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

The effects of therapy with four commonly used immunosuppressants--azathioprine, prednisolone, cyclophosphamide, and cyclosporine, on (UVI)-induced skin carcinogenesis were studied in the albino hairless (HRA/Skh-1) mouse. Following 30 weeks' exposure to UVI (290-400 nm) alone, 87% of mice developed skin tumors; the mean incidence of tumors at that time was 2.4 per mouse; and the tumors were predominantly papillomas (72%), with the remainder being carcinomas (25%) and keratoacanthomas (3%). Mice received immunosuppressive drug therapy beginning shortly after the start of UVI and continuing for up to 28 weeks. All drugs were given at immunosuppressive levels and dosages were comparable on a body weight basis to those used in clinical transplantation. Prednisolone had no effect on UVI-induced tumor development. Cyclosporine caused a moderate reduction in the latent period for tumor induction. Azathioprine and cyclophosphamide had strong promoting effects; the latent period for tumor induction was shortened and the tumor yield per mouse was increased (4.3 and 5.7 tumors per mouse, respectively, at 30 weeks after the start of UVI). Azathioprine, but not cyclophosphamide, also induced a larger proportion of carcinomas (43% and 15%, respectively). The results suggest that for kidney transplant recipients treated with the standard immunosuppressive drug regimen of azathioprine/prednisone, the increased susceptibility of the sun-exposed skin of these patients to squamous cell carcinoma is likely to be contributed to by specific promotion by the azathioprine therapy of the carcinogenic effects of sunlight.
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PMID:Effects of immunosuppressive therapy on the induction of skin tumors by ultraviolet irradiation in hairless mice. 362 91

Dietarily administered butylated hydroxytoluene (BHT) has previously been shown to inhibit UV radiation induction of carcinogenesis, erythema, and ornithine decarboxylase (ODC) activity. Butylated hydroxytoluene feeding also resulted in significant increases in epidermal absorption and it was suggested that BHT's photoprotective properties might be attributable to a diminution of UV radiation dose reaching respective target sites. To explore this possibility, the contribution of stratum corneum to BHT's photoprotective action was examined. SKH-Hr-1 hairless mice were fed diets containing 0.5% (w/w) BHT for 2 weeks prior to experimentation. Control animals received the unsupplemented ration. Stratum corneum from both groups was isolated and spectral transmission recorded. Transmission, between 280-320 nm, was approximately 65% greater through stratum corneum obtained from control animals compared with that of BHT-treated animals. Further evidence of the biologic significance of this BHT effect upon stratum corneum absorption was obtained when stratum corneum was first removed by tape-stripping, the animals irradiated with 0.45 J/cm2 of UVB, and epidermal ODC activity determined. BHT provided the usual inhibition of ODC activity induction in nonstripped animals, but ODC activity induction in BHT-treated, tape-stripped animals was restored to levels that did not significantly differ from controls. The protective effect exhibited by the stratum corneum could not be attributed to BHT-induced alteration of physical dimension, as neither the thickness of stratum corneum nor the number of stratum corneum layers, as determined from measurement of NaOH-distended frozen sections, differed from controls. Although the mechanism remains obscure, these data support the contention that systemically administered BHT results in diminished levels of UV radiation reaching potential epidermal target sites and delimits a large component of the photoprotective effect to the stratum corneum.
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PMID:A mode of action for butylated hydroxytoluene-mediated photoprotection. 373 85

Epidermal thickness and optical transmission were measured as functions of time in mice exposed daily to UV radiation. The experiments were performed to facilitate an evaluation of the optical influence of epidermal hyperplasia in the process of UV-carcinogenesis. Groups of albino hairless mice were exposed daily to the radiation from fluorescent sunlamps, emitting mainly UVB. With daily doses below the threshold for inducing edema the epidermal thickness increased, while the rate of change diminished gradually with time; the epidermal transmission decreased correspondingly. The speed at which the process progressed in time appeared to be proportional to the daily dose, over a wide dose range. The thickness of the stratum corneum also increased during the experiment. This thickness appeared to be roughly a constant fraction (22%) of the thickness of the whole epidermis. Later in the experiments, a degenerative stage was observed. At this time skin tumors occurred, causing substantial deviations in the epidermal thickness. With daily doses equal to the minimal edema dose, a dramatic acute increase of epidermal thickness was observed.
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PMID:UV-induced epidermal hyperplasia in hairless mice. 377 93

The cell proliferation in hairless mouse epidermis was studied before tumor development following a single application of a carcinogenic dose (2 mg) of N-methyl-N-nitrosourea (MNU). The number of basal and suprabasal cells, the mitotic index (MI) and the mitotic rate (MR) were scored in histological sections. The [3H]thymidine labeling index (LI) and the mean grain count (MGC) were scored in histological sections or in smears of basal cells. Flow cytometric two-parameter analyses of cellular DNA and protein content were performed on isolated epidermal basal cells. An increased MR and a slight but consistent epidermal hyperplasia were found. A 24-h study performed 25 weeks after MNU application showed that the MR and MI were altered in a circadian stage-dependent manner with considerably increased values around noon when the circadian rhythms had their peaks, followed by normal values around midnight. The LI was generally increased, but showed a normal circadian rhythm with high values at night and low values during day. The MGC was reduced at night and in the morning when the LI values were high. The results show that a single carcinogenic dose of MNU caused alterations in the epidermal growth kinetics that persisted until tumor development. The altered growth parameters, however, had circadian rhythms that were in phase with control rhythms. Assuming a constant size of the proliferative compartment, the increased mitotic activity indicated a considerable shortening of the mean cell cycle time.
Carcinogenesis 1987 Feb
PMID:Persisting long-term effects of a single carcinogenic dose of methylnitrosourea on epidermal growth in mice. 380 11

The cell kinetic, tumorigenic and carcinogenic effects of the short acting, alkylating carcinogen N-methyl-N-nitrosourea (MNU) on hairless mouse epidermis were investigated. The epidermal mitotic rate, the mitotic index, and the number of basal and suprabasal cells were scored in histological sections. Incorporation of [3H]thymidine and flow cytometric analysis of cellular DNA and protein content were performed on isolated basal cells at intervals for up to 10 days after a single application of either 1 or 10 mg MNU. The ensuing tumor rates and yields were observed for up to 48 weeks after 1 mg MNU and 30 weeks after 10 mg MNU. Generally, MNU induced an initial delay in epidermal cell cycle progression with an accumulation of cells in the S and G2 phases. Some days after treatment the delayed cells were released and entered mitosis. One milligram MNU caused a moderate delay of cells in S and G2, lasting for 2-3 days, and this was followed by a release leading to an increased number of suprabasal cells on day 7. The highest dose of MNU caused a more pronounced delay in transit through S and G2 and seemed to be followed by rapid regenerative proliferation. The subsequent tumor crop after 10 mg was significantly higher than that seen after the lowest dose. The present cell kinetic results are consistent with previous data from the study of other carcinogens, all showing a carcinogen-induced initial reduction in DNA synthesis after appropriate doses. A delay in transit through G2 phase was found as well, indicating that a general delay in cell cycle progression may follow the application of most (or all) carcinogens.
Carcinogenesis 1987 Mar
PMID:Carcinogenic doses of methylnitrosourea induce dose response related delay in transit through S and G2 phases in mouse epidermis: a cell kinetic study. 381 31

The effect of two immunosuppressive agents, azathioprine and cyclophosphamide, with and without UVB sunscreen protection on UV-induced skin carcinogenesis was studied in the albino hairless mouse. In a daily treatment regime spanning 9 weeks, groups of mice were immunosuppressed with either drug, and were exposed to minimally erythemal doses of a light source simulating the UV portion of the solar spectrum. The accumulated UV exposure alone induced skin tumours in 77% of mice. Azathioprine, but not cyclophosphamide, significantly enhanced the incidence of UV tumorigenesis. Photoprotection by topical application of one of two commonly used UVB sunscreens, 2-ethyl-hexyl-p-methoxycinnamate (2-EHMC) or octyl-N-dimethyl-p-aminobenzoate (o-PABA), reduced the UV tumour incidence to zero in immunologically normal mice and to 8-15% in immunosuppressed mice. Unexpressed latent tumour initiations were revealed in all sunscreen-protected groups by the subsequent application of a tumour promoter, croton oil. In immunologically normal mice 2-EHMC had allowed initiations in 39% of UV-irradiated mice, and o-PABA in 16.5%. However, in UV-irradiated mice immunosuppressed with azathioprine there had been initiations in 78% of mice protected with 2-EHMC and 65% of mice protected with o-PABA. Photoprotected mice immunosuppressed with cyclophosphamide did not show the same increase in UV-initiations (22% with 2-EHMC, 23% with o-PABA). These results provide evidence that azathioprine increases the susceptibility of the skin to UV carcinogenesis. However, UVB sunscreens afford effective protection from overt tumour expression in the absence of a tumour promoter.
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PMID:Effect of immunosuppressive agents and sunscreens on UV carcinogenesis in the hairless mouse. 387 83

Chloracne is a follicular hyperkeratosis produced by exposure to certain halogenated aromatic compounds. The rabbit ear bioassay has been used successfully for testing the acnegenic activity of compounds, but the lack of reference data in this species limits its usefulness in correlating chloracne to other toxic effects such as skin carcinogenesis. In this study, a prototype chloracnegen, 3,4,3',4'-tetrachloroazoxybenzene (TCAOB), was used. Five strains of mice (hairless, rhino, rhino+, DBA/2J, and C57BL/6) were treated topically with 100 microliters of 0.001, 0.01, or 0.1% TCAOB daily for 3-9 wk. Skin and liver histology were performed and hepatic enzyme activities measured. At the 0.001% TCAOB level, induction of hepatic aniline hydroxylase and cytochrome P-450 occurred in the C57BL/6 mice and induction of cytochrome c reductase occurred in the rhino mice. Dose-dependent gross and histologic skin lesions, characteristic of follicular hyperkeratosis, were observed in the rhino and hairless strains at the 0.01% and 0.1% levels. These two strains also had induction of hepatic cytochrome c reductase, cytochrome P-450, and aniline hydroxylase at TCAOB concentrations of 0.01 or 0.1%. These results suggest that the rhino and hairless strains of mice may be useful in the study of chloracne.
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PMID:Assessment of the chloracnegenic response induced by 3,4,3',4'-tetrachloroazoxybenzene in mice. 400 34

It has become increasingly evident that both quantity and quality of dietary lipid can influence the developmental course of several major forms of cancer in experimental animals. Using the hairless mouse-ultraviolet (UV) model, we had previously demonstrated that unsaturated lipid compared to equivalent levels of hydrogenated lipid enhanced photocarcinogenesis with respect to both tumor latency and multiplicity. In the present study using the same model, we have examined the effect of unsaturated lipid level and antioxidants upon epidermal lipid peroxidation and UV carcinogenesis. Sixteen groups of 45 animals each were used in the study, representing all combinations of three design variables: (a) a semipurified diet containing 4, 2, or 0.75% corn oil or 4% soybean oil; (b) 2% (w/w) antioxidant supplement or no supplementation; and (c) an escalating regimen of UV radiation to a cumulative dose of 70 J/cm2 or no irradiation. The nonirradiated groups served as nutritional controls and as subjects for epidermal lipid peroxidation measurements. An approximate linear relationship between lipid level and tumor latency was observed, with 4% levels of unsaturated lipid producing maximum enhancement of photocarcinogenesis. Furthermore with increasing lipid level the numbers of tumors per animal increased. Antioxidants caused significant increases in tumor latency and decreases in tumor multiplicity but only at the highest lipid level used in these studies. Thiobarbituric acid values of epidermal homogenates also increased in relation to the level of dietary lipid intake. Epidermal thiobarbituric acid values from antioxidant supplemented animals were significantly lower regardless of lipid intake levels. From these data we conclude that (a) dietary lipid level has a direct effect upon the carcinogenic response to UV both in regard to tumor latency and tumor multiplicity; (b) antioxidants produce an inhibitory effect almost equal to the degree of exacerbation of carcinogenesis evoked by increasing lipid levels, at least for the range studied; and (c) dietarily administered antioxidants inhibit the formation of epidermal thiobarbituric acid reacting materials. These data strongly imply that free radical reactions, specifically lipid peroxidation, play a role in at least a part of the photocarcinogenic response.
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PMID:Relation of antioxidants and level of dietary lipid to epidermal lipid peroxidation and ultraviolet carcinogenesis. 406 76

The effect of 5 mg hydroxyurea (HU) i.p. on epidermal DNA synthesis in female hairless mice was assessed by measuring labelling indices and specific activity after 3HTdR injection, flow cytometry (FCM) and cell sorting of prelabelled basal cells. HU causes an almost immediate block in DNA synthesis lasting until 2-2.5 h. During this time the fraction of cells in S remains stationary, 1.20 of normal. From 2.5 to 12.5 h DNA synthesis is resumed, but in cells recruited from G1 or G0. The HU-blocked cells do not move out of S until after 12.5 h. Hence, from 2.5 to 12.5 h, the fraction of cells in S increases to 2.5 of normal, which means that entry into S is open, but exit is blocked. From 12.5 h flux through S is high. The blocked cells are now released and the fraction of cells in S falls to 0.7 of normal at 24.5 h. At 36.5 h a probable new wave of DNA synthesis is indicated. The results also show that 3HTdR is available for at least 20 min after i.p. injection. The consequences of these results for the interpretation of the effect of HU pretreatment on methylnitrosourea skin carcinogenesis are discussed.
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PMID:Effects of hydroxyurea on DNA synthesis in hairless mouse epidermis. 612 31

Cell kinetic variables in normal untreated hairless mice were studied in order to observe possible age-related changes. Generally, groups of 4 male and 4 female mice were subjected to study at various ages from one to 115 weeks. The number of basal and suprabasal cells per microscopic field was observed, and after injection of tritiated thymidine the mean labelling index, the average specific activity and the mean grain count were scored. After injection of Colcemid, the average number of Colcemid-arrested mitoses was counted. With flow cytometry the fraction of cells in S and in G2 + M was also observed. In general, both the number of suprabasal cells and the proliferative variables were significantly lower in the very young mice. They increased to slightly above normal values at about 20-22 weeks of age, and then fluctuated a little with two additional possible peaks at 40-50 and around 80 weeks, respectively, and two troughs some weeks after the peaks. However, this rhythmicity was slight and not significant. Thus the only significant age-related pattern was that very young mice have a thin epidermis and low proliferative variables. These values increase up to the age of 20 weeks, and from then on there are no obvious and significant alterations, only slight rhythmic undulations almost within normal limits. The importance of cell kinetic changes with age for epidermal carcinogenesis is discussed in relation to these observations.
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PMID:Age-related changes of epidermal cell kinetics in the hairless mouse. 614 23


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