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)

Biochanin A was studied for its capacity to inhibit benzo(a)pyrene (BP) induced neoplasia in female Swiss Webster mice. To investigate the effect of biochanin A on the initiation step, biochanin A (500 mg/kg) was administered orally 48 hours prior to BP (3 mg/mouse), which was also given orally. This sequence of biochanin A and BP administration was repeated once a week for a total of 4 weeks. At 26 weeks after the last treatment, all the mice were sacrificed. To investigate the effect of biochanin A on the promotion step, a single subcutaneous injection of 0.5 mg of BP was given within 24 hours after birth, and biochanin A (0.125 mg/mouse) was injected intraperitoneally 3 times a week for 6 weeks after weaning. In the initiation protocol, the concomitant administration of biochanin A showed significant inhibition of the mean number of lung tumors (P less than 0.001) and the incidence of carcinoma of the forestomach (P less than 0.02). In the promotion protocol, biochanin A significantly inhibited the incidence (P less than 0.01) and the multiplicity (P less than 0.001) of pulmonary adenoma, compared with the group treated with BP alone. These results suggest that biochanin A inhibitory potential in the initiation, as well as in the promotion step of BP carcinogenesis in female Swiss-Webster mice.
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PMID:Inhibitory effects of biochanin A on benzo(a)pyrene induced carcinogenesis in mice. 139 95

The efficacies of the non-steroidal, anti-inflammatory drug sulindac and the schistosomicidal agent oltipraz in inhibiting lung tumorigenesis was measured in A/J mice. Lung tumors (15.7 tumors/mouse) were induced by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK; 9.1 mg/mouse) administered in drinking water for 7 weeks. Feeding mice with sulindac (123 mg/kg diet), 2 weeks before carcinogen treatment until they were killed reduced tumor multiplicity by 53%. Oltipraz (250 mg/kg diet), however, has no effect on tumorigenesis. The absorption and metabolism of NNK were compared in the stomachs and intestines isolated from mice fed AIN-76A diet or sulindac + diet. Sulindac had no effect on alpha-carbon hydroxylation, pyridine N-oxidation or carbonyl reduction of NNK. Mouse lung explants were cultured with 4.7 microM [5-3H]NNK for 4 or 8 h. The addition of 1 mM sulindac to the culture medium reduces the alpha-carbon hydroxylation and pyridine N-oxidation of NNK. However, the administration of sulindac in the diet prior to the excision of the lung explants had no effect on these two metabolic pathways. We compared the levels of sulindac and its sulfide and sulfone metabolites in the lungs, livers and plasma of mice fed an AIN-76A diet containing 130 mg sulindac/kg for 2 weeks. The sulfide metabolite was the most abundant of the three compounds in plasma (17.6 pmol/microliters) and liver tissues (17.7 pmol/mg) but it could not be detected in lung tissues. These results show that non-steroidal anti-inflammatory drugs constitute a new class of chemopreventive agents in lung tumorigenesis. The tumor chemopreventive activity of sulindac is not mediated by the sulfide metabolite responsible for its anti-inflammatory activity.
Carcinogenesis 1992 Mar
PMID:Effects of sulindac and oltipraz on the tumorigenicity of 4-(methylnitrosamino)1-(3-pyridyl)-1-butanone in A/J mouse lung. 154 22

Diallyl sulfide (DAS), a component of garlic oil, has been shown to inhibit tumorigenesis by several chemical carcinogens. Our previous work demonstrated that DAS inhibited the metabolic activation of carcinogenic nitrosamines, including the tobacco-specific 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), in rat lung and nasal mucosa microsomes. In the present study, the effects of DAS on the tumorigenicity and the metabolism of NNK in A/J mouse lung were examined. Female A/J mice at 7 weeks of age were pretreated with DAS (200 mg/kg body wt in corn oil, p.o) daily for 3 days. Two hours after the final DAS treatment, the mice were either given a single dose of NNK (2 mg/mouse, i.p.) and kept for an additional 16 weeks for determining the production of pulmonary tumors, or were killed immediately so as to measure the microsomal activity in metabolizing NNK. In comparison to the vehicle control group, DAS pretreatment significantly decreased the incidence of NNK-induced lung tumors (37.9 versus 100%) and the tumor multiplicity (0.6 versus 7.2 tumors/mouse). In pulmonary metabolism of NNK, DAS pretreatment reduced the rates of formation of keto aldehyde, keto alcohol, NNAL-N-oxide, and NNK-N-oxide by 70-90%. In addition, the formation of NNK oxidative metabolites from NNK in the liver microsomes from DAS-pretreated mice was remarkably reduced. DAS also inhibited the metabolism of NNK in mouse lung microsomes in vitro. These results demonstrate that DAS is an effective chemopreventive agent against NNK-induced lung tumorigenesis, probably by inhibiting the metabolic activation of NNK.
Carcinogenesis 1992 May
PMID:Inhibitory effects of diallyl sulfide on the metabolism and tumorigenicity of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A/J mouse lung. 158 6

Evidence for the involvement of free radicals in nitrosamine carcinogenesis comes mainly from increased lipid peroxidation as a result of nitrosamine treatment. More direct evidence for nitrosamine-induced oxidative DNA damage has been lacking. In this study we examined the levels of 8-oxodeoxyguanosine or 8-hydroxydeoxyguanosine (8-OH-dG) in tissue DNA of mice and rats treated with the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Multiple doses of NNK (0.25 or 0.50 mg/mouse, 3 times weekly for 3 weeks) administered by gavage resulted in a significant elevation of 8-OH-dG in lung DNA, from 2.1 to 3.8 adducts/10(5) dG for the lower dose or to 6.6 adducts/10(5) dG for the higher dose, 2 h after the last NNK administration. A single dose treatment of NNK by gavage (4 mg/mouse) also resulted in an increase of this lesion in the lung DNA, however, the increase was not statistically significant. In liver, however, the increase was only significant by multiple doses at the higher dose, from 2.3 to 3.4 adducts/10(5) dG. This lesion appeared to be repaired efficiently. At 4 and 24 h after NNK treatment, the 8-OH-dG levels declined to the basal levels in both liver and lung. A single dose of NNK (20 mg/rat) also caused a significant increase of 8-OH-dG from 3.0 to 5.1 adducts/10(5) dG in rat lung DNA. An increase of 8-OH-dG in liver DNA was also seen, however, it was not statistically significant. Unlike the liver and the lung, the 8-OH-dG levels in rat kidney, a non-target tissue, were inert to NNK treatment. These results provide for the first time direct evidence supporting the role of oxidative DNA damage in NNK lung tumorigenesis.
Carcinogenesis 1992 Jul
PMID:Increased 8-oxodeoxyguanosine levels in lung DNA of A/J mice and F344 rats treated with the tobacco-specific nitrosamine 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone. 163 97

As previously shown by 32P-postlabeling, I-compound levels are reduced in target tissue DNA of animals exposed to one of several non-genotoxic hepatocarcinogens, e.g. 2,3,7,8-tetrachlorodibenzo-p-dioxin, carbon tetrachloride, peroxisome proliferators and choline-devoid diet. I-compound levels are further reduced, sometimes to undetectable levels, in chemically induced, transplantable rat (Morris) hepatomas and hepatocellular carcinomas induced by peroxisome proliferators or choline-devoid diet. The current study investigated I-compounds in spontaneous hepatic adenomas of genetically susceptible male C3H mice. DNA samples from individual tumors, background livers (non-tumor bearing lobe from tumor bearing mouse) and non-tumor bearing normal livers taken from 22-24 month old animals were analyzed by 32P-postlabeling. I-compound profiles were qualitatively comparable among the three types of tissues. However, levels of most I-compounds were 2.6-5.0 times lower in tumors than in background liver and non-tumor bearing normal liver. There were virtually no differences between background liver and normal liver. Taken together with the previously reported I-compound deficiency in carcinogen-induced hepatomas, the present observations on genetically initiated neoplasms suggest that this phenomenon may play a role in hepatocarcinogenesis and maintenance of neoplasia.
Carcinogenesis 1991 Dec
PMID:Specific reduction of I-compound levels in DNA from spontaneous hepatomas of 22-24 month old male C3H mice. 174 44

Our recent studies have shown that polyphenols present in green tea (GTP) possess significant antigenotoxic activity and afford protection against polycyclic aromatic hydrocarbon-induced skin tumor initiation in mice. In this study we assessed the effect of oral feeding and topical application of GTP on ultraviolet B (UVB) radiation-induced skin carcinogenesis in female SKH-1 hairless mice. Chronic oral feeding of GTP (0.1%, w/v) in drinking water resulted in significantly (P less than 0.01) lower tumor yield (percent of animals with tumors and number of tumors per mouse) and extended TDT50 (P less than 0.05), as compared to animals receiving normal drinking water. Topical application of GTP before UVB irradiation also afforded protection against photocarcinogenesis; however, the protective response was lower than that observed by oral feeding of GTP in drinking water. These results, in conjunction with our prior publications, suggest that consumption of green tea may reduce the risk of some forms of human cancer induced by both physical and chemical environmental carcinogens.
Carcinogenesis 1991 Aug
PMID:Protection against ultraviolet B radiation-induced photocarcinogenesis in hairless mice by green tea polyphenols. 186 Jan 73

Cepharanthine, isolated from Stephania cepharantha, is one of the bisbenzylisoquinoline-type alkaloids. We have found that it inhibits tumor promotion after topical application in two-stage carcinogenesis in mouse skin. Epidermal ornithine decarboxylase activities inhibited by topical application of cepharanthine, with an 5 micrograms/mouse) and mezerein (5 micrograms/mouse) were found to be inhibited by topical application of cepharanthine, with a ED50 of 1.2 mumol and 1.4 mumol respectively. These inhibitory effects of cepharanthine are considered to be related to its antitumor activity in two-stage carcinogenesis in mouse skin. Cell-mediated immunosuppression by TPA was unaffected by topical application of cepharanthine. A diet containing 0.005% cepharanthine (about 0.5 mg mouse-1 day-1) slightly suppressed the two-stage promotion of skin tumors by twice-weekly applications of 2.5 micrograms TPA for 2 weeks (first stage) followed by twice-weekly applications of 2.5 micrograms mezerein for 23 weeks (second stage) in ICR mice following initiation by 50 micrograms 7,12-dimethylbenz[a]anthracene. Oral administration of cepharanthine inhibits the tumor promotion in two-stage carcinogenesis in mouse skin.
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PMID:Cepharanthine inhibits two-stage tumor promotion by 12-O-tetradecanoylphorbol 13-acetate and mezerein on skin tumor formation in mice initiated with 7,12-dimethylbenz[a]anthracene. 190 98

The ability of the hyperplasiogenic irritant ethyl phenylpropiolate (EPP) to act as a tumor promoter in two-stage carcinogenesis and to stimulate cellular events commonly cited as markers of tumor promoter action was evaluated. Treatment of adult, inbred SENCAR (SSIN) mice, initiated with 7,12-dimethylbenz(a)anthracene, with 5 mg of EPP twice weekly resulted in 100% of the mice developing tumors (4.8 tumors/mouse) after 40 weeks of promotion. Treatment with 3 mg EPP (twice weekly) resulted in 52% of the mice developing tumors (0.9 tumor/mouse). This treatment regimen with EPP produces a sustained epidermal hyperplasia without being overtly toxic. In addition, a 5-mg dose of EPP induced ornithine decarboxylase activity to a level comparable to that induced by the tumor promoter phorbol 12-myristate 13-acetate (PMA): 2.3 nmol CO2/mg protein/h for EPP versus 4.5 nmol CO2/mg protein/h for PMA versus 0.04 nmol CO2/mg protein/h for acetone control. Likewise, the time course of ornithine decarboxylase induction by EPP was the same as that seen with PMA (maximum induction at approximately 6 h). Vascular permeability of the dorsal skin increased significantly in response to EPP (8 times that seen in acetone controls) and exhibited the same kinetics as that seen after exposure to PMA. Activity of protein kinase C (PKC), the cellular receptor for PMA, decreased by 75 to 95% 48 h after treatment with PMA. In contrast, EPP treatment resulted in less than a 20% decrease in PKC activity 48 h after treatment. This slight decrease in PKC activity is thought to be an indirect effect caused by the hyperproliferative and inflammatory reactions, because EPP was found to be inactive as an in vitro activator of PKC. These results indicate not only that EPP is a good tumor promoter that causes morphological and biochemical responses similar to those induced by PMA, but also that the action of EPP is apparently mediated via a mechanism that does not involve direct interaction with PKC.
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PMID:Tumor-promoting activity of ethyl phenylpropiolate. 191 82

The ability of five chemopreventive agents to inhibit 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumors in A/J mice was determined. The carcinogen was administered in the drinking water during 7 weeks (at doses of 9.2 to 3.1 mg/mouse). Three chemopreventive agents: (dose, g/kg diet) ellagic acid (4.0), 2(3)-BHA (5.0), and sulindac (0.13) inhibited the multiplicity of lung adenomas by 52, 88, and 52%, respectively, when compared to NNK controls. beta-Carotene + retinol (2.14 + 0.009), in combination, and selenium (0.0022) were ineffective. NNK was absorbed more rapidly from the duodenum than from the stomach and was metabolized in both tissues. The activation of NNK by alpha-carbon hydroxylation and its deactivation by pyridine N-oxidation was more extensive in the duodenum than in the stomach. Carbonyl reduction of NNK was 10 times higher in the duodenum. Liver microsomes were more active than lung microsomes in the alpha-carbon hydroxylation of NNK, suggesting that some liver isozymes of cytochrome P-450 have a high affinity for NNK. Pyridine N-oxidation was five times more extensive in lung microsomes than in liver microsomes. Collectively, these results demonstrate that NNK given orally to A/J mice provides a suitable model from which to assess the relative activity and mechanisms of action of chemopreventive agents in pulmonary carcinogenesis.
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PMID:Lung tumorigenicity of NNK given orally to A/J mice: its application to chemopreventive efficacy studies. 205 45

Tumor initiating potential was tested for eight pyrolysates of carbohydrates in a two-stage mouse skin carcinogenesis model using 12-O-tetradecanoylphorbol-13-acetate (TPA) as the promoter. The pyrolysates were levoglucosan (LG-I), levoglucosenone (LG-II), furfural (FF), 5-(hydroxymethyl)-2-furfural (HMF), glyoxal (GL), methylglyoxal (MGL), 3-deoxy-D-glucosone (DG) and thiazolidine (TZ). The total initiating doses were 200 mumol for LG-I and DG, 25 mumol for LG-II and 500 mumol for FF, HMF, GL, MGL and TZ. 7,12-Dimethylbenz[a]anthracene (DMBA) was used as a positive control agent applied to a total dose of 100 micrograms. All compounds were topically administered to the dorsal skin twice weekly for 5 weeks with or without TPA treatment for the following 47 weeks. In conjunction with promotion TZ induced skin tumors in 40% of the mice (average 0.65 tumors/mouse), FF in 25% (0.40/mouse), LG-I in 25% (0.35/mouse) and LG-II, HMF, DG and GL in 10-20% (0.11-0.25/mouse) respectively whereas DMBA induced skin tumors in 100% of the animals (6.7/mouse). MGL did not induce any tumors during the experiment and no tumors appeared in any of the groups treated with test chemicals alone. As assessed by Fisher's exact test, tumor incidences were significant in the TZ (0.01 less than P less than 0.05) and DMBA (P less than 0.01) groups as compared with the dimethylsulfoxide (DMSO) followed by TPA groups (5%, 0.05/mouse). Statistical analyses with Peto's trend test revealed significant tumor development in the LG-I (P less than 0.01), LG-II (0.05 less than P less than 0.01), FF (0.01 less than P less than 0.05) and TZ (P less than 0.01) followed by TPA groups (compared with DMSO + TPA). The results indicate that LG-I, LG-II, FF and TZ potentially possess tumor initiating activity, while HMF, GL, MGL and DG do not, as judged by the statistical analysis based on the incidences and development of the skin papillomas and/or carcinomas. A positive correlation between tumor initiating potential and clastogenic activity based on calculated ID50 (50% initiating dose) and published CD20 (20% clastogenic dose) values was evident for LG-II, FF and TZ, while LG-I was an exception.
Carcinogenesis 1991 Jul
PMID:Initiating activity of eight pyrolysates of carbohydrates in a two-stage mouse skin tumorigenesis model. 207 Apr 81


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