cytotoxic activity. To elucidate this possibility, monocytes were first preincubated in medium alone for a longer period, and after losing their spontaneous activity they were further incubated with or without IL 1. Such "aged" monocytes did not develop cytotoxic activity in response to IL 1 but did in response to other agents known to induce macrophage cytotoxicity, such as endotoxin or lymphokine-containing supernatants. Therefore, the major effect of IL 1 actually seemed to prolong the cytotoxic state of monocytes. These results also suggest that IL 1 released by macrophages or monocytes may play a role in host defense against neoplastic cells by acting on monocytes as an autostimulating factor.
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PMID:Role of interleukin 1 in promoting human monocyte-mediated tumor cytotoxicity. 387 93

A transplantable mouse fibrosarcoma, HSDM(1), produces a potent bone resorption-stimulating factor. The factor can be extracted from the tumor tissue and harvested from the medium of clonal strains of HSDM(1) tumor cells growing in monolayer culture. It has several chemical and biological properties of a prostaglandin. Using radioimmunoassay techniques, we have shown that HSDM(1) cells synthesize and secrete large quantities of prostaglandin E(2) (PGE(2)). The specific bone resorption-stimulating activity of the HSDM(1) factor extracted from the tumor is high and approximately equal to that of PGE(2) as measured in a bone tissue culture system in vitro. Indomethacin, a potent inhibitor of PGE(2) synthesis in HSDM(1) cells, also inhibits production by the cells of the bone resorption-stimulating factor, and has no detectable nonspecific effects on the bone culture assay system. Mice bearing the HSDM(1) tumor have higher levels of both calcium and PGE(2) in serum than control mice. We conclude that PGE(2) is the bone resorption-stimulating factor produced by HSDM(1) tumor cells, and that secretion of PGE(2) by the tumor in vivo accounts for the relative hypercalcemia observed in tumor-bearing animals. The HSDM(1) tumor cell system constitutes a new model for studying the pathogenesis of hypercalcemia associated with certain malignant tumors.
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PMID:Evidence that the bone resorption-stimulating factor produced by mouse fibrosarcoma cells is prostaglandin E 2 . A new model for the hypercalcemia of cancer. 434 6

A case is reported of a man who experienced hypercalcemia as a result of developing liver and renal-cell cancer. Repeated skeletal surveys and bone scans failed to reveal any bone metastases. The hypercalcemia was unresponsive to hydration and oral phosphate. However, it responded immediately to oral administration of indomethacin. The mechanism of this calcium-lowering effect is unknown. On the death of the patient, biopsies of the metastic liver and lung tissue were performed. The liver metastatis yielded 7 times the PGE (prostaglandin E)-like and 5 times the PGF-like material found in the normal adjacent liver. The lung metastatis yielded only 1/2 the PGE-like and PGF-like material obtained from normal adjacent lung. The results of this case study would indicate that some forms of hypercalcemia secondary to neoplastic disease are responsive to indomethacin and may be due to increased PG production by the tumor tissue.
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PMID:Indomethacin-responsive hypercalcemia in a patient with renal-cell adenocarcinoma. 483 87

It is proposed that nonimmunologic microenvironmental stimuli such as interferons and E-type prostaglandins (PGE) can modulate macrophage tumoricidal activity in local tissue immunity. These agents act as "local hormones" since they have a high catabolic rate and short biologic half-life in serum. Interferons provide a common pathway for induction of cytotoxic macrophages by diverse agents such as viruses, bacterial lipopolysaccharides, and double-stranded RNA, and PGE act as a biologic "resistor" to control expression of activated macrophage tumor killing. Since both PGE and interferons are secretory products of activated macrophages, it is envisioned that they could act in negative and positive feedback mechanisms to intrinsically modify macrophage functional activity. Finally, tumors may defend themselves from attack by activated tumoricidal macrophages by releasing high levels of PGE that subvert local macrophage activity.
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PMID:E-type prostaglandins and interferons: yin-yang modulation of macrophage tumoricidal activity. 616 Mar 77

Macrophages (M phi diameter) from three mouse strains with genetically distinct M phi diameter deficits (C3H/HeJ, A/J, and P/J) were unable to develop high cytolytic and cytotoxic activity against tumor cells in vitro when exposed to agents (MAF and IFN-beta) that strongly increased the tumoricidal capacity of M phi diameter from nondefective C3H/HeN mice. Nevertheless, the tumoricidal deficits of M phi diameter from the defective strains did not affect their suppressive capacity on Con A-induced lymphoproliferation, nor their ability to react to IFN-beta by decreasing suppressive activity. In fact, natural suppressive activity and IFN-beta-induced changes in the suppression of M phi diameter from C3H/HeJ, A/J, and P/J mice were highly comparable to those of C3H/HeN M phi diameter, thus stressing the dissociation between the mechanisms governing M phi diameter suppression and M phi diameter tumoricidal activity. Analysis of the modulation by MAF and IFN-beta of M phi diameter ability to release the oxygen metabolites O2- and H2O2, molecules possibly involved in the effector mechanism of both M phi diameter cytotoxicity and suppression, revealed a close correlation with the patterns of suppressive activity in both nondefective and defective strains. In contrast, no correlation between the production of oxygen-reactive species and M phi diameter tumoricidal activity was observed. The ability of MAF- and IFN-beta-treated M phi diameter to produce PGE, a molecule of major importance in M phi diameter-mediated suppression and possibly involved also in the regulation of M phi diameter tumoricidal activity, again paralleled M phi diameter suppressive capacity. Thus, the mechanisms controlling M phi diameter antitumor activity appeared to be clearly distinct from those involved in M phi diameter suppression.
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PMID:Dissociation between macrophage tumoricidal capacity and suppressive activity: analysis with macrophage-defective mouse strains. 631 95

Topical application of prostaglandin E1 or E2 onto the mouse skin results in a 2- to 3-fold increase of the cyclic AMP level in epidermis within 5 min. (15S)-15-methyl-PGE1 is more active in this respect, whereas PGD2 and PGF2 alpha are ineffective. The level of cyclic GMP is not altered by E- or F-prostaglandins. A single PGE2 application desensitizes the cyclic AMP response of mouse epidermis to further treatments in a dose dependent and agonist-specific manner. Delayed and longlasting refractoriness of PGE2-induced cyclic AMP accumulation is also caused by hyperplasiogenic skin irritants such as the phorbol ester tumor promoter TPA or the nonpromoting agents RPA and A23187. The non-irritant skin mitogen 4-O-methyl-TPA does not evoke desensitization. TPA-induced PGE2 refractoriness cannot be prevented by inhibitors of protein synthesis, anti-inflammatory steroids, indomethacin or phentolamine. The development of tachyphylaxis does not seem to be related to endogenous formation of PGE or cyclic AMP. A 2-fold increase of epidermal cyclic AMP observed within 1-2 h of TPA application can be inhibited by indomethacin treatment and correlates with delayed accumulation of PGE2 in TPA-treated epidermis, whilst immediate PGE accumulation (5-10 min after TPA application) which has been shown to be critical for development of TPA-induced epidermal hyperplasia is not accompanied by any change of the intraepidermal cyclic AMP level. It is concluded that mouse epidermis contains two types of PGE-regulated effector systems, one of which is coupled to adenylate cyclase, one of which is not. Only the latter system is involved in the induction of hyperplasia. At least as far as the mitogenic effect is concerned, cyclic AMP does not seem to be involved in TPA action.
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PMID:Prostaglandins, cyclic nucleotides and the effect of phorbol ester tumor promoters on mouse skin in vivo. 631 56


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