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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The carcinogenic process is usually multifactor in its causation and multistep in its evolution. It is likely that entirely different molecular mechanisms underlie the many steps in this process. In contrast to initiating carcinogens, the action of the tumor-promoting phorbol esters does not appear to involve covalent binding to cellular DNA and they are not mutagenic. Recent studies in cell culture have revealed two interesting biologic effects of the phorbol esters and related macrocyclic plant diterpenes. The first is that at nanomolar concentrations they induce several changes that resemble those seen in cells transformed by chemical carcinogens or tumor viruses. These include altered morphology and increased saturation density, altered cell surface fucose-glycopeptides, decrease in the LETS protein, increased transport of deoxyglucose, and increased levels of plasminogen activator and ornithine decarboxylase. In transformed cells exposed to phorbol esters the expression of these features is further accentuated. Phorbol esters do not induce normal cells to grow in agar but they do enhance the growth in agar of certain transformed cells. The second effect of the phorbol esters is inhibition of terminal differentiation. This effect extends to a variety of programs of differentiation and is reversible when the agent is removed. With certain cell culture systems induction of differentiation, rather than inhibition, is observed. Both the transformation mimetic and the differentiation effects are exerted by plant diterpenes that have tumor-promoting activity but not by congeners that lack such activity. The primary target of phorbol esters appears to be the cell membrane. Early membrane-related effects include enhanced uptake of 2-deoxyglucose and other nutrients, altered cell adhesion, induction of arachidonic acid release and prostaglandin synthesis, inhibition of the binding of epidermal growth factor to cell surface receptors, altered lipid metabolism, and modifications in the activities of other cell surface receptors. A model of "two stage" carcinogenesis encompassing the known molecular and cellular effects of initiating carcinogens and tumor promoters is presented. According to this model, initiating carcinogens induce stable alterations in the cellular genome but these are not manifested until tumor promoters modulate programs of gene expression and induce the clonal outgrowth of the initiated cell.
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PMID:Action of phorbol esters in cell culture: mimicry of transformation, altered differentiation, and effects on cell membranes. 39 70

Chemical carcinogenesis in certain tissues occurs in at least two stages: initiation, producing irreversible tissue alterations, and promotion (by agents, themselves non-carcinogenic), enhancing the outgrowth of transformed cells. Among the various tumour-promoting compounds isolated from croton oil, phorbol-12-myristate-13-acetate (PMA), is the most potent. Cell culture studies have shown that the phorbol diesters and structurally related substances induce a variety of dramatic changes in diverse eukaryotic cells. Spreading, differentiation, metabolism, DNA synthesis, expression of cell surface glycopeptides, deoxyglucose transport, as well as polyamine, plasminogen activator and ornithine decarboxylase activity are altered. These findings indicate that tumour promoters potentiate expression of the transformed phenotype in cells already malignantly transformed and also induce reversible manifestations of the transformed phenotype in normal cells. It is not known whether these agents additionally influence host effector systems involved in antitumour resistance. The present study is concerned with the effects of PMA on spontaneous in vitro cytotoxicity by macrophages and/or natural killer (NK) cells, and on the resistance to rat fibrosarcoma in vivo considered to depend on these normal effectors, in particular on mononuclear phagocytes.
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PMID:Suppression of natural antitumour defence mechanisms by phorbol esters. 51 55

Effect of beta-carotene on content of some metabolites of lipid peroxidation and activity of ornithine decarboxylase was studied in rat gastric mucosal membrane during gastric carcinogenesis developed after administration of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Intragastric administration of MNNG led to a significant increase in content of diene ketones and malonic dialdehyde in the gastric mucosal membrane within a day, while beta-carotene normalized or decreased considerably the MNNG produced accumulation of these lipid peroxidation products. In acute experiments with MNNG beta-carotene administered per os at a dose of 0.5 mg per animal did not affect the pronounced activation of ornithine decarboxylase in the gastric mucosal membrane. However, in chronic experiments with MNNG repeated administration of beta-carotene led to statistically significant decrease of the constitution-dependent enzymatic activation in the gastric mucosal membrane and to inhibition of locus formation with abnormally high activity of ornithine decarboxylase. The findings suggest that anticarcinogenic effect of the natural antioxidant beta-carotene was shown at the step of carcinogenesis promotion.
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PMID:[Potential cancer-protective effect of beta-carotene in experimental stomach carcinogenesis]. 129 27

R8605 belongs to the third generation retinoid and was found during the systematic screening of cancer chemopreventive agents in our institute. Based on the theory of multistage carcinogenesis, the anti-carcinogenic and anti-promoting effects of R8605 as well as its possible anti-promoting mechanisms were studied. Experiments proved that R8605 (50 mg/kg and 25 mg/kg, i.g.) significantly inhibited the growth of skin papillomas induced by 7, 12-dimethylbenz[a]anthracene and croton oil in mice and exhibited a potent anti-promoting action. In addition, R8605 (50 mg/kg and 25 mg/kg, i.g.) strongly inhibited the induction of ornithine decarboxylase (ODC) activity of mouse skin epidermis by croton oil. At a dose of 100 mg/kg of R8605 (i.g.) croton oil-induced ear edema in mice was suppressed. These results suggest that the anti-promoting effect of R8605 might be associated with its anti-inflammatory action and its inhibitory effect on ODC activity.
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PMID:[Anti-carcinogenic and anti-promoting effects of retinoid R8605]. 129 41

Chemoprevention of colon cancer is emerging as an alternative to therapy with a broad potential for reducing cancer incidence in defined high-risk groups and the general population. Besides several chemopreventive agents in use and under investigation, D,L-alpha-difluoromethylornithine (DFMO) and piroxicam have been shown to effectively inhibit colon carcinogenesis in rodents. A variety of proliferation-related parameters have been suggested as potential intermediate markers of cancer risk that could be used to monitor the progress of chemoprevention in clinical trials. We have investigated the effect of chemopreventive agents, DFMO, and piroxicam on mucosal ornithine decarboxylase (ODC) and tyrosine-specific protein kinase (TPK) activities during different stages of azoxymethane (AOM)-induced colonic carcinogenesis in male F344 rats in order to examine the plausibility of using these enzymes as intermediate biochemical markers of colon cancer. Groups of male F344 rats were fed modified AIN-76A diets containing 0 or 150 ppm piroxicam or 4000 ppm DFMO and given s.c. injections of AOM dissolved in normal saline at a dose of 15 mg/kg body weight/week, once weekly, for 4 weeks. Vehicle control groups received s.c. equal volumes of normal saline. Groups of animals were then sacrificed at 0, 4, 16, 24, and 32 weeks after AOM or saline treatment, and their colonic mucosa was analyzed for ODC and TPK activities. AOM treatment significantly increased mucosal ODC as well as TPK activities. AOM-induced ODC and TPK activities were significantly suppressed by dietary DFMO progressively at all stages of colon carcinogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of chemopreventive agents on intermediate biomarkers during different stages of azoxymethane-induced colon carcinogenesis. 130 73

The present study demonstrates that biogenic silica fibers (BSF), previously shown to promote skin tumors in mice and more recently to promote the induction of mesotheliomas when injected into the pleural cavity of rats, rapidly induces epidermal ornithine decarboxylase (ODC) activity in SENCAR mice following topical application. The time course for induction of epidermal ODC by BSF was very similar to that observed following topical treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA). Maximal ODC activity was observed 4-6 h following treatment with BSF. Cycloheximide (70 mg/kg i.p.) partially inhibited (61%) the induction of ODC by BSF at 5 h. In addition, retinoic acid (RA, 5 micrograms per mouse given 30 min before BSF) effectively inhibited BSF-induced ODC by 68%, while indomethacin (100 micrograms per mouse 2 h before BSF) had little or no effect. Copper(II) bis(diisopropylsalicylate) (2 mumol 30 min before BSF), an effective inhibitor of TPA-induced ODC activity and tumor promotion, also had little or no effect on BSF-induced ODC. The work described in this paper suggests that BSF induces epidermal ODC by a very specific mechanism that exhibits both similarities and differences with that of the phorbol ester, TPA. Nevertheless, this response strongly supports the conclusion that BSF is an effective tumor promoter in mouse skin and that ODC induction is an integral part of the mechanism of action of this environmental promoter.
Carcinogenesis 1992 Apr
PMID:Induction of epidermal ornithine decarboxylase activity in mouse skin exposed to biogenic silica fibers. 131 27

To challenge the theory of tissue specificity of tumor promoters, the biochemical and tumor promoting effects of okadaic acid (OA), a potent tumor promoter on mouse skin, were studied in the mucosa of rat glandular stomach. OA strongly inhibited protein phosphatases 1 and 2A, and increased 4-fold the phosphorylation of elongation factor 2 in vitro in the mucosa. Intubation of 10 micrograms (12.4 nmol) OA induced ornithine decarboxylase in the mucosa. Tumor promotion of OA was studied in the glandular stomach initiated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in a two-stage carcinogenesis experiment. OA in drinking water, 10 micrograms (12.4 nmol) per rat per day from weeks 9-55 of the experiment, and 20 micrograms (24.8 nmol) from weeks 56-72, significantly enhanced development of the neoplastic changes in the glandular stomach (P < 0.05). The neoplastic changes included adenomatous hyperplasias and adenocarcinomas, both of which correspond to papillomas and carcinomas in a two-stage mouse skin carcinogenesis experiment. The percentages of neoplastic change-bearing rats of the groups treated with MNNG plus OA, MNNG alone or OA alone were 75.0, 46.4 and 0% respectively. OA enhanced tumorigenesis in the MNNG-initiated glandular stomach of rats through the same mechanisms of action as in mouse skin. The OA pathway mediated through inhibition of protein phosphatases 1 and 2A is applicable to various organs as a general mechanism of tumor promotion.
Carcinogenesis 1992 Oct
PMID:An alternative theory of tissue specificity by tumor promotion of okadaic acid in glandular stomach of SD rats. 133 Mar 44

Squalene inhibited the effect of tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), such as increased 32Pi incorporation into phospholipids of HeLa cell membrane, induction of Epstein-Barr-virus early antigen in Raji cell and induction of ornithine decarboxylase in mouse skin. Squalene also markedly suppressed the promoting activity of TPA on skin carcinogenesis in 7,12-dimethylbenz[a]anthracene-initiated mice.
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PMID:Inhibition by squalene of the tumor-promoting activity of 12-O-tetradecanoylphorbol-13-acetate in mouse-skin carcinogenesis. 133 56

The intriguing observation has been made that 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] receptors are present in tissues not involved in calcium homeostasis and that 1,25(OH)2D3 exerts an antiproliferative, differentiation-promoting action in a variety of cancer cell lines, including cells of the large intestine. It was therefore deemed of interest to study 1,25(OH)2D3 expression and biological activity in a murine model of colon carcinogenesis. Colon carcinogenesis was induced in male rats by the sequential administration of 1,2-dimethylhydrazine dihydrochloride (DMH). Levels and binding characteristics of 1,25(OH)2D3 receptors were assessed in control and DMH-treated rat colonic mucosal high-speed supernatants. In concurrent studies, 1,25(OH)2D3 was administered (s.c., 400 ng/rat) prior to, together with and after DMH challenge and the activity of ornithine decarboxylase (ODC), a growth-related DMH-induced enzyme, was determined in colonic cytosols. Serum Ca2+ levels were measured concurrently. Rats submitted to identical treatment schedules were killed 10 weeks after termination of DMH administration and the whole colon was opened and examined for tumors. The results show that (i) rat colonic mucosa possesses a single class of high-affinity 1,25(OH)2D3 receptors; (ii) DMH administration provokes a marked reduction (50%) in 1,25(OH)2D3 binding sites without affecting Kd values; (iii) DMH administered concurrently with 1,25(OH)2D3 suppressed the vitamin D-induced hypercalcemia and restored serum Ca2+ concentrations to basal levels; and (iv) 1,25(OH)2D3 delivered prior to DMH challenge obliterated the typical DMH-induced early colonic ODC activity peak and markedly reduced (50%) the number of colon adenocarcinomas. The present findings indicate that a colon-specific potent carcinogen interferes with the biological expression of 1,25(OH)2D3 and that vitamin D administered prior to a carcinogenic insult is able to reduce significantly the incidence of colon tumors, presumably acting as an antiproliferative or differentiation-promoting agent.
Carcinogenesis 1992 Dec
PMID:A protective role of 1,25-dihydroxyvitamin D3 in chemically induced rat colon carcinogenesis. 133 76

Ornithine decarboxylase (ODC) has been shown by biochemical analysis, to be important for cell proliferation and carcinogenesis in a variety of tissues, including the liver. We detected messenger RNA (mRNA) specific for the enzyme ODC in 18 patients with hepatocellular carcinoma by an in situ hybridization technique using a radiolabelled ODC probe on formalin-fixed liver specimens. Adjacent uninvolved liver tissues were used as controls. Among the adjacent uninvolved liver tissues, five showed evidence of cirrhosis. Poorly differentiated hepatocellular carcinoma has significantly higher levels of ODC mRNA than does well-differentiated hepatocellular carcinoma, which in turn has a significantly higher ODC mRNA level than adjacent uninvolved liver tissues; tissues showing evidence of cirrhosis, on the other hand, had a significantly lower ODC mRNA level than adjacent uninvolved liver tissue. This pattern of ODC gene expression in hepatocellular carcinoma is similar to the pattern of expression of other oncogenes in liver tumours. The quantitative detection of ODC mRNA in hepatocellular carcinoma by in situ hybridization may help elucidate the potential role of ODC in hepatocarcinogenesis.
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PMID:Detection of ornithine decarboxylase messenger RNA in human hepatocellular carcinoma by in situ hybridization. 133 80


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