Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The production of superoxide anion radicals by murine peritoneal exudate cells (PECs) following intraperitoneal (i.p.) injection of mouse skin tumor promoters was assessed in vitro by the reduction of nitroblue tetrazolium (NBT). Phorbol-12-myristate-13-acetate (PMA) or mezerein when administered i.p. to CD-1 female mice at a dose of 0.1 microgram caused an inflammatory response in the peritoneal cavity. PMA (0.1 microgram) also caused an increase in the number of PEC reducing NBT, i.e. formazan-positive PECs (20% positive cells) as compared to vehicle control from 15 min through 2 h following i.p. administration to unmanipulated mice. In the same system, dose-response studies demonstrated that 4-O-methyl-phorbol myristate acetate (4-O-Me-PMA) and mezerein were approximately 50 times less active than PMA, while phorbol dibutyrate (PDB), phorbol diacetate (PDA), phorbol and the calcium ionophore A23187 did not cause an increase in the number of formazan-positive PECs at the doses used. When the same compounds (0.1 microgram) were administered to mice which had been pretreated i.p. with thioglycollate 6 days prior to the experiment, PMA, PDB, 4-O-Me-PMA, mezerein and A23187 all caused an increase in the number of formazan-positive PECs 2 h after treatment. The PEC which reduced NBT in response to tumor promoters were predominantly adherent and esterase positive cells, suggesting they were macrophages. These results indicate that in vivo administration of tumor promoters results in the production of superoxide anion radicals by murine peritoneal macrophages and that the physiological state of the macrophages is important in the response to tumor promoters.(ABSTRACT TRUNCATED AT 250 WORDS)
Carcinogenesis 1989 May
PMID:Tumor promoters differ in their ability to stimulate superoxide anion radical production by murine peritoneal exudate cells following in vivo administration. 253 13

The role of arachidonic acid (AA) metabolism in the stimulation of oxygen radical production by murine peritoneal macrophages treated with tumor promoters was assessed. In vivo administration of the phospholipase A2 inhibitor dibromacetophenone, the anti-inflammatory steroid fluocinolone acetonide or the lipoxygenase inhibitor nordihydroguiaretic acid just prior to i.p. injection of phorbol-12-myristate-13-acetate (PMA, 100 ng) into unmanipulated CD-1 female mice resulted in a dose-dependent decrease in the number of peritoneal exudate cells (PEC) producing superoxide anion radical (O2) as assessed by the reduction of nitroblue tetrazolium, i.e. the formation of formazan-positive PEC. The cycloxygenase inhibitor indomethacin had no effect on the number of formazan-positive PEC caused by PMA treatment. The ability of PMA, phorbol-12,13-dibutyrate mezerein, phorbol-12,13-diacetate and 4-O-Me-PMA to stimulate the production of oxygen radicals by murine peritoneal macrophages correlated with their ability to stimulate the release of [3H]AA equivalents from the macrophages. The calcium ionophore A23187 which stimulated significant [3H]AA equivalent release did not stimulate superoxide anion radical production by the macrophages. PMA administered i.p. to SENCAR mice increased the number of formazan-positive PEC 4-to 5-fold compared with similarly treated C57BL/6 mice. PMA also stimulated the release of twice the amount of [3H]AA equivalents from peritoneal macrophages from SENCAR mice compared with that released by macrophages from C57BL/6 mice. The addition of low concentrations of AA (1-10 microM) in vitro to casein-elicited murine peritoneal macrophages treated with low concentrations of PMA (1 ng/ml) resulted in a 2-fold potentiation of the amount of superoxide anion radical produced compared with PMA treatment alone as assessed by the reduction of cytochrome c. These results demonstrate that AA and/or a lipoxygenase product can potentiate the production of oxygen radicals by murine peritoneal macrophages treated with tumor promoters.
Carcinogenesis 1989 Oct
PMID:Arachidonic acid potentiates superoxide anion radical production by murine peritoneal macrophages stimulated with tumor promoters. 255 22

The ability of the non-promoter phorbol diacetate (PDA) to modulate superoxide anion radical production by the complete tumor promoter phorbol myristate acetate (PMA) or the second stage promoter mezerein was assessed. Superoxide anion radical production was measured by the superoxide dismutase inhibitable reduction of nitroblue tetrazolium (NBT) to a blue intracellular formazan precipitate. These studies demonstrated that superoxide anion radical production by murine peritoneal exudate cells (PEC) stimulated by i.p. injection with mezerein (100 ng) is inhibited in a dose-dependent manner by co-administration with PDA (1-1000 ng). There was no effect on the number of formazan-positive PEC when PDA was co-administered with PMA. In a two-stage tumor promotion bioassay in female SENCAR mice initiated with 25.6 micrograms dimethylbenz[a]anthracene (DMBA) followed by first stage promotion with PMA (4X, 2 micrograms), co-administration of mezerein (2 micrograms) with 2 micrograms or 20 micrograms PDA reduced the number of papillomas after 14 weeks by 38% and 44%, respectively, compared with mezerein treatment alone. PDA (20 micrograms) when co-administered with mezerein (2 micrograms) does not inhibit mezerein induced hyperplasia in mouse skin. These results suggest a correlation between the ability of PDA to inhibit both superoxide anion radical production and tumor promotion by mezerein.
Carcinogenesis 1986 Oct
PMID:Phorbol diacetate inhibits superoxide anion radical production and tumor promotion by mezerein. 301 85

We have found that maximum stimulation (greater than 10-fold) of kinase activity of a bovine brain preparation of calcium- and phospholipid-dependent protein kinase (PKC) by 12-O-tetradecanoylphorbol-13-acetate (TPA) occurs in the presence of phospholipid, but in the absence of added Ca2+. In effect, nM concentrations of TPA substitute for mM concentrations of added Ca2+, and the two agents are not synergistic. Biologically active analogs of TPA such as phorbol-12,13-dibutyrate (PDBu), 12-O-hexadecanoyl-16-hydroxyphorbol-13-acetate (HHPA) or mezerein were also effective activators of PKC, as were the chemically unrelated tumor promoters teleocidin and aplysiatoxin, when tested at nM concentrations in the absence of added Ca2+. On the other hand, the biologically inactive compounds phorbol, 4-alpha-phorbol-12,13-didecanoate (4-alpha-PDD), HHPA-13,20-diacetate and 1,2-dihydro-20-deoxy-HHPA did not affect PKC activity in the absence or presence of Ca2+. Our results are consistent with a stereochemical model in which the hydrophilic domains of certain diterpenes, teleocidin and aplysiatoxin interact specifically with PKC apoenzyme, while their hydrophobic domains interact with phospholipid, thus forming an enzymatically active ternary complex.
Carcinogenesis 1985 Feb
PMID:Activation of protein kinase C by tumor promoting phorbol esters, teleocidin and aplysiatoxin in the absence of added calcium. 315 4

The synthesis of potential metabolites of 1-nitropyrene, resulting from oxidation at the K-regions, is described. Reaction of 1-nitropyrene with OsO4 gave the cis-4,5- and 9,10-dihydrodiols. These were separated and oxidized with activated MnO2 to give the corresponding 4,5- and 9,10-diones; further oxidation to the highly mutagenic lactones, 1- and 3-nitro-5H-phenanthro[4,5-bcd]pyran-5-one, was observed in these reactions. Reduction of the 4,5-dione with KBH4 gave the trans-4,5-dihydrodiol, which was identical to one of the metabolites of 1-nitropyrene. Reduction of the 9,10-dione gave an unstable trans-9,10-dihydrodiol, which was characterized as its diacetate. The u.v. spectra, n.m.r. spectra and h.p.l.c. retention times of these compounds are presented.
Carcinogenesis 1986 Sep
PMID:Synthesis of K-region derivatives of the carcinogen 1-nitropyrene. 374 29

The effect of phorbol ester tumour promoters on the release of superoxide anion radicals .O2- by human peripheral leukocytes and the role of such radicals in tumour promotion of mouse skin was studied. No significant difference was found between complete [12-O-tetradecanoylphorbol-13-acetate (TPA)] as compared with incomplete [12-O-retinoylphorbol-13-acetate (RPA), 12-O-(2Z,4E,6,8)tetradecatetraenoylphorbol-13-acetate (Ti8), mezerein] tumour promoters upon induction of .O2- when measured by the reduction of ferricytochrome c. The semisynthetic phorbol esters 12-O-ethacrynylphorbol-13-acetate (EPA) and 4-O-methyl-TPA were less active, and phorbol diacetate, phorbol and ionophore A 23187 were found to be inactive in stimulating superoxide anion radicals. TPA-induced .O2- release from leukocytes was strongly inhibited by Cu(II)-(diisopropylsalicylate)2 (CuDIPS), and, to a lesser extent, by ethacrynic acid, nordihydroguaiaretic acid and quercetin. Retinoic acid exhibited only a moderate inhibitory effect. No .O2- release was observed in epidermal cell cultures upon TPA treatment. When analysed by the alkaline elution technique, TPA-induced .O2- release from leukocytes did not lead to measurable DNA damage in co-cultivated keratinocytes even in the presence of DNA repair inhibitors. In multi-stage-tumourigenesis experiments including two-stage promotion, retinoic acid, ethacrynic acid and CuDIPS were unable to inhibit tumour promotion in mouse skin when applied in combination with TPA in first stage promotion. gamma-Irradiation at a dose level shown to cause DNA damage in vitro could not replace TPA as a stage I-promoting agent. It is concluded that superoxide anion radicals--if related to promotion at all--may play a role in stage II rather than in stage I of mouse skin tumour promotion.
Carcinogenesis 1984 Dec
PMID:On the role of superoxide anion radicals in skin tumour promotion. 609 35

The effects of intraurethral or i.p. administration of a mouse skin tumor promoter phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), on rodent urinary bladder transitional epithelium were studied. TPA, when instilled into the urinary bladder of inbred rats (female Fischer, F344) or mice (C3H, ICR, C57BL X DBA/2 F1) at a dose as low as 0.16 nmol, led to a significant (about 10-fold) increase in bladder ornithine decarboxylase (EC 4.1.1.17) (ODC) activity. Peak ODC activity was observed at about 6 hr, and enzyme activity returned to base levels about 14 hr after intravesical TPA. Administration of TPA i.p. in dimethyl sulfoxide also induced vesical ODC at 4 hr after treatment. The magnitude of vesical ODC induction correlated well with the ability of a series of phorbol esters to promote mouse skin tumor formation (TPA greater than phorbol didecanoate greater than phorbol dibenzoate, and phorbol diacetate or phorbol did not induce bladder ODC activity). Mezerein, a second stage mouse skin tumor promoter, induced urinary bladder ODC as much as TPA did. Increased ODC activity by TPA was the result of an increased amount of ODC protein localized mostly (greater than 60%) in urinary bladder mucosa. Intraurethrally administered TPA induced transitional cell hyperplasia starting at Day 2, and it persisted for about 7 days. The urothelium regained normal histology 13 days after TPA treatment. TPA bound specifically and with high affinity to murine bladder mucosa and muscularis particulate preparations. Scatchard analysis of mucosal binding revealed a Kd of 0.82 nM; at saturation, 2.43 pmol were bound per mg protein. Since TPA binds specifically to urinary bladder epithelium, and the induction of ODC activity is one of the properties of tumor promoters, one may conclude that TPA may promote urinary bladder carcinogenesis. Intravesical saccharin also induced urinary bladder ODC activity, but TPA at equimolar quantity was far more potent than saccharin. Thus TPA, being a structurally well-defined molecule, may be a useful compound to study the phenomenon of the tumor promotion stage in urinary bladder carcinogenesis.
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PMID:Specific binding, stimulation of rodent urinary bladder epithelial ornithine decarboxylase, and induction of transitional cell hyperplasia by the skin tumor promoter 12-O-tetradecanoylphorbol-13-acetate. 631 23

Rodent and human skin maintained in short-term organ culture was treated with 3H-labelled 7,12-dimethylbenz[a]-anthracene. Extracts of the rodent tissue and culture fluid in which either mouse, rat or human skin had been maintained were found to contain radioactive material that possessed the chromatographic characteristics of trans-1,2-dihydro-1,2-dihydroxy-7,12-dimethylbenz[a]anthracene when it was examined in two different h.p.l.c. systems. When the metabolite was treated with hot mineral acid, the two radioactive products formed co-chromatographed with the phenols that were formed when the reference dihydrodiol was similarly treated. Acetylation of the isolated metabolite yielded a single product that had chromatographic properties identical to those of the diacetate of the reference dihydrodiol. Taken together these data show that the 1,2-dihydrodiol of 7,12-dimethylbenz[a]anthracene is formed as a metabolite of this hydrocarbon by rodent and human skin maintained in short-term organ culture.
Carcinogenesis 1983 Oct
PMID:Formation of the 1,2-diol as a metabolite of 7,12-dimethylbenz[a]-anthracene by rodent and human skin. 641 86

Normal primary rat tracheal epithelial (RTE) cells were isolated and exposed in culture to tumor promoters and irritants of diverse chemical classes. The phorbol derivative class of tumor promoters greatly stimulated colony forming efficiency (CFE) in culture. The efficacies of the agents tested were ranked in the order: mezerein greater than 12-O-tetradecanoyl-phorbol-13-acetate (TPA) greater than phorbol didecanoate greater than phorbol dibutyrate greater than phorbol dibenzoate greater than 4-O-methyl TPA greater than phorbol diacetate. The parent alcohol phorbol did not stimulate CFE under the conditions tested. The indole alkaloid tumor promoter teleocidin stimulated CFE at concentrations at least 10-fold lower than those required for TPA. Other irritants and non-phorbol ester tumor promoters such as anthralin, benzoyl peroxide, calcium ionophore A23187, and ethylphenyl propiolate were either inactive or reduced CFE. Phenobarbital marginally stimulated CFE at one concentration but reduced CFE at higher concentrations. Increases in CFE elicited by TPA and analogs were dependent upon the time of addition of TPA to the cultures. Maximum increases in CFE were observed when the cells were plated into medium containing TPA. If TPA was added 40 h after plating, stimulation of CFE did not occur. This 40 h time interval may represent a crucial period for the commitment of RTE stem cells to proliferation or differentiation. Whether the stimulation of colony formation seen in normal RTE cells exposed to phorbol derivatives also occurs in carcinogen-altered cells, thereby causing their proliferative expansion, remains to be determined.
Carcinogenesis 1984 Dec
PMID:The effect of 12-O-tetradecanoylphorbol-13-acetate and other tumor promoters on the colony formation of rat tracheal epithelial cells in culture. 643 93

Treatment of human HL-60 promyelocytic leukemia cells with phorbol-12-myristate-13-acetate (PMA), a tumor promoter and inducer of differentiation, stimulated the incorporation of label from L-[methyl-3H]methionine into the cellular phospholipids. Such a stimulation of phospholipid methylation was not observed in an HL-60 cell variant that is resistant to phorbol ester-induced differentiation. Enhanced methylation of phospholipids was detected 6 h after treatment and reached a maximum level of about twice the control level at 24-48 h. The degree of phospholipid methylation was dependent on the phorbol ester dose. The stimulation in phospholipid methylation by PMA was confirmed by measuring the activity of phosphatidylethanolamine methyltransferase in cellular lysates. After 24 or 48 h of exposure, the enzyme activity was elevated in the HL-60 cell lysates but not in the resistant cells. Phospholipid methylation was also stimulated after treatment of the HL-60 cells with the phorbol diester phorbol-12,13-dibutyrate or teleocidin, which is not a phorbol ester compound. These two chemicals and PMA are tumor promoters and inducers of cell differentiation in the HL-60 cells. Phorbol-12,13-diacetate and 4-O-methyl PMA, which are not tumor promoters or inducers of cell differentiation in the HL-60 cells, did not stimulate phospholipid methylation. The possible role of enhanced phospholipid methylation in cell differentiation of the HL-60 by these chemicals is discussed.
Carcinogenesis 1982
PMID:The control of phospholipid methylation by phorbol diesters in differentiating human myeloid HL-60 leukemia cells. 681 75


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