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)

Both peripheral blood monocytes and neutrophils are known to be capable of lysing a variety of extracellular tumor and non-tumor cell targets. The HL-60 human promyelocytic leukemia cell line has served as a useful model of human granulocyte and macrophage differentiation in studies from many laboratories. We have previously reported that phorbol diesters, which induce differentiation along the macrophage pathway, stimulate HL-60 cells to become strikingly cytotoxic to a variety of red cell targets. We now report that agents known to differentiate HL-60 along the granulocyte pathway (retinoic acid, dimethyl sulfoxide, 5-azacytidine) do not, in themselves, induce HL-60 to become cytotoxic. However, previous exposure (3-5 days) to these granulocyte pathway active agents markedly enhances phorbol diester-triggered killing. This enhancement is particularly striking at decreased effector:target ratios (as low as one effector per five targets) and is also demonstrated by a shift to lower concentrations of the phorbol diester dose-response curve. Retinoic acid is the most effective of the three agents tested, although priming (previous exposure) with dimethyl sulfoxide or 5-azacytidine also markedly enhances killing. These studies demonstrate that HL-60-mediated killing may be dissected pharmacologically into at least two distinct steps and further support the utility of this model system in studies of the development of macrophage-like cytotoxic cells. This system has also proven to be useful in the characterization of cytokines which mimic the differentiation effects of retinoic acid and dimethyl sulfoxide (J. A. Leftwich and R. E. Hall, manuscript in preparation).
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PMID:Enhancement of phorbol diester-induced HL-60-mediated cytotoxicity by retinoic acid, dimethyl sulfoxide, and 5-azacytidine. 242 33

Retinoids have chemopreventive activity for epithelial tumors in a variety of systems, including the two-stage tumorigenesis system of mouse skin in which only the promotion stage is inhibited. We asked whether dietary vitamin A deficiency could affect the skin tumorigenic response, prior to major changes in body weight or general health of the animals. Two regimens were tested to induce vitamin A deficiency. SENCAR mice were either (a) fed a vitamin A-deficient diet from 4 or 9 weeks of age or (b) their mothers were fed the diet from the time of birth of the experimental animals which were then weaned on the same diet. The latter regimen produced typical symptoms of vitamin A deficiency in the offspring by Weeks 12-14 and all the mice died by Week 19; the former regimen permitted sufficient accumulation of retinol and its esters to sustain life for up to 45 and 75 weeks, respectively, in the majority of mice. For our experiments, vitamin A depletion was produced by placing the mothers on the deficient diet at birth of the experimental animals. A single topical dose of 20 micrograms of 7,12-dimethylbenz(a)anthracene (DMBA) was used as the initiator at 3 weeks of age and 1 to 2 micrograms of 12-O-tetradecanoylphorbol-13-acetate (TPA) once weekly as the tumor promoter for 10 weeks (from Week 4 through 13 of the experiment). Fifty-five % of mice (n = 40) on Purina laboratory chow (mean body weight, 31.4 g) developed skin tumors (2.58 per mouse) at 12 weeks, versus 2.5% (0.05 papillomas per mouse) of mice (n = 40) kept on the purified vitamin A-deficient diet (mean body weight, 30.3 g), a 98% decrease in tumor/mouse. Retinoic acid (RA) (1-3 micrograms/g diet) supplementation after Week 12 caused a rapid tumorigenic response in 95% of the mice by week 22. This tumor response occurred to a reduced extent in the absence of continued TPA treatment up to Week 13. Even though tumor incidence increased within 1 week of RA and 95% of the mice showed the tumorigenic response, the number of tumors per mouse was about 50% of that observed in mice maintained on standard Purina diet. This was confirmed in an experiment in which the mice were maintained for life either on Purina or on the RA (3 micrograms/g) containing purified diet, the latter being the control group for the effect of vitamin A deficiency on skin tumorigenesis.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Inhibition of initiator-promoter-induced skin tumorigenesis in female SENCAR mice fed a vitamin A-deficient diet and reappearance of tumors in mice fed a diet adequate in retinoid or beta-carotene. 250 90

A single topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA) was found to induce mRNA of a metallothionein (MT) gene or genes in the skin of Sencar mice, and papillomas produced by repeated applications of TPA were shown to have elevated levels of MT mRNA. Induction of MT mRNA was maximal 4-8 h after application of TPA and returned to the control level 24 h later. A dose-dependent increase of MT mRNA was observed with doses of TPA of 1-5 micrograms. Of the other promoters tested, phorbol-12, 13-didecanoate, mezerein, and the ionophore A23187 also induced MT mRNA, but 4-O-methyl-TPA and benzoyl peroxide did not. Phorbol and 4 alpha-phorbol-12,13-didecanoate, which are not promoters, also did not induce MT mRNA. Retinoic acid and 1 alpha, 25-dihydroxyvitamin D3, inhibitors of tumor promotion, did not induce MT mRNA themselves or inhibit the induction of MT mRNA by TPA. In C57BL/6 promotion-resistant mice, TPA caused only slight induction of MT mRNA. These data suggest a correlation between induction of MT mRNA and epidermal hyperplasia. The constitutive elevation of MT mRNA levels in papillomas may be due to the loss, during the process of tumor promotion, of some mechanism regulating MT gene expression.
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PMID:Induction of metallothionein mRNA by tumor promoters in mouse skin and its constitutive expression in papillomas. 254 29

Retinoic acid has the ability to act as either a weak first stage promoter or a weak complete promoter in the initiation-promotion protocol for skin carcinogenesis in the SENCAR mouse. The retinoid analog RO-10-9359 lacks this tumor promoting activity. Both retinoids however inhibit 12-O-tetradecanoylphorbol-13-acetate (TPA) promotion. Additional comparisons revealed that retinoic acid alone can induce dark keratinocytes, a characteristic of tumor promoters, while RO-10-9359 cannot. Retinoic acid but not RO-10-9359 can induce an immediate chemiluminescence response in human polymorphonuclear cells. Both retinoids, however, inhibit a TPA-induced response. Since the chemiluminescence response is believed to be due to oxygen free radical generation, the data suggest that the ability of retinoic acid but not RO-10-9359 to promote tumors and induce dark cells may be due to initial oxidative reactions at the cell membrane.
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PMID:The first stage and complete promoting activity of retinoic acid but not the analog RO-10-9359. 258 Jun 48

Retinoids that cause inhibition of methylcholanthrene-induced neoplastic transformation of C3H/10T1/2 cells enhance gap-junctional communication in carcinogen-initiated cells. Dose-response studies using retinoids of diverse structures and potency demonstrated a good correlation between these two events. Junctional permeability was enhanced by retinol and tetrahydrotetramethylnaphthalenyl propenylbenzoic acid (TTNPB) at concentrations from 10(-10) to 10(-6) M, and by retinoic acid between 10(-8) and 10(-6) M, the same concentrations that inhibited neoplastic transformation. Retinoic acid inhibited permeability at 10(-10) M, at which concentration transformation was enhanced. Retinoids caused similar alteration sin communication in parental 10T1/2 cells. Communication between initiated and 10T1/2 cells was not influenced by TTNPB. The tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) inhibited junctional communication in initiated cells, in 10T1/2 cells and between these two cell lines. After repeated exposure of 10T1/2 cells to TPA only retinoid-enhanced communication was blocked; in contrast, basal communication became refractory. It is proposed that much of the chemopreventive action of retinoids can be explained by the enhanced junctional communication of growth regulatory signals.
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PMID:Enhancement of gap junctional communication by retinoids correlates with their ability to inhibit neoplastic transformation. 276 67

Elevated transglutaminase activity and formation of cornified envelopes are markers of terminal differentiation in mouse epidermal cells. Epidermal transglutaminase catalyzes cornified envelope formation and in cultured cells is inducible by calcium ion or phorbol ester tumor promoters. Retinoic acid also induces transglutaminase activity but inhibits cross-linked envelope formation. This apparent paradox might be resolved by the observation that the retinoic acid-induced transglutaminase appears to be either a different enzyme or a markedly altered form of the epidermal enzyme. The retinoic acid-induced transglutaminase is soluble in aqueous buffers, is thermolabile at pH 9.0, 37 degrees C, and elutes from an anion exchange column at 0.4 M NaCl. In contrast, the epidermal enzyme is particulate and requires detergent for solubilization, is relatively thermostable, and elutes from the anion exchanger at 0.25 M NaCl. The retinoic acid-induced enzyme is probably identical with the "tissue" transglutaminase present in liver and in other cells. It is proposed that the transglutaminase induced by retinoic acid may play a role in the inhibition by retinoids of calcium and tumor promoter-induced differentiation.
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PMID:Retinoic acid-induced transglutaminase in mouse epidermal cells is distinct from epidermal transglutaminase. 285 76

The mechanisms by which topically applied retinoic acid to mouse skin inhibits tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced epidermal ornithine decarboxylase activity were analyzed. Retinoic acid inhibition of the induction of epidermal ornithine decarboxylic activity was not the result of nonspecific cytotoxicity, production of a soluble inhibitor of ornithine decarboxylase, or direct effect on its activity. In addition, inhibition of TPA-caused increased ornithine decarboxylase activity does not appear to be due to enhanced degradation and/or post-translational modification of ornithine decarboxylase by transglutaminase-mediated putrescine incorporation. We found that retinoic acid inhibits the synthesis of ornithine decarboxylase caused by TPA. Application of 10 nmol TPA to mouse skin led to a dramatic induction of epidermal ornithine decarboxylase activity which was paralled by increased [3H]difluoromethylornithine binding and an increased incorporation of [35S]methionine into the enzyme. Application of 17 nmol retinoic acid 1 h prior to application of 10 nmol TPA to skin resulted in inhibition of the induction of activity which accompanied inhibition of [3H]difluoromethylornithine binding and [35S]methionine incorporation into ornithine decarboxylase protein as determined by the tube-gel electrophoresis of the enzyme immunoprecipitated with monoclonal antibodies to it. Inhibition of ornithine decarboxylase synthesis was not the result of the inhibitory effect of retinoic acid on general protein synthesis. The results indicate that retinoic acid possibly inhibits TPA-caused synthesis of ornithine decarboxylase protein selectively.
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PMID:Inhibition of phorbol ester-caused synthesis of mouse epidermal ornithine decarboxylase by retinoic acid. 286 59

The effect of glucocorticosteroids, retinoids, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and the tumor promoter phorbol myristate acetate (TPA) on the expression of transglutaminase activity in vitro differentiating bone marrow-derived mouse and rat mononuclear phagocytes (BMDMP) and mouse and human myeloid leukemia cell lines was assessed. Dexamethasone was found to induce an increase of about 100% in transglutaminase activity in mouse and rat BMDMP. The effect was time- and dose-dependent, and specific for steroids with glucocorticoid activity. Retinoic acid (RA) suppressed transglutaminase activity in mouse BMDMP (approximately 50%) and enhanced it in rat BMDMP (100-200%). Other retinoids were less effective. 1,25(OH)2D3 had little effect on transglutaminase expression in mouse BMDMP and suppressed it in rat BMDMP (approximately 60%). TPA exerted a suppressive effect (approximately 50%) on transglutaminase activity of both rat and mouse BMDMP. In murine (P388D1 and J774.2) and human (ML3, HL-60, KG-1, HEL, U937) myeloid leukemia cell lines, dexamethasone enhanced transglutaminase activity to a varying degree (100-1,000%), RA suppressed it in P388D1 cells (approximately 70%) and enhanced it in the other cell lines (100-1,500%), 1,25(OH)2D3 induced a rather small augmentation of enzyme expression, whereas TPA suppressed enzyme expression (70-100%). The species-specific differences previously observed by us for the effect of RA, dexamethasone and 1,25(OH)2D3 on the formation of BMDMP from mouse and rat bone marrow progenitor cells are now shown to extend also to effects on expression of transglutaminase activity. From a mechanistic point of view it is of interest that dexamethasone uniformly enhanced transglutaminase activity, whereas TPA suppressed it. RA and 1,25(OH)2D3 induced either suppression or enhancement in the various cell types, with no correlation between the direction of the effect of the two agents. The data suggest that modulation of transglutaminase activity by the four agents occurs via disparate mechanisms.
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PMID:Modulation of transglutaminase activity in mononuclear phagocytes and macrophage-like tumor cell lines by differentiation agents. 287 97

Retinoic acid (RA) induces tissue transglutaminase (TGASE) and inhibits terminal differentiation induced either by calcium ion or by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in primary mouse epidermal cells in culture. The relevance of these effects on cultured cells to the antipromoting action of RA was investigated in female BALB/c and CD-1 mice in vivo. Tissue TGASE was distinguished from epidermal TGASE on the basis of different thermolability at pH 9 or elution from the anion exchanger Mono Q. After topical application of 3 to 5 micrograms (10 to 17 nmol) of RA to the shaved back skin, the specific activity of tissue TGASE increased up to 30-fold primarily in the basal cell fraction of Percoll-separated epidermal cells. Enzyme activity returned to basal levels by 7 days. Treatment with TPA (10 micrograms or 17 nmol/mouse) induced an increase in epidermal TGASE which reached a maximum at 12 h after application, primarily in suprabasal cells. RA applied 1 h before TPA caused no reduction of TPA-induced epidermal TGASE, but the increase in tissue TGASE due to RA was markedly inhibited by TPA. The effects of TPA and RA on TGASE activities in primary epidermal cells in culture were similar to those in vivo except that RA reduced the induction of epidermal TGASE by TPA. In culture the induction of epidermal TGASE by TPA was independent of Ca2+ concentration in the medium above 0.03 mM, but cornified envelope formation was markedly enhanced by Ca2+ above the level required for maintaining a basal cell population (0.03 to 0.05 mM). The TPA-induced formation of cornified envelope in the presence of elevated Ca2+ was completely inhibited by RA if cells were pretreated with RA for 24 h. Our results are consistent with RA causing a reprogramming of epidermal cells that alters their response to differentiation stimuli.
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PMID:Modulation of tissue and epidermal transglutaminases in mouse epidermal cells after treatment with 12-O-tetradecanoylphorbol-13-acetate and/or retinoic acid in vivo and in culture. 289 34

Retinoic acid induces the differentiation of NTERA-2 cl. D1 human embryonal carcinoma (EC) cells into neurons, cells permissive for the replication of human cytomegalovirus (HCMV), and other cell types that cannot as yet be classified but are distinguishable from the stem cells. We tested several additional agents for their ability to induce the differentiation of these EC cells. No differentiation was induced by butyrate, cyclic AMP, cytosine arabinoside, the tumor promoter 12-0-tetradecanoylphorbol 13-acetate (TPA), or the chemotherapeutic agent cis-diaminedichloroplatinum, although morphological changes were detected at the highest concentrations of these agents that permitted cell survival. However, retinal, retinol, 5-bromouracil 2'deoxyribose (BUdR), 5-iodouracil 2'deoxyribose (IUdR), hexamethylene bisacetamide (HMBA), dimethylacetamide (DMA), and dimethylsulfoxide (DMSO) all induced some neuronal differentiation, but to a lesser extent than retinoic acid. Also, BUdR, IUdR, HMBA, and DMA induced the appearance of many cells permissive for the replication of HCMV. Differentiation was, in all cases, accompanied by the loss of SSEA-3, a globoseries glycolipid antigen characteristically expressed by human EC cells. However, another glycolipid antigen, A2B5, which appears in 60%-80% of differentiated cells 7 days following retinoic acid induction, was detected in less than 20% of the cells induced by the other agents studied. This implies that the HCMV-permissive cells induced by retinoic acid are not identical to those induced by BUdR, IUdR, and DMA.
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PMID:Differentiation of TERA-2 human embryonal carcinoma cells into neurons and HCMV permissive cells. Induction by agents other than retinoic acid. 301 99


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