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)

By introduction of conjugated double bonds into the long-chain fatty acid residue of the phorbol ester tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) the promoting efficacy is abolished, whereas hyperplasiogenic and irritant activities are not impaired. By means of such "disarmed" phorbol esters (with 12-O-retinoylphorbol-13-acetate, RPA, being the most suitable one) the process of skin tumor promotion can be divided into two stages. Stage 1, brought about by short-term (single) treatment with TPA, leads via an induction of cellular proliferation to an apparently irreversible change in skin which is proposed to involve the expression of the neoplastic phenotype. A subsequent long-term (multiple) treatment with RPA (stage 2), results in the appearance of papillomas. There is no positive evidence for a critical role of phorbol ester receptor occupancy and protein kinase C activation or of free radicals such as superoxide anions in stage 1. Retinoic acid inhibits stage 1 only when applied several hours prior to TPA, whereas indomethacin exhibits the strongest inhibitory effect on stage 1 when applied 3 hr after TPA. The indomethacin effect can be specifically overcome by prostaglandin F2 alpha (PGF2 alpha) and correlates with an accumulation of PGF2 alpha in skin 3-4 hr after TPA treatment. After 12-O-retinoylphorbol-13-acetate (RPA) application no prostaglandin accumulation is seen at this time. It is proposed that the expression of the neoplastic phenotype ("conversion" of initiated cells) is accomplished in the course of a PGF2 alpha-mediated metaplastic process which normally plays a physiological role in the wound response.
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PMID:Multistage tumor promotion in skin. 644 Aug 93

A previous paper reports that the potent tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), has a time-dependent effect on mouse epidermal gap junctions. A single topical application of 1.0 micrograms TPA results in the absence of gap junctions from mouse interfollicular epidermis between 18 and 30 h post-treatment. This paper describes the dose-dependent effect of TPA on mouse epidermis. Observations indicate that only promoting doses of TPA affect the gap junctions. Similarly, while a low dose of the hyperplasiogenic compound mezerein (1.0 microgram) is ineffective, a higher dose (4.0 micrograms) results in a significant reduction in the gap junction number. One and two applications of TPA had identical effects. The potent inhibitor of both stage I and stage II of tumor promotion, Fluocinolone acetonide, used in combination with TPA, completely suppressed the hyperplasiogenic and the gap junction modulating effects of TPA. Retinoic acid, which inhibits only stage II of tumor promotion, did not influence the gap junction eliminating property of TPA. Tosylphenylalanine chloromethyl ketone which is a mild but specific inhibitor of only stage I of tumor promotion counteracted the action of TPA on gap junctions to some extent, which remained present in smaller numbers than in normal tissue at 24 h after the treatment. These results suggest that gap junctions are essential and specifically relevant to stage I tumor promotion.
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PMID:The relevance of gap junctions to stage I tumor promotion in mouse epidermis. 649 19

The mechanisms, cell surface structures, and cell types involved in the phorbol 12,13-dibutyrate (P(Bu)2)-induced binding between human lymphocytes were studied. Induction of cell aggregation by 20 min treatment with P(Bu)2 required Ca2+, an intact membrane, functional microfilaments, and the possible participation of an esterase or, less likely, a protease. Trypsin-sensitive cell surface structures were needed and neuraminidase (NANase) treatment slightly increased the intercellular binding. Retinoic acid, an anti-tumor promoting agent, was inhibitory. Calmodulin-dependent processes, microtubules, phospholipid methylation, intracellular levels of cyclic adenosine monophosphate, and cellular secretion did not seem to be involved. Cell conjugation between 24 hr P(Bu)2-treated and untreated cells required participation of trypsin-sensitive cell surface structures in each of the interacting cells and NANase treatment of one partner slightly increased the intercellular binding. Thymocytes, T cells, mature B and Epstein-Barr virus-transformed B cells aggregated while pre-B, early B, and intermediate B lymphocytes derived from representative malignancies did not. The lack of aggregation was not due to the absence of phorbol ester receptors. It is concluded that the P(Bu2)-induced intercellular binding is mediated by cell surface proteins, depends on certain enzymatic activities and metabolic events and involves certain cell types.
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PMID:Characterization of the phorbol 12,13-dibutyrate (P(Bu)2) induced binding between human lymphocytes. 658 88

Nanomolar concentrations of 4 beta-phorbol 12,13-dibutyrate markedly enhanced the redistribution of concanavalin A receptors, the common leukocyte antigen and the Lyt-3 antigen in human blood lymphocytes, as measured by cap formation. The effect on the lateral mobility of these cell surface molecules was dose dependent and occurred within a few minutes of treatment. 12-O-Tetradecanoyl phorbol 13-acetate, another tumor promoter, was similarly active. 4 alpha-Phorbol 12,13-didecanoate, which does not have tumor-promoting activity, did not enhance cap formation. The effect of various drugs and treatments indicated that the phorbol ester-enhanced cap formation was energy and temperature dependent and required functional microfilaments. Retinoic acid, an antitumor-promoting agent, was inhibitory and trifluoperazine, an inhibitor of calmodulin-dependent processes, had a minor inhibitory effect. Protein secretion and synthesis, extracellular Ca2+/Mg2+ and functional microtubules did not seem to be involved. The enhanced capping was inhibited by the alkylating agents tosyl phenylalanyl chloromethyl ketone and tosyl lysyl chloromethyl ketone but not by other protease inhibitors. The effect of various amino acid derivatives suggested the participation of an esterase. A comparative study of dose response, kinetics and sensitivity to drugs indicated a direct correlation between the phorbol 12,13-dibutyrate-enhanced redistribution of membrane glycoconjugates and the phorbol ester-induced binding (adhesion) between human blood lymphocytes, a phenomenon previously described.
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PMID:Phorbol 12,13-dibutyrate enhances lateral redistribution of membrane glycoproteins in human blood lymphocytes. 659 96

Necessary for growth and differentiation in many normal tissues and capable of inducing differentiation in human promyelocytic cell lines, retinoids were the subject of this study. Specifically, effects of 13-cis-retinoic acid and 13-trans-retinoic acid on the growth of normal human bone marrow cells in soft-agar system were studied. Both short-term incubation and continuous exposure to retinoic acid caused a decreased number of granulocyte colonies and an increased cluster-to-colony ratio. This effect was concentration-dependent. Examination of specimens stained with Wright-Giemsa or nitro blue tetrazolium stains showed a progressive increase in the percentage of immature granulocytic precursors with increasing concentrations of retinoic acid. No effect of retinoic acid was seen on a number of human tumor cell lines. Retinoic acid blocked both differentiation and proliferation and appeared to do so by specific, noncytotoxic mechanisms in normal human bone marrow cells.
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PMID:Inhibition of differentiation and proliferation of colony-stimulating factor-induced clonal growth of normal human marrow cells in vitro by retinoic acid. 660 27

Cells derived from the G-subline of the Dunning R-3327 rat prostatic adenocarcinoma were selected on the basis of their inducibility for alkaline phosphatase (AP) activity by retinoic acid. A p-nitrophenylphosphate-agarose overlay procedure was used to identify AP-inducible clones. The frequency of AP-inducible cells in one rapidly growing tumorigenic clone, designated 9-1C, has remained at 100% during at least 4 months of continuous culture. In culture, 9-1C cells had a mean population-doubling time in log phase of 14 hr. Retinoic acid (10 microM) did not significantly affect the rate of growth in log phase. It did, however, cause the cultures to saturate at a cell density which was 40% lower than that of control cultures. This effect on saturation density was reversible within 24 hr after removing retinoic acid from the medium. Retinoic acid-treated cells occupied greater areas on the culture dish surface, and the cross-sectional area of these cells, measured on dispersed cells by light-scatter flow cytometry, was 35 to 40% greater than that of control cells. The inducibility of 9-1C cells for AP activity decreased as the culture density increased. Cells of the 9-1C clone produced tumors when injected into male and female Fischer X Copenhagen F1 rats. No histological differences were detected between tumors grown in male and female rats. Although the tumors were poorly differentiated, primitive acinar-like structures were observed. Cells staining uniformly positive for AP activity were distributed randomly throughout the tumors. In the acinar-like structures, AP activity was localized only on the apical surfaces of the cells lining the lumens. This was also the site of enzyme activity in acini of the lateral component of the dorsolateral prostate, the source of the original R-3327 tumor. In the lateral prostatic component, AP activity was also found in the basal region of the acini, and the secretory material filling the lumens was strongly positive for the enzyme. These two regions of the tumor acini were negative for AP activity. With the exception of activity in capillaries at the basal surface, the acini of the dorsal component of the dorsolateral prostate were devoid of AP activity.
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PMID:Effect of retinoic acid on the growth and morphology of a prostatic adenocarcinoma cell line cloned for the retinoid inducibility of alkaline phosphatase. 661 77

Retinoic acid (RA) treatment of murine S91-C2 melanoma cells has been found to augment the activity of glycoprotein: sialyltransferase in a dose-dependent and time-dependent process. The enzymatic activity in cells treated with 10 microM RA reached a maximal level, 3-fold higher than in untreated cells, 72 h after initiation of treatment. In contrast, the addition of RA directly into the reaction mixture had no stimulatory effect on sialyltransferase. The endogenous glycoproteins to which sialic acid is transferred from cytidine monophosphate (CMP)-[14C] sialic acid by the action of sialyltransferase have been identified by fluorography after polyacrylamide gel electrophoresis. One of these acceptors, a glycoprotein of Mr 160 000, comigrated in gel electrophoresis with a cell surface sialoglycoprotein that can be labeled by the periodate-tritiated borohydrate procedure more intensely on intact RA-treated than on untreated cells. Removal of sialic acid residues exposed on the surface of either control or RA-treated cells enhanced 2- to 3-fold the transfer of sialic acid to endogenous acceptors. These results suggest that the increased sialyltransferase activity in RA-treated melanoma cells may be responsible for the enhanced sialylation of certain cell surface glycoproteins. RA treatment of several other tumor cell lines also resulted in stimulation of sialyltransferase activity indicating that this effect of RA is not limited to the S91-C2 melanoma cells.
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PMID:Stimulation of sialyltransferase activity of melanoma cells by retinoic acid. 664 95

Skin tumors in mice can be induced by the sequential application of a subthreshold dose of a carcinogen (initiation phase) followed by repetitive treatment with a noncarcinogenic tumor promoter. The initiation phase requires only a single application of either a direct-acting carcinogen or a procarcinogen which has to be metabolized before being active; it is essentially an irreversible step which probably involves a somatic cell mutation as evidenced by a good correlation between the carcinogenicity of many chemical carcinogens and their mutagenic activities. There is a good correlation between the skin-tumor-initiating activities of several polycyclic aromatic hydrocarbons (PAH) and their ability to bind covalently to epidermal DNA. Results from our laboratory as well as others suggest that "bay region" diol-epoxides are the ultimate carcinogenic form of PAH carcinogens. Potent inhibitors and stimulators of PAH tumor initiation appear to affect the level of the PAH diol-epoxide reacting with specific DNA bases. REcent data suggest that the tumor-promotion stage involves at least 3 important steps: (1) the induction of embryonic-looking cells (dark cells) in adult epidermis; (2) an increased production of epidermal prostaglandins and polyamines; (3) sustained proliferation of dark cells. Retinoic acid specifically inhibits step 2, whereas the anti-inflammatory steroid fluocinolone acetonide is a potent inhibitor of steps 1 and 3. The mechanism and the importance of a specific sequence for each step in chemical carcinogenesis in mouse skin will be discussed in detail.
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PMID:Multistage chemical carcinogenesis in mouse skin. 678 33

Rat hepatoma cells were cultured in a medium with suboptimal concentration of fetal calf serum. In this low serum culture, retinoic acid inhibited the cell proliferation and enhanced the number of receptors for epidermal growth factor (EGF). On the contrary, teleocidin, a possible naturally occurring tumor promoter from Streptomyces, was a weak mitogen and inhibited EGF binding. A concurrent treatment of AH66 cells with these two compounds showed that they acted antagonistically. Retinoic acid inhibited the mitogenic action of teleocidin, while teleocidin suppressed the retinoic-acid enhancement of the number of EGF receptors. Retinoic acid could not prevent the alterations of the cell surface properties induced by a prolonged treatment with teleocidin. Furthermore, these two compounds appeared to be involved in the regulation of glycoprotein synthesis and the stimulation of cellular glycoprotein synthesis by retinoic acid was abolished by teleocidin. The present data suggest that retinoic acid selectively antagonizes the mitogenic action of teleocidin, and also indicate that the hepatoma cell cultures appear to prove a useful system for exploring the mechanisms of action of both retinoic acid and teleocidin.
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PMID:Antagonistic action of retinoic acid and teleocidin on the proliferation and epidermal growth factor binding of rat hepatoma cells. 679 26

The biology of tumor formation by the initiation-promotion protocol differs from that of the complete carcinogenesis process. In the latter case, the latency period is longer and tumor yield is less, but carcinomas appear much earlier. Retinoic acid, a potent inhibitor of both the induction of ODC activity and tumor promotion by TPA, failed to inhibit both the induction of ODC activity and tumor formation by DMBA. 7,8-Benzoflavone, which did not inhibit the induction of ODC activity by TPA, inhibited the induction of ODC activity and tumor formation by DMBA. The results indicate that: (a) mechanism of the induction of ODC activity and tumor formation by a complete carcinogen appears to be different from that of the tumor promoter TPA; (b) DMBA-induced ODC activity may be an important component of the mechanism of DMBA carcinogenesis; and (c) although there is a wealth of data that indicate the efficacy of the retinoids in the prevention of a variety of cancers in experimental animals, including mammary carcinogenesis by DMBA (3,5), the present results and those reported by others (2) are not in agreement with a universal effect of retinoic acid in the prevention of carcinogenesis.
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PMID:The differential effects of retinoic acid and 7,8-benzoflavone on the induction of mouse skin tumors by the initiation-promotion protocol and by the complete carcinogenesis process. 680 91


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