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

To investigate the liver tumor promoting effects of phenytoin (5,5-diphenylhydantoin; DPH), 5 week old male D2B6F1 mice were given a single i.p. dose of 90 mg N-nitrosodiethylamine (NDEA)/kg body wt in tricaprylin. Control groups received tricaprylin alone. After 2 weeks, the mice were given a diet containing 500, 250 or 125 p.p.m. DPH. Ten mice from each treatment group were killed at 30 weeks of age, at which time 10/10 mice given 500 p.p.m. DPH after NDEA initiation had developed multiple hepatocellular foci and adenomas. Such lesions were found only in 2/10 mice given NDEA alone. By 60 weeks, when the experiment was concluded, the incidences (and multiplicities, in units of tumors per tumor-bearing mouse) of hepatocellular adenomas were 60% (1.8 +/- 0.8), 100% (11.6 +/- 5.5), 77% (4.4 +/- 3.3) or 71% (2.6 +/- 1.3) in mice exposed to NDEA alone, or NDEA followed by 500, 250 or 125 p.p.m. DPH respectively. Hepatocellular carcinomas (87% incidence) and hepatoblastomas (33% incidence) were found only in mice given 500 p.p.m. DPH following NDEA initiation. Dose-dependent and profound increases in hepatic CYP2B-mediated benzyloxyresorufin O-dealkylase activity were detected in livers of B6C3F1 mice exposed for 14 days to dietary DPH (125, 250, 500 or 1000 p.p.m.). Similar increases in this activity were observed in D2B6F1 mice exposed to 500 and 250 p.p.m. for 30 or 60 weeks. Thus, increased hepatic CYP2B activity in mice exposed to DPH correlates with the tumor promoting effect of this compound.
Carcinogenesis 1993 Nov
PMID:Tumor promotion by an anticonvulsant agent, phenytoin, in mouse liver: correlation with CYP2B induction. 824 47

To ascertain the possible relationship between animal lifespan and the rate of tumor development, the results of carcinogenesis studies in various species treated with similar doses of a carcinogenic nitrosamine have been compiled from the literature. Comparable experiments in 20 species of mammals, reptiles, birds, amphibians and fish were analyzed. The animals received approximately 1000 mg/kg body wt (400-2500 mg/kg) lifetime total dose of nitrosodiethylamine (NDEA). Animals with lifespans varying from 3 years (mouse) to > 50 years (snake) developed tumors with latent periods of roughly 1 year (range 0.5-1.9 year), showing no relationship to lifespan. The evidence suggests that the time dependence of tumor development is more likely related to the cumulative dose of carcinogen than to lifespan and the rate of aging.
Carcinogenesis 1993 Nov
PMID:Life-span and cancer: the induction time of tumors in diverse animal species treated with nitrosodiethylamine. 824 69

Mirex, an organochlorine pesticide and non-genotoxic rodent hepatocarcinogen, is also a potent non-phorbol ester-type promoter of mouse skin tumors. Mirex, unlike most other skin tumor promoters, is not a significant epidermal hyperplasiogen even at a maximally promoting dose (200 nmol). Experiments described here examined whether tumor promotion by mirex and 12-O-tetradecanoylphorbol-13-acetate (TPA) are mediated through different mechanisms as indicated by their additivity when co-applied to 7,12-dimethyl-benz[a]anthracene (DMBA, 200 nmol)-initiated female CD-1 mouse skin. Instead of the additive response of 14 plus 5 tumors/mouse predicted from mice promoted for 20 weeks (2x/week) with either mirex (200 nmol) or TPA (2 nmol) respectively, their co-application yielded 35 tumors/mouse. This synergy with TPA was specific to mirex since a structurally related compound, chlordecone (Kepone) was inactive. Mirex plus TPA-promoted papillomas contained a c-Ha-ras A182-->T mutation as frequently (13/14) as those promoted by mirex or TPA alone, suggesting that these DMBA-initiated/co-promoted papillomas were not atypical in this genotypic marker. Promotional synergy with mirex was only observed with a submaximal promoting dose of 2 nmol TPA; 5 or 8 nmol TPA plus mirex gave additive or less tumor multiplicities. This synergistic multiplicity with mirex plus 2 nmol TPA (35 tumors/mouse) approximated the sum of individual responses to 200 nmol mirex (14 tumors/mouse) and the maximally promoting dose of TPA (12 nmol), 24 tumors/mouse, suggesting that mirex potentiated the promotional activity of TPA, as well as promoted through a mirex-specific mechanism. Epidermal DNA synthesis induced by 2 nmol TPA was potentiated by mirex, further supporting a role for mirex in potentiation of epidermal TPA activity. Collectively, these studies suggest that mirex affects two possibly related responses: (i) promotion through a distinct mirex-specific mechanism, and (ii) potentiation of a mechanism mediating the promotional activity of TPA.
Carcinogenesis 1994 Jan
PMID:Synergistic interaction between the non-phorbol ester-type promoter mirex and 12-O-tetradecanoylphorbol-13-acetate in mouse skin tumor promotion. 829 47

The present study was designed to further evaluate the growth and progression of papillomas to squamous cell carcinomas (SCCs) in groups of animals receiving initiating doses of 7,12-dimethylbenz[a]anthracene (DMBA) producing relatively low papilloma yields following long term promotion (60 weeks) with 12-O-tetradecanoylphorbol-13-acetate (TPA). For comparison, groups of animals were initiated with various doses of DMBA and then promoted with mezerein (MEZ), benzoyl peroxide (BzPo) and chrysarobin (CHRY). Following initiation, groups of female SENCAR mice received the following promoter doses: TPA (1.0 or 2.0 micrograms per mouse); MEZ (2.0 micrograms per mouse); BzPo (20.0 mg per mouse); and CHRY (52.8 micrograms per mouse). The maximum papilloma to SCC conversion ratio obtained with TPA in the current study was 0.32. This value was in the range of maximum conversion ratios obtained with the other compounds: MEZ, 0.40; CHRY, 0.32 and BzPo, 0.19. In general, the highest papilloma to SCC conversion ratios observed with TPA as the promoter were obtained in groups that received the lowest doses of DMBA and had relatively low papilloma burdens. A comparison of papilloma to SCC conversion in groups of mice promoted with TPA, MEZ or CHRY and having similar papilloma yields, revealed very similar conversion ratios. Comparison of the BzPo group with a similar papilloma yield indicated that the conversion ratio was slightly lower with this promoter. The present results indicate that in mice promoted with TPA and having relatively low papilloma numbers, a larger proportion of these papillomas progress to SCCs during continued promoter treatment. Furthermore, the results suggest that papillomas behave similarly in their ability to progress to SCCs regardless of the promoter used when comparing groups of mice with similar tumor numbers. The data are discussed in terms of possible mechanisms for the observed results.
Carcinogenesis 1993 Sep
PMID:Further studies on the influence of initiation dose on papilloma growth and progression during two-stage carcinogenesis in SENCAR mice. 840 6

Bisbenzylisoquinoline alkaloids, cepharanthine, berbamine and isotetrandrine, were isolated from Stephania cepharantha Hayata. These compounds inhibit arachidonic acid-induced inflammation in mice. We have found that cepharanthine inhibits tumor promotion after topical application and oral administration in two-stage carcinogenesis in mouse skin. Furthermore, topical application of berbamine (2 mumol/mouse) and isotetrandrine (2 mumol/mouse) markedly suppressed the tumor-promoting effect of 12-O-tetradecanoylphorbol-13-acetate (1 microgram) in mouse skin initiated with 7,12-dimethylbenz[a]anthracene (50 micrograms), at a grade corresponding to that of cepharanthine.
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PMID:Bisbenzylisoquinoline alkaloids inhibit tumor promotion by 12-O-tetradecanoylphorbol-13-acetate in two-stage carcinogenesis in mouse skin. 845 Oct 36

Previously we have shown that dietary retinoids are essential for papilloma formation induced by either an initiation-promotion or a complete skin carcinogenesis protocol. The present study was conducted to further determine the effect of dietary retinoic acid (RA) on papilloma formation and the conversion of papillomas to carcinomas. Skin tumors were induced in 3 week old female SENCAR mice by an initiation-promotion protocol with one application of 20 micrograms of 7,12-dimethylbenz[a]anthracene (DMBA), followed by 20 weekly applications of 2 micrograms of 12-O-tetradecanoylphorbol-13-acetate (TPA). Mice were fed RA at one of the three doses: 0.3 (nutritionally marginal dose), 3 (near physiological) and 30 (pharmacological) micrograms/g of diet. Mice fed 30 micrograms of RA/g of diet had the same survival rate as the other two groups despite a lower body weight and all three groups had similar papilloma incidence, which reached 100% at age 18 weeks. Mice fed 3 micrograms of RA/g of diet had the highest papilloma yield (approximately 14 papillomas/mouse) of all groups and it peaked between weeks 18 and 38 of age. These papillomas later regressed such that mice from all three groups had about the same papilloma yield at week 44 of age. Mice fed 30 micrograms of RA/g of diet failed to develop any visible carcinoma, while mice fed 0.3 or 3 micrograms/g showed 1.9% conversion of papillomas to carcinomas. Therefore, dietary RA at 30 micrograms/g of diet inhibited the conversion of papillomas to carcinomas without affecting papilloma incidence. In addition, dietary RA at 30 and 0.3 micrograms/g of diet lowered papilloma yield.
Carcinogenesis 1993 Mar
PMID:Effects of dietary retinoic acid on skin papilloma and carcinoma formation in female SENCAR mice. 845 33

SENCAR mice were used to determine the effects of the provitamin A compound beta-carotene on papilloma formation and the conversion of papillomas to carcinomas in a two-stage protocol with one application of the initiator 7,12-dimethylbenz[a]anthracene (DMBA, 20 micrograms) and 20 weekly applications of the promotor 12-O-tetradecanoylphorbol-13-acetate (TPA, 2 micrograms). A purified vitamin A-free diet was supplemented with beta-carotene at four levels (0.6, 6, 60 and 600 micrograms/g of diet) for female mice and two levels (60 and 600 micrograms/g) for male mice. Dietary supplementations of beta-carotene did not result in significant changes in body weight and survival of female and male mice. However, papillomas developed more rapidly and papilloma incidence (% mice with papillomas) reached its maximum (100%) sooner in male mice fed 600 micrograms of beta-carotene/g of diet than those fed 60 micrograms/g. There were smaller differences in papilloma incidence among the dietary groups in female mice, but the papilloma incidence again reached 100% sooner in mice fed 600 micrograms of beta-carotene/g of diet. Female and male mice fed 600 micrograms of beta-carotene/g of diet had significantly higher papilloma yields (average number of papillomas/mouse) than other dietary groups and a very low percentage of these papillomas converted to carcinomas in these mice. Thus, beta-carotene at 600 micrograms/g inhibited the conversion of papillomas to carcinomas in both sexes. In addition, papilloma yields were higher in female mice and these papillomas regressed more quickly than those in the corresponding groups of male mice. In conclusion, dietary beta-carotene caused differential effects on papilloma and carcinoma yields and sex-dependent differences in papilloma formation in female and male SENCAR mice treated with DMBA and TPA in a two-stage carcinogenesis protocol.
Carcinogenesis 1993 Apr
PMID:Differential effects of dietary beta-carotene on papilloma and carcinoma formation induced by an initiation-promotion protocol in SENCAR mouse skin. 847 37

Many arylalkyl isothiocyanates are potent inhibitors of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in rats and mice. In the mouse, 4-phenylbutyl isothiocyanate (PBITC) and 6-phenylhexyl isothiocyanate (PHITC) exhibited greater inhibition than benzyl isothiocyanate (BITC) and phenethyl isothiocyanate (PEITC). The present study was conducted to investigate the structure-activity relationships of these four arylalkyl isothiocyanates for their inhibition of NNK oxidation and effects on xenobiotic-metabolizing enzymes in rats and mice. A single dose (0.25 or 1.00 mmol/kg) of each isothiocyanate was given to F344 rats 6 or 24 h before death. The rates of NNK oxidation were decreased in microsomes from the liver, lung and nasal mucosa of rats. Generally, PEITC was more potent than BITC but less potent than PBITC and PHITC. The rates in rat liver microsomes were decreased at 6 h but recovered or increased at 24 h; the rates in rat lung microsomes were markedly decreased at both 6 and 24 h; and the rates in rat nasal mucosa microsomes were also significantly decreased. The same treatment decreased the rat liver N-nitrosodimethylamine demethylase activity dramatically and ethoxyresorufin O-dealkylase and erythromycin N-demethylase activities moderately. However, the rat liver microsomal pentoxy-resorufin O-dealkylase activity was decreased at 6 h but increased at 24 h, with PEITC showing the most marked induction. The rat liver NAD(P)H:quinone oxidoreductase activity was increased 1.4- to 3.3-fold, with PEITC being most effective; and the glutathione S-transferase activity was increased slightly. Similarly, at a single dose of 0.25 mmol/kg (5 mumol/mouse) 24 h before death, PEITC, PBITC, PHITC but not BITC, decreased NNK oxidation in mouse lung microsomes by 40-85%, with PBITC and PHITC showing greater inhibition. Furthermore, all four isothiocyanates extensively inhibited NNK oxidation in rat lung and nasal mucosa microsomes as well as mouse lung microsomes in vitro, with PEITC (IC50 of 120-300 nM) being more potent than BITC (IC50 of 500-1400 nM) but less potent than PBITC and PHITC (IC50 of 15-180 nM). PHITC was a very potent competitive inhibitor of NNK oxidation in mouse lung microsomes with apparent K(i) values of 11-16 nM. These results indicate that PBITC and PHITC are more potent inhibitors of NNK bioactivation in rats and mice than PEITC. In addition, these arylalkyl isothiocyanates could be effective in protecting against the actions of a broad spectrum of carcinogenic or toxic compounds.
Carcinogenesis 1993 Jun
PMID:Structure-activity relationships of arylalkyl isothiocyanates for the inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone metabolism and the modulation of xenobiotic-metabolizing enzymes in rats and mice. 850 4

Chemoprotective effect of dietary selenium (as sodium selenite or as Se-rich egg) on mouse skin tumor induced by topical application of 2'-(4-nitrophenoxy)oxirane (NPO) as tumor initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as tumor promoter was evaluated in relation to the dietary source and levels of selenium. Selenium supplementation (0.3 p.p.m.) to the basal diet (0.07 p.p.m. Se) as sodium selenite or as Se-rich egg brought about a 40 or 37% reduction respectively, in the incidence of papilloma formation at 12 weeks after NPO treatment. Tumor yield (number of papillomas per mouse) at 14 weeks after NPO treatment in the basal diet group, basal diet supplemented with 0.3 p.p.m. Se as sodium selenite group and basal diet supplemented with 0.3 p.p.m. Se as Se-rich egg group were 7.5 +/- 2.1, 2.7 +/- 2.3 and 4.1 +/- 3.5 respectively. Dietary supplementation of 1.0 p.p.m. See as Se-rich egg to the basal diet reduced the incidence and the multiplicity of papillomas during the early phase of promotion (11 weeks) but its antitumor activity decreased thereafter, indicating that the accumulation of tissue selenium above the saturated level may not be beneficial. Selenium concentrations in blood, liver and skin tissue of mice in basal diet group (0.33 +/- 0.02, 0.54 +/- 0.10 and 0.21 +/- 0.03 p.p.m. respectively) increased significantly ( P < 0.05) by the supplementation of 0.3 p.p.m. Se as selenite (0.58 +/- 0.02, 1.17 +/- 0.10 and 0.31 +/- 0.05 p.p.m. respectively), 0.3 p.p.m. Se as Se-rich egg (0.59 +/- 0.02, 1.25 +/- 0.11 and 0.33 +/- 0.06 p.p.m. respectively) and 1.0 p.p.m. Se as Se-rich egg (1.20 +/- 0.05, 2.32 +/- 0.28 and 0.51 +/- 0.01 p.p.m. respectively). Glutathione peroxidase activity in blood of mice of the basal diet group (2.4 +/- 0.4 EU/mg) increased significantly (P < 0.05) by dietary selenium supplementation (3.8 +/- 0.6 EU/mg in 0.3 p.p.m. Selenite; 3.7 +/- 0.8 EU/mg in 0.3 p.p.m. Se as Se-rich egg; 4.9 +/- 0.9 EU/mg in 1/0 p.p.m. Se as Se-rich egg) and the enzyme activities in liver and skin tissue also increased by 0.3 p.p.m. Se (as selenite or Se-rich egg) supplementation, but no further increases in their activities were obtained by 1.0 p.p.m. Se (as Se-rich egg). It is, therefore, concluded that a moderate level of dietary selenium (0.3 p.p.m.) has an efficient chemopreventive activity at the promotional stage of carcinogenesis and that dietary selenium rich egg as well as dietary selenite exerted antitumor activity.
Carcinogenesis 1995 Dec
PMID:Evaluation of chemopreventive effect of dietary selenium-rich egg on mouse skin tumor induced by 2'-(4-nitrophenoxy)oxirane and 12-O-tetradecanoylphorbol-13-acetate. 860 75

The heterocyclic amines produced during the cooking of meat, including amino(alpha)carboline (AalphaC) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), are potent bacterial mutagens and are carcinogenic in rodents. PhIP is mutagenic in the small intestine, but its mutagenicity in the colon, where most human intestinal cancers arise, has not been reported, nor has the mutagenicity of AalphaC. In this study, AalphaC (800 p.p.m.) was fed for 30 and 45 days and PhIP (100 and 400 p.p.m.) was fed for 30, 60 and 90 days to groups of F1 (C57BL/6 x SWR) mice hemizygous for multiple tandem copies of a lacI transgene (the Big Blue mouse) and heterozygous at the endogenous Dlb-1 locus. The mutant frequencies were assayed at Dlb-1 and at lacI in the small intestine and at lacI in the colon. PhIP induced mutations at both loci in the small intestine and induced slightly fewer mutations in the colon. The accumulation of mutations at both loci appears to be linear with both PhIP concentration and duration of exposure and, thus, with dose (concentration x duration). The linear increase with time is in agreement with predictions about the effectiveness of chronic treatment protocols for tests of in vivo mutagenicity. Unlike PhIP, AalphaC induced mutations specifically in the colon and not in the small intestine, thereby showing a dramatic tissue specificity. The rate (mutations/p.p.m. day) was similar to PhIP.
Carcinogenesis 1996 Oct
PMID:Intestinal mutagenicity of two carcinogenic food mutagens in transgenic mice: 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and amino(alpha)carboline. 889 98


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