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)

Several structurally different tumor promoters altered to various degrees both glutathione (GSH) peroxidase (EC 1.11.1.9) and ornithine decarboxylase (ODC, L-ornithine carboxy-lyase, EC 4.1.1.17) activities in mouse epidermis in vivo. At 5 h after their application to the skin, the complete tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) and the stage 2 promoter mezerein were the most potent in inhibiting GSH peroxidase activity and inducing ODC activity. In comparison, the effects of anthralin, phorbol-12,13-didecanoate, benzoyl peroxide, H2O2, and phorbol-12,13-dibenzoate were much smaller, whereas the nontumor promoter phorbol, the hyperplastic agent ethyl phenylpropiolate, and the stage 1 promoter 4-O-methyl TPA did not alter GSH peroxidase and ODC activities. Various treatments including i.p. injections of 40 micrograms of Na2SeO3 and 100 mumol of GSH and/or topical applications of 40 mumol of D-alpha-tocopherol (vitamin E) 20 or 15 min, respectively, before tumor promoter treatment inhibited in an additive manner the effects of either TPA or mezerein on both GSH peroxidase activity and ODC induction. Moreover, these Na2SeO3, GSH, and/or vitamin E treatments inhibited in the same additive manner the tumor-promoting activity of TPA in the initiation-promotion protocol. However, when tested in the 2-stage promotion protocol with 4 doses of TPA followed by twice weekly applications of mezerein, Na2SeO3 plus vitamin E and GSH plus vitamin E treatments inhibited remarkably the tumor-promoting activity of mezerein but were ineffective in the first stage of promotion. The sequence and magnitude for the effects of 7,12-dimethylbenz[alpha]anthracene (DMBA) on GSH peroxidase and ODC activities were very different from those of the tumor promoters. In contrast with their antitumor-promoting activity, the treatments with Na2SeO3 plus vitamin E and GSH plus vitamin E failed to inhibit the carcinogenicity of a single large dose of DMBA and even enhanced the induction of skin tumors by repeated applications of subcarcinogenic doses of DMBA. These results suggest that the promoting component of DMBA carcinogenesis may be different from that of TPA. Moreover, the anticarcinogenicity of Na2SeO3, GSH, and vitamin E may be linked to their ability to facilitate or enhance the activity of the natural GSH-dependent antioxidant protective system of the epidermal cells during the later stages of skin tumor promotion.
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PMID:Effects of combined treatments with selenium, glutathione, and vitamin E on glutathione peroxidase activity, ornithine decarboxylase induction, and complete and multistage carcinogenesis in mouse skin. 309 11

Ornithine decarboxylase (ODC, EC 4.1.1.17) activity was measured, without exogenous stimulation, in the liver, oesophagus and lung of Wistar rats which were vitamin A deficient or supplemented with retinol or retinoic acid. The enzyme basal activity in such deficiency conditions was higher, when compared with controls, in the oesophagus and especially in the lungs. Retinoic acid normalized enzyme activity only at high doses (300 micrograms/day). In the liver, initial retinol deficiency did not sensitively modify ODC activity, and retinoic acid then stimulated the enzyme abnormally. This phenomenon could not be observed at later stages of vitamin deficiency (but there again without cytological abnormalities or thymidine incorporation disturbances): liver ODC response then became comparable to that of other tissues. These results highlight the particular basal hyperactivity of pulmonary ODC during the initial stages of vitamin A deficiency, indicative of an enhanced tendency to cell proliferation. A special stimulating effect of retinoic acid on ODC, contemporary with early deficiency, was observed in the liver; this effect was not observed at a later stage in normally fed rats.
Carcinogenesis 1988 Dec
PMID:Ornithine decarboxylase basal activity in liver, oesophagus and lung of vitamin A deficient rats, and the effect of retinoic acid. 319 61

We have shown that retinoic acid, applied either to the skin or administered in diet, inhibits skin tumor promotion by TPA. Retinoic acid does not inhibit the initiation step of mouse skin carcinogenesis. Our results indicate that retinoic acid inhibits both stage I and stage II of tumor promotion, and the inhibition of tumor promotion depends upon the duration of retinoic acid treatment. The inhibition of skin carcinogenesis by retinoic acid is not universal; retinoids exhibit specificity towards carcinogens and tumor promoters. In conclusion, the results presented indicate that the inhibition of TPA-induced ODC gene expression may be one of the mechanisms contributing to the antitumor promoting property of the retinoids. However, other mechanisms concerning the effect of retinoic acid on chromatin structure (Porter et al., 1986), glycoprotein synthesis (Levin et al., 1983), peptide growth factors (Sporn et al., 1986), induction of transglutaminase (Lichti and Yuspa, 1985) and the host-immune system (Dennert, 1985) may also explain the molecular basis of retinoid action.
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PMID:Inhibition of phorbol ester-induced ornithine decarboxylase gene transcription by retinoic acid: a possible mechanism of antitumor promoting activity of retinoids. 328 48

The development of a satisfactory rodent model for cancer of the large intestine began with the discovery by Laqueur and associates in 1962 that the plant product, cycasin (methylazoxymethanol glycoside), is a potent carcinogen for rodents. Soon after that, DMH, AOM, and MAM were found to be even more efficient intestinal carcinogens in rats. These three compounds, plus two direct acting carcinogens (MNNG, MNU) are used almost exclusively in current animal investigations. Although all these chemicals have some degree of activity in all rodents, they are most effective in rats. Various rat strains differ somewhat in susceptibility, Sprague-Dawley being the most sensitive to these carcinogens. Cancers of the large intestine in the animal model resemble adenocarcinomas in humans, and they spread in a similar manner except that metastases to the liver and lung are very uncommon in animals. Animal studies support epidemiological and human experimental observations of dietary factors involved in colorectal cancer formation. Most physicians believe that the majority of colorectal cancers develop from preexisting adenomas. Morson has shown that large adenomas and villous adenomas have a greater risk of developing cancer than small adenomas. Hill has theorized that there are different factors responsible for the formation of small adenomas from normal mucosa, for the growth of small to large adenomas, and for the development of cancer from large adenomas. Animal studies provide some support for this concept. Weak intestinal carcinogens tend to induce more benign adenomas than carcinomas. Very small doses of strong carcinogens also induce some adenomas and a few early polypoid intestinal cancers after a long latent period. Moderate to large amounts of DHM, for example, induce only malignant lesions even when these lesions are as small as 1 mm. These observations suggest a relationship between adenomas and carcinomas. There is also biochemical evidence to support the staged progression of carcinogenesis. An example is the graded increases in ODC activity that occur in tissues undergoing tumorigenesis.
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PMID:Animal model for colorectal cancer. 403 97

Adriamycin (ADR) failed to inhibit and paradoxically enhanced the biological action of 12-O-tetradecanoylphorbol-13-acetate (TPA) in mouse epidermis in vivo and in vitro. In the presence of ADR, the tumor promoter caused a greater sequential rapid increase and prolonged decrease in glutathione (GSH) peroxidase (GSH:H2O2 oxidoreductase, EC 1.11.1.9) activity accompanied by a greater decrease in the ratio of reduced (GSH)/oxidized (GSSG) glutathione in isolated epidermal cells. The ability of ADR to deplete the intracellular level of GSH correlated with its ability to increase basal and TPA-induced ornithine decarboxylase (ODC, L-ornithine carboxylase, EC 4.1.1.17) activities. In vivo, topical ADR treatments also enhanced TPA-induced ODC activity as well as the tumor-promoting ability of TPA in the two-stage system of mouse skin carcinogenesis. Since lipid peroxidation has been associated with ADR toxicity, these data suggest that the enhancement of the tumor-promoting ability of TPA by ADR may be the result of an increased oxidative challenge that overwhelms the GSH-dependent antioxidant protective system of the epidermal cells.
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PMID:Enhancement by adriamycin of the effects of 12-O-tetradecanoylphorbol-13-acetate on mouse epidermal glutathione peroxidase activity, ornithine decarboxylase induction and skin tumor promotion. 407 83

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

Ornithine decarboxylase activity and polyamine concentrations were determined in the lungs of mice from 0 to 20 h after treatment with 12-O-tetradecanoylphorbol-13-acetate (17.7 nmol in 0.2 ml acetone/mouse). In CFLP mice, which responded to carcinogen with development of lung-adenomas, a single topical application of TPA to hairless mouse skin increased ornithine decarboxylase activity in the lung. In contrast, in C3H/He-mg mouse strain, which were resistant to lung-adenoma production, TPA application did not increase ODC activity of the lungs.
Carcinogenesis 1983 Oct
PMID:Effect of 12-O-tetradecanoylphorbol-13-acetate on polyamine metabolism in mice sensitive and resistant to lung-adenoma. 661 64

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

The activity levels of L-ornithine carboxy-lyase (ODC) (E.C. 4.1.1.17) and S-adenosyl-L-methionine carboxy-lyase (SAM-D) (E.C.4.1.1.50) were determined in individual papillomas induced in mouse skin by a two-stage technique, and in normal mouse epidermis. Cycloheximide treatment abolished both enzyme activities. In normal epidermis the ODC activity was barely detectable, whereas the tumors exhibited high levels of ODC. Levels of SAM-D activity above those of normal epidermis were detected in some papillomas, but in contrast to ODC the SAM-D activity levels were not consistently increased in skin tumors. By pooling a great number of papillomas, the variations in ODC and SAM-D activities between different papillomas could be minimized so that reliable measurements of the biological half-lives of ODC and SAM-D in the tumors were obtained using cycloheximide treatment. The half-life of SAM-D in squamous papillomas was 45 min, almost identical to the 41 min half-life of the 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced level of this enzyme in normal mouse epidermis. In contrast, the ODC activity of the mouse skin papillomas declined at a rate similar to that in TPA-treated epidermis for only the first 15-20 min after cycloheximide injection. Thereafter, at time points when protein synthesis was approximately 90% inhibited, the ODC activity reverted to high levels. These results show that the high level of ODC activity in squamous papillomas is stabilized. This observation is compatible with the hypothesis that the control mechanism of the ODC activity level in these tumors is severely deranged. This change in polyamine turnover pattern may be related to altered differentiation of the epidermal cells, which constitute the main bulk of cells in these tumors.
Carcinogenesis 1982
PMID:Ornithine decarboxylase activity in chemically induced mouse skin papillomas. 708 70

A single topical application of 17 nmol 12-O-tetradecanoyl-phorbol-13-acetate (TPA) to the skin of hairless mice induces characteristic transient alterations in the epidermal cells turnover and maturation (0.96 h), associated in time with characteristic changes in the activities of L-ornithine carboxy-lyase (E.C. 4.1.1.17) (ODC) and S-adenosyl-L-methionine carboxy-lyase (E.C.4.1.1.50) (SAM-D) and in the accumulation of polyamines. The effects on these responses of local pretreatment of the skin with retinoic acid 1 h prior to TPA were investigated at selected time points. Retinoic acid inhibited the TPA-induced ODC activity and the ensuing accumulation of putrescine, but did not alter the TPA-induced SAM-D activity or the molar ratio of spermidine/spermine. This pretreatment also decreased in number of dividing basal cells in the first TPA-induced synchronized wave of proliferating cells. However, during the subsequent period of proliferation, the number of dividing cells in the retinoic acid pretreated group was comparatively increased. Hence, at four levels of retinoic acid (0.17, 1.70, 17.0 and 170 nmol), which all inhibited the TPA-induced ODC effectively, there was no change in the total number of basal cells that divided during 16-48 h after TPA-application. Theory is put forward the retinoic acid might exert its antitumorigenic effect during tumor promotion with TPA by interfering with the rate and/or quality of epidermal cell maturation, rather than by inhibiting cell proliferation.
Carcinogenesis 1982
PMID:Effect of retinoic acid pretreatment on 12-O-tetradecanoylphorbol-13-acetate-induced cell population kinetics and polyamine biosynthesis in hairless mouse epidermis. 708 72


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