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)

Effects of methylglyoxal bis(butylamidinohydrazone) (MGBB), a reversible inhibitor of ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (AdoMetDC), on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced increases of ODC and AdoMetDC activities, ODC and mRNA level and polyamine contents in mouse skin were investigated in connection with tumor formation. Formation of papillomas by applications of TPA to 7,12-dimethylbenz[a]anthracene (DMBA)-initiated mouse skin was effectively inhibited by simultaneous topical applications of MGBB, MGBB also dose-dependently inhibited the ability of TPA to induce increases of ODC activity, ODC mRNA level and the accumulation of putrescine and spermidine in mouse skin. Induction of AdoMetDC activity was not affected by the drug. These inhibitory effects of MGBB on ODC induction and tumor promotion were more evident in multiple application experiments than with a single application of the drug.
Carcinogenesis 1988 Feb
PMID:Inhibition of mouse skin tumor promotion and of promoter-induced epidermal polyamine biosynthesis by methylglyoxal bis(butylamidinohydrazone). 312 83

Double applications of 12-O-tetradecanoylphorbol-13-acetate (TPA) to mouse skin at intervals of greater than 48 h led to a larger induction of ornithine decarboxylase (ODC) and a smaller increase of DNA and RNA synthesis than did a single application. The largest induction of S-adenosylmethionine decarboxylase occurred at a 120 h interval between coupled TPA applications. The change in ODC activity was followed by a parallel change in putrescine level. At intervals less than 24 h, the first application of TPA appeared to induce a refractory state; the second application of TPA did not induce the polyamine biosynthetic enzymes nor cause an accumulation of polyamines. The effect of the second application of TPA on the synthesis of DNA and RNA was considerably less at all times than that of a single application.
Carcinogenesis 1983
PMID:The difference between the effects of single and double applications of 12-O-tetradecanoylphorbol-13-acetate, a potent tumor promoter, on polyamine metabolism and nucleic acid synthesis in mouse epidermis. 618 49

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

A single application of 12-O-tetradecanoyl-phorbol-13-acetate (TPA) to hairless mouse skin induces increased activity of epidermal L-ornithine carboxy-lyase (E.C.4.1.1.17) (ODC) with a peak at 5 h, and S-adenosyl-L-methionine carboxy-lyase (E.C.4.1.1.50) (SAM-D) with a broad peak at 20-36 h. The temporal sequence of the accumulation of polyamines; i.e. putrescine, spermidine and spermine, and the rate of DNA synthesis was investigated. All four parameters were measured in the same tissue-samples and multiple peaks of DNA synthesis and of individual polyamines were demonstrated. In the period from 0-12 h, there was an initial decrease in the rate of DNA synthesis. In this period changes in the molar ratio of spermidine/spermine were negatively correlated to the rate of DNA synthesis. From 12-48 h, however, changes in the molar ratio of spermidine/spermine had an almost identical time course with rates of change of DNA synthesis. Based on corresponding cell kinetic results it is suggested that the spermidine/spermine ratio reaches a maximum peak during the S-phase of the cell cycle. The relation between the rate of DNA-synthesis and the spermidine/spermine ratio as well as the ordered time sequence for the accumulation of putrescine and the induction of ODC and SAM-D activities, suggest a strong interdependence and a strict regulation of these events in hairless mouse epidermis induced to proliferate by TPA.
Carcinogenesis 1981
PMID:Changes in epidermal polyamine biosynthesis and specific activity of DNA following a single application of 12-O-tetradecanoyl-phorbol-13-acetate to hairless mouse skin. 727 34

The effects of 17 beta-estradiol (E2) on the levels of ornithine decarboxylase (ODC), S-adenosylmethionine decarboxylase (SAMDC), and of the polyamines putrescine, spermidine and spermine in the kidneys of castrated male hamsters were determined. The i.p. injection of E2 into male hamsters led to renal ODC levels three times above the control levels 6--12 h after treatment. Similarly, the renal ODC levels in hamsters treated with chronic doses of E2 for 60--180 days were 1.5--1.9 times the corresponding enzyme levels in control, sham-operated animals. With a series of estrogen analogues, there was a direct correlation between the rise in renal ODC in vivo and the binding to renal estradiol receptor sites in vitro. The hamster kidney levels of the polyamines putrescine, spermidine and spermine all declined during the 180-day experimental period. A single i.p. injection of E2 led to a 70% increase in renal SAMDC activity 12 h after treatment. However, the administration of E2 for 180--270 days was without effect on the normal age-dependent decline in SAMDC levels noted in kidneys. These results indicate that, like other carcinogens and promoters, E2 increases the levels of ODC and of polyamines in its target tissue and that the rise in ODC is mediated by a specific estradiol-binding protein.
Carcinogenesis 1981
PMID:Elevated levels of ornithine decarboxylase and polyamines in the kidneys of estradiol-treated male hamsters. 731 57

The responses of male noninbred rat colonic epithelial ornithine decarboxylase (EC 4.1.1.17) (ODC) and S-adenosyl-L-methionine decarboxylase (EC 4.1.1.50) (SAMD) activities following topical administration of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) or bile salts were studied. A single intrarectal installation of 13 mumol of MNNG resulted in a significant (p < 0.001) 20-fold peak ODC activity after 4 hr, with a prompt return to control levels by 12 hr. Stimulation of SAMD activity was less pronounced but significant (p < 0.01), with a broad 2-fold peak over controls. No significant responses of colonic epithelial enzyme activities were detected following a single intrarectal instillation of N-methyl-N'-nitroguanidine, a noncarcinogenic and nonmutagenic metabolite of MNNG, at a dose equimolar to that of MNNG. Bile salts significantly (p < 0.001) induced ODC with almost the same kinetic pattern as that observed after MNNG administration in the following order: sodium deoxycholate > sodium chenodeoxycholate > sodium cholate. Activations of SAMD were similar for these 3 bile salts. Glycine- or taurine-conjugated deoxycholate showed ODC and SAMD enzyme activations similar to that of nonconjugated deoxycholate. No significant enzyme response was seen after sodium dehydrocholate treatment. Stimulation of activities of both enzymes was directly dependent on bile salt dose. Induced ODC and SAMD activities were principally localized in colonic epithelium. Deoxycholate-stimulated enzyme activities were significantly inhibited by cycloheximide. Enzyme stimulations by active compounds were accompanied by morphological changes such as mucosal cell degeneration, mucus depletion, submucosal congestion, and punctate hemorrhage, followed by submucosal leukocytic cellular infiltration. These data support the concept that initiating and promoting events may be involved in colon carcinogenesis.
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PMID:Early induction of rat colonic epithelial ornithine and S-adenosyl-L-methionine decarboxylase activities by N-methyl-N'-nitro-N-nitrosoguanidine or bile salts. 744 10

Orotic acid (OA), a known promoter of carcinogenesis, significantly stimulated proliferation of K 562 leukemic cells even at as high a concentration as 0.1 mM. This effect was accompanied by a significant increase of the activity of two key enzymes of the polyamine pathway, i.e. ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (SAMDC). The induction of ODC activity was associated with increased expression of the ODC gene. The participation of ODC in early events evoked by OA in leukemic cells was confirmed by the decrease of the stimulatory effect of OA on cell proliferation in the presence of alpha-difluoromethylornithine (DFMO)--an irreversible inhibitor of ODC. The involvement of protein kinase C (PK-C) and cyclic nucleotide-dependent kinases in OA action on K 562 leukemic cells was demonstrated by a significant reduction of cell proliferation by addition of H-7 (1-(5-isoquinolinesulphonyl)-2-methylpiperazine). Since PK-C is involved both in induction of ODC activity and in membrane transport of polyamines, H-7 significantly inhibited the proliferation of K 562 leukemic cells even in the presence of OA and exogenous putrescine. The importance of extracellular sources of polyamines for leukemic cell growth was shown by supplementation of the incubation medium with putrescine. Exogenous putrescine significantly enhanced the concentration of spermidine and spermine within the cell and increased the number of cells. The effect of OA on natural killer (NK) cell cytotoxicity was also examined. Rat peripheral blood mononuclear cells were used as effector cells and K 562 cells as targets. OA, progressively with dose, significantly decreased specific lysis when targets were preincubated with it. On the other hand, pretreatment of PBMC effector cells with OA, regardless of the applied concentration, did not affect the amount of 51Cr released from lysed cells. OA as a promoter of carcinogenesis stimulates proliferation of leukemic cells and impairs their responsiveness to NK activity. ODC/polyamine system and PK-C appear to be involved in OA action on K 562 cells. The presented observations are important from a practical point of view, since an elevated blood concentration of OA resulting from the impaired kidney function in hematological proliferative diseases may accelerate their progression.
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PMID:The effect of OA on proliferation and polyamine metabolism of K 562 leukemic cells and their responsiveness to natural killer cell activity. 759 26

In these experiments we tested the hypothesis that constitutive activation of polyamine(PA) biosynthesis may contribute to mammary carcinogenesis. Spontaneously immortalized normal human MCF-10A breast epithelial cells were infected with the retroviral vector pLOSN containing a cDNA which codes for a truncated and more stable ornithine decarboxylase (ODC), the rate-limiting enzyme in PA synthesis. Upon chronic selective pressure with alpha-difluoromethyl-ornithine (DFMO) (an irreversible inhibitor of ODC), infected MCF-10A cells exhibited an approximately 250-fold increase in ODC activity, which persisted despite discontinuation of DFMO. ODC-over-expressing MCF-10A cells showed a modest decrease in S-adenosylmethionine decarboxylase and an increase in spermidine/spermineN1-acetyltransferase. Analysis of cellular PA profile revealed a selective accumulation of putrescine without alterations in spermidine and spermine contents. Lesser degrees of increased ODC activity were obtained reproducibly by re-exposing the cells to incremental small doses of DFMO. We observed a bell-shaped dose-related positive effect of ODC activity on clonogenicity in soft agar of MCF-10A cells. Since anchorage-dependent growth was actually reduced, such positive influence on this feature of transformation was not a non-specific consequence of a growth advantage provided by ODC over-expression. In addition, we observed a close parallelism between the dose-dependent effects of ODC expression on clonogenicity and activity of the ERK-2 kinase, a central element of the MAPK cascade. Our data demonstrate an interaction between PA and the MAPK signalling pathway and suggest that the latter may be involved in ODC-induced transformation of mammary epithelial cells.
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PMID:Ornithine decarboxylase over-expression stimulates mitogen-activated protein kinase and anchorage-independent growth of human breast epithelial cells. 900 57

Weekly administrations of the potent carcinogen 1,2-dimethylhydrazine (DMH) predominantly induce carcinoma of the colon by nearly 100% after six months' treatment in rats. Polyamines, and especially the key enzyme of polyamine de novo synthesis ornithine decarboxylase (ODC) are well-known to play an important role in cell growth and tumor carcinogenesis. Male Wistar rats were s. c.-injected with a single dose of 20 mg DMH/kg b. wt. and five to eight animals were sacrificed 4, 8, 12, 24, 72, 120, 168, and 240 hours after injection of DMH or the basic solution, respectively. Additionally, seven animals were simultaneously treated with the ODC inhibitor alpha-difluoromethylornithine (DFMO) and sacrificed seven days after a single DMH injection. A single s. c.-dosage of the colon carcinogen DMH resulted in dissimilar activation patterns of polyamine metabolism in the various organs studied: in distal and less pronounced in proximal colonic mucosa ODC and putrescine are significantly increased seven days after application of DMH and DNA polymerase after ten days; in small intestinal mucosa ODC activity is significantly elevated after seven days and especially S-adenosylmethionine decarboxylase activity is significantly and prolonged increased between twelve and 72 hours after DMH injection; while spermidine/spermine N1-acetyltransferase activity is significantly elevated in liver after 168 and 240 hours, no changes compared to controls are found in the pancreas. DFMO treatment completely prevents DMH-induced activation of polyamine de novo synthesis and DNA polymerase in colon and small intestine. These data prove completely different and -interestingly-late appearing activation patterns of DMH on intracellular polyamine metabolism in various organ systems and further elucidate the complex metabolic changes following carcinogen treatment.
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PMID:Dissimilar activation patterns of the carcinogen dimethylhydrazine (DMH) on intracellular polyamine metabolism in various organs. 901 96


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