Biomedical subjects

N Ito

Publications and source records attributed to N Ito.

At least 469 records · Page 26Linked to original sources

PubMed1990

Enhancing effects of various gastric carcinogens on development of pepsinogen-altered pyloric glands in rats.

To assess the possibility of establishing an in vivo, medium-term bioassay system for gastric carcinogens and promoters, a total of 220 male WKY rats were divided into two groups. Group 1 animals were treated first with a single dose of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) (160 mg/kg body wt) and starting 2 weeks later administrated one of five gastric carcinogens, a gastric promoter, one of five non-gastric carcinogens or no treatment, as a control, for 14 weeks. Saturated sodium chloride solution (1 ml) treatments were given by gastric intubation at weeks 4, 6, 8 and 10. Group 2 rats received 1 ml of DMSO instead of MNNG and were then treated in the same way as group 1. Analysis of pyloric mucosa sections for pepsinogen altered pyloric glands (PAPG) detected immunohistochemically after the animals were killed at week 16 revealed increased lesion numbers in group 1, with all gastric carcinogens and promoters examined. However, none of the five non-gastric carcinogens exerted any significant modification of PAPG development. The results strongly suggest that the experimental protocol consisting of the following four components: (i) adoption of PAPG as the end-point marker lesion; (ii) single dose of MNNG as initiator; (iii) test chemical administration for 14 weeks; and (iv) administration of saturated sodium chloride solution during the test chemical exposure, could be used effectively for the detection of gastric carcinogens as well as promoters of gastric carcinogenesis in a relatively short time period.

Animals↗

PubMed1990

Regression of butylated hydroxyanisole (BHA)-induced hyperplasia but not dysplasia in the forestomach of hamsters.

The reversibility of butylated hydroxyanisole (BHA)-induced hamster forestomach hyperplasia was examined histopathologically. Groups of 10-15 male Syrian golden hamsters were treated with 2% BHA, for 12, 24 or 48 weeks and in each case then placed on basal diet until termination of the experiment at week 72, or treated with 2% BHA continuously for 72 weeks. Although sequential sampling revealed that BHA-induced hyperplasia reverted after cessation of antioxidant treatment, dysplastic lesions such as squamous cell dysplasia and basal cell dysplasia persisted and tended to increase with time on BHA. Basal cell dysplasia was observed in some hamsters later than squamous cell dysplasia, i.e. those treated with BHA for 24 weeks or more and killed up to 48 weeks later. Whereas the increase in labeling index evident in areas of hyperplasia during treatment returned to control level after cessation, this was not the case for the dysplastic lesions which continued to demonstrate elevated proliferation. The results thus suggest that basal cell dysplasia, including regions of squamous cell dysplasia, may be of particular importance as a precursor pre-neoplastic lesion.

Animals↗

PubMed1990

Early proliferative responses of forestomach and glandular stomach of rats treated with five different phenolic antioxidants.

The effects of 8 weeks of oral administration of five different phenolic antioxidants, e.g. catechol (CC), resorcinol, hydroquinone (HQ), 2-tert-butyl-4-methylphenol (TBMP) and propylparabene (PP), on forestomach and glandular stomach epithelium of male F344 rats were evaluated using a combined immunohistochemical and histopathological approach. Treatment with CC and TBMP induced a significant elevation of DNA synthesis in the forestomach epithelium, associated with hyperplasia. CC administration also brought about an increase of DNA synthesis in the pyloric gland mucosa, cell proliferation in this case being reflected by an increment in the crypt height. In addition to causing an increase in the pepsinogen-isozyme-1-altered pyloric glands (PAPG), which are considered to be putative preneoplastic precursor lesions in the rat glandular stomach, CC treatment was associated with submucosal growth of pyloric mucosal cells tending to decreased pepsinogen isoenzyme 1 binding. However, DNA synthesis values in these latter areas were lower than in pyloric glands of the control group. In contrast, other phenolic compounds, resorcinol, HQ and PP, did not induce any changes in the stomach mucosa. The present results demonstrated strong proliferative responses in the stomach epithelium for CC and TBMP, indicative of promoting potential in both cases, and suggest that CC and TBMP may exert detrimental effects leading to promotion of stomach carcinogenesis or cancer development via an early proliferative response.

Animals↗

PubMed1990

Comparison of initiation potential of 2-amino-3-methylimidazo[4,5-f]quinoline and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline in an in vivo carcinogen bioassay system.

A new approach to low-dose assessment of carcinogenic potential was applied to food contaminant pyrolysis products. Single intragastric doses of the carcinogenic pyrolysates, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) or 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline MeIQx), were given 12 h after two-thirds partial hepatectomy (PH) to F344 male rats. Two weeks thereafter the animals were placed on a basal diet containing 0.05% phenobarbital (PB) for 6 weeks combined with an i.p. administration of D-galactosamine (300 mg/kg) to facilitate growth of initiated cells. Both IQ and MeIQx clearly caused initiation of hepatocarcinogenesis as revealed by induction of preneoplastic placental-form glutathione-S-transferase-positive (GST-P+) hepatocyte foci composed of more than three cells (approximately 30 microns in diameter). A similar protocol without performance of PH before pyrolysate administration gave a positive result only for the IQ-treated group indicating that cell proliferation is essential during the low-dose, one-shot initiation step. IQ was found to be two to three times more potent in inducing GST-P+ foci using both protocols. The current approach could find application in practical carcinogenicity screening of chemicals, for which only small amounts are available.

Animals↗

PubMed1990

Correlation between medium-term liver bioassay system data and results of long-term testing in rats.

The effects of hepatocarcinogens (ethionine, thioacetamide, phenobarbital), non-hepatocarcinogens [N-ethyl-N-(4-hydroxybutyl)nitrosamine (EHBN), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)] and a hepatoinhibitor [(butylated hydroxyanisole (BHA)] were compared in medium- and long-term in vivo systems. In experiment I, 2 weeks after a single injection of diethylnitrosamine (DEN) groups of male F344 rats received chemical administration for 6 weeks, combined with partial hepatectomy at week 3 and were killed at the end of week 8. In experiment II, animals were treated in the same manner and then given basal diet and tap water (group 1) or chemical continuously (group 2) until the 2 year timepoint. Numbers and areas of glutathione S-transferase placental form (GST-P)-positive foci developing in the liver under medium-term bioassay conditions (experiment I) were found to closely correlate with eventual hepatocellular carcinoma incidences after continuation of test chemical administration (experiment II). Thus all of the hepatocarcinogens enhanced both the induction of GST-P-positive focal lesions and liver tumors. While non-hepatocarcinogens exerted no such effects, their influence being limited to inducing lesions in their own respective target organs such as urinary bladder cancers in the EHBN case and glandular stomach adenocarcinomas with MNNG, BHA demonstrated inhibition potential in both experiments. The observed correlation between long- and medium-term results strongly indicates the applicability of our medium-term bioassay system for detection of liver carcinogens.

Animals↗

PubMed1990

Immunohistochemical demonstration of carcinogen-DNA adducts in target and non-target tissues of rats given a prostate carcinogen, 3,2'-dimethyl-4-aminobiphenyl.

An immunohistochemical procedure was applied which allows accurate localization of DNA lesions within organs and tissues of rats given 3,2'-dimethyl-4-aminobiphenyl (DMAB) using polyclonal antibodies against DMAB-DNA adducts. Dose-related nuclear staining was observed in organs regardless of DMAB-carcinogenic organotropism. In the male accessory sex organs, the lateral lobe of the prostate, a non-target site, demonstrated a similar staining intensity to that found for the ventral prostate and seminal vesicle, target sites. Orchiectomy and pretreatment with ethinyl estradiol resulted in a moderate to slight decrease in binding in the accessory sex organs. No observable decrease in staining intensity was evident in most organs 168 h after the administration of DMAB. These findings suggest that DNA adduct formation itself is not necessarily sufficient for tumor induction.

Aminobiphenyl Compounds↗

PubMed1990

Effects of dietary perilla oil, soybean oil and safflower oil on 7,12-dimethylbenz[a]anthracene (DMBA) and 1,2-dimethyl-hydrazine (DMH)-induced mammary gland and colon carcinogenesis in female SD rats.

The effects of diet supplemented with perilla oil, which contains a large amount of n-3 alpha-linolenic acid, and n-6 linoleic acid rich soybean and safflower oil supplemented diets on 7,12-dimethylbenz[a]anthracene (DMBA)- and 1,2-dimethylhydrazine (DMH)-induced mammary gland and colon carcinogenesis were investigated in female SD rats. Groups of 23 or 24, 5 week old animals were first given three s.c. injections of 40 mg/kg body wt DMH followed by a single intragastric administration of 50 mg/kg body wt DMBA within 2 weeks of the commencement. Starting 1 week after the DMBA treatment, they were administered pellet diet containing 10% perilla oil, soybean oil or safflower oil for the succeeding 33 weeks. Histological examination revealed that the resultant numbers of mammary tumors per rat were significantly lower in rats given perilla oil diet (4.4 +/- 2.5) than in the soybean oil diet group (6.5 +/- 3.9). Furthermore, colon tumor incidence was significantly lower in animals receiving the perilla oil supplement (18.2%) than in those given safflower oil diet (47.4%), and the numbers of colon tumors per rat tended to be lowest in rats administered perilla oil. Also the incidence of nephroblastomas in rats receiving perilla oil diet (0%) was significantly lower than that for the soybean oil diet group (23.8%). The results thus indicate that the alpha-linolenic acid (n-3)-rich perilla oil diet inhibits development of mammary gland, colon and kidney tumors as compared to linoleic acid (n-6)-rich safflower or soybean oil diet.

1,2-Dimethylhydrazine↗

PubMed1990

Different carcinogenic responses in a variety of organs, including the prostate, of five different rat strains given 3,2'-dimethyl-4-aminobiphenyl.

Tumorigenic response in the prostate of F344, ACI, Lewis, CD and Wistar rat strains to 3,2'-dimethyl-4-aminobiphenyl (DMAB) was examined in relation to development of other types of tumors. Rats of each strain aged 6 weeks were divided into two groups receiving DMAB s.c. at a dose of 50 mg/kg body wt once every other week for 10 times, with or without 1 week dietary ethynyl estradiol (EE) pretreatment. The experiment was terminated at week 60, carcinomas of the ventral prostate, all of microscopic size, being respectively found in 50, 17, 21, 15 and 0% of F344, ACI, Lewis, CD and Wistar strain animals treated with EE plus DMAB. The tumor yield correlated well with DMAB-DNA adduct formation. One invasive adenocarcinoma also developed in the periurethral part (occupying both of lateral and dorsal areas) of the prostate. The final survival rates were 46, 24, 65, 4 and 0% in F344, ACI, Lewis, CD and Wistar rats respectively. DMAB administration without EE pretreatment resulted in similar incidences of prostate tumors and mortalities. Tumors arose in greater than 14 different sites with strain dependency, lesions predominating in the skin/subcutis of ACI and F344, preputial gland of F344, urinary bladder of ACI, and mammary glands of CD rats respectively. Consideration of mortality and the relative incidence of prostate cancer and other types of tumors indicates the F344 rat strain to be the most appropriate for investigation of DMAB prostate carcinogenesis.

Aminobiphenyl Compounds↗

PubMed1990

Enhancing effects of sodium phenobarbital and N,N-dibutylnitrosamine on tumor development in a rat wide-spectrum organ carcinogenesis model.

A wide-spectrum organ carcinogenesis model for detection of cancer modifiers in various organs was assessed in F344 male rats. After sequential treatment with diethylnitrosamine, N-methylnitrosourea, and dihydroxy-di-N-propylnitrosamine, rats were fed 500 p.p.m. sodium phenobarbital (PB: carcinogen for the liver, promoter for the thyroid) in the diet or 50 p.p.m. N,N-dibutylnitrosamine (DBN: carcinogen for the upper digestive tract, liver and urinary bladder) in the drinking water. Upon histopathological investigation at experimental weeks 18 and 24, PB was found to increase significantly the incidences of hyperplasias and adenomas of the thyroid and the numbers and areas of placental glutathione S-transferase-positive foci in the liver. DBN increased the lung tumor incidences at week 18, and brought about significant increases in both numbers and areas of lung tumors per rat at week 24. Furthermore, DBN enhanced the occurrences of hyperplasias and papillomas of the esophagus as well as hyperplasia for the forestomach at both time points. In addition, significant numbers of esophageal carcinomas and lingual papillomas developed in the group given DBN after pretreatment with the three carcinogens at week 24. Assessment of lesion yield thus clearly revealed enhancement of carcinogenesis by the test chemicals in their respective target organs, indicating the advantage of the wide-spectrum organ carcinogenesis model for detection of cancer modifiers within a limited time period in multiple organs.

Animals↗

PubMed1990

Epithelial cell proliferation in rat forestomach and glandular stomach mucosa induced by catechol and analogous dihydroxybenzenes.

An investigation of antioxidant-induced lesions in stomach epithelia was performed using F344 rats of both sexes. Histopathological changes, levels of DNA synthesis and pepsinogen isozyme 1 altered pyloric gland (PAPG) induction were assessed following 4 weeks oral administration of catechol (CC) or analogs such as hydroxyhydroquinone (HHQ), protocatechuic acid (PCA), protocatechualdehyde (PCAH), dopamine and DL-dopa. While epithelial hyperplasia of the forestomach was only observed in the groups given CC, DNA synthesis in this epithelium was increased in groups of both sexes treated with CC, HHQ or dopamine. In the glandular stomach, CC induced submucosal growth of pyloric mucosal cells and an increase in crypt height associated with an elevation of DNA synthesis and numbers of PAPG. In contrast, dopamine brought about significant reduction in DNA synthesis in the pyloric mucosa of both sexes. The other CC analogs did not exert any obvious influence on glandular stomach mucosa. Since cell proliferation is well correlated to tumor promotion, the results suggested that HHQ and dopamine may have promoting potential for rat two-stage forestomach carcinogenesis in common with CC, while dopamine might be expected to inhibit glandular stomach carcinogenesis.

Animals↗

PubMed1990

Stomach carcinogenicity of caffeic acid, sesamol and catechol in rats and mice.

The carcinogenic potential of caffeic acid, sesamol and catechol was examined in male and female F344 rats and B6C3F1 mice, groups of 30 animals being treated with diets containing 2% caffeic acid, 2% sesamol or 0.8% catechol for 104 weeks (rats) or 96 weeks (mice). Histological examination revealed that caffeic acid induced forestomach squamous cell carcinoma in 57% (P less than 0.001 vs. controls) and 50% (P less than 0.001) of male and female rats, respectively, whereas sesamol was associated with squamous cell carcinoma at incidences of 31% (P less than 0.001) in male rats, and 38% (P less than 0.001) and 17% (P less than 0.05) in male and female mice, respectively. Catechol induced glandular stomach adenocarcinomas in 54% (P less than 0.001) and 43% (P less than 0.001) of male and female rats, respectively. The results thus clearly demonstrated that all three antioxidants are carcinogenic in rodent stomach epithelia.

Animals↗

PubMed1990

Modulation of c-myc expression by transforming growth factor beta 1 in human hepatoma cell lines.

The effects of transforming growth factor beta 1 (TGF-beta 1) on cell proliferation of human hepatoma cell lines, PLC/PRF/5 and Mahlavu, were investigated under serum-free conditions. DNA synthesis was strongly inhibited in the PLC/PRF/5 cells by addition of TGF-beta 1 (0.5 to 4.0 ng/ml), but remained unchanged in the Mahlavu cells. Also the expression of c-myc mRNA was suppressed by the addition of TGF-beta 1 in the PLC/PRF/5 cells but not in the Mahlavu cells. These results indicate that TGF-beta 1 might regulate cell growth, in part, by modulating c-myc expression, although there is no direct proof that c-myc expression is really relevant to DNA synthesis mediated by TGF-beta 1.

Carcinoma, Hepatocellular↗

PubMed1990

Selective induction of prostate carcinomas in F344 rats treated with intraperitoneal injections of N-hydroxy-3,2'-dimethyl-4-aminobiphenyl.

Groups of F344 and Wistar rats were given an intraperitoneal injection of N-hydroxy-3,2'-dimethyl-4-aminobiphenyl (N-OH-DMAB) at a dose of 5 mg/kg body weight with a 1-week dietary pretreatment with ethinyl estradiol (EE), and this regimen was repeated 10 times at one-week intervals. Additional groups were given N-OH-DMAB 10 times without the dietary EE pretreatment. The total experimental period was 60 weeks. Carcinomas and atypical hyperplasias of the prostate developed in 8 (42%) and 16 (84%) of 19 F344 rats without the dietary EE treatment and in 1 (6%) and 7 (39%) of 18 rats with the EE diet, respectively. No prostatic tumors were found in Wistar rats, although atypical hyperplasias were observed in 6 of 18 rats with and 4 of 8 rats without the EE supplementation. Tumor yields in other organs were extremely low, resulting in good survival of the animals. A comparison of the results with those obtained for DMAB suggests that intraperitoneal administration of N-OH-DMAB in F344 provides a better induction method for models of prostate carcinogenesis.

Aminobiphenyl Compounds↗

PubMed1990

Structure-activity relations in promotion of rat urinary bladder carcinogenesis by phenolic antioxidants.

The urinary bladder tumor-promoting potentials of the phenolic antioxidants, 2-tert-butyl-4-methylphenol (TBMP), propylparaben, catechol, resorcinol and hydroquinone, which are structurally related to butylated hydroxyanisole (BHA), were investigated in 170 male F344 rats. The animals were initially given 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) as an initiator in their drinking water for 4 weeks. Three days later, groups of 20 rats received diet containing 1.0% TBMP, 3% propylparaben, 0.8% catechol, 0.8% resorcinol, 0.8% hydroquinone or basal diet alone until the end of week 36. Significant increases in the incidences and average numbers of the putative preneoplastic lesions, papillary or nodular (PN) hyperplasia, and papillomas of the urinary bladder were only observed in the group given TBMP after BBN. Development of these lesions was not enhanced by diet containing the other test compounds and no induction was associated with any of the test chemicals alone. The results thus clearly showed that TBMP, which most closely resembles BHA, promoted urinary bladder carcinogenesis. The similar effects of TBMP and BHA on urinary bladder carcinogenesis suggest a direct link between chemical structure and biological potency.

Animals↗

PubMed1990

Cellular differentiation and histogenesis of rat glandular stomach cancers.

The gastric and intestinal phenotypic expressions of tumor cells in 18 adenomatous hyperplasias, 33 well-differentiated adenocarcinomas, and 16 undifferentiated adenocarcinomas (4 poorly differentiated adenocarcinomas, 10 signet-ring cell carcinomas and 2 mucinous adenocarcinomas) induced by N-methyl-N'-nitro-N-nitrosoguanidine or 4-nitroquinoline-1-oxide in the rat glandular stomach were studied by histochemical stainings for mucin and immunohistochemical staining for pepsinogen isozyme 1 (Pg 1). By histochemical staining for mucin [by the paradoxical concanavalin A method, the modified method with labeled peanut lectin, the galactose oxidase-Schiff (GOS) reaction, and the sialidase-GOS reaction] and immunohistochemical staining of Pg 1, gastric cancer cells of each histological group could be clearly classified into a gastric type, including mucous neck cell pyloric gland cell, and surface mucous cell subtypes, and an intestinal type, including goblet-cell, and intestinal absorptive cell subtypes. All tumors examined in this work consisted mainly of gastric-type cells but intestinal-type tumor cells were occasionally found among the gastric-type tumor cells. The incidences of intestinal-type cells in adenomatous hyperplasias (11.1%) and small well-differentiated adenocarcinomas (28.6%) were significantly less (P less than 0.05) than that in large well-differentiated adenocarcinomas (68.4%). The incidence of intestinal-type cells in small undifferentiated adenocarcinomas (25.0%) was also less than that in large ones (58.3%). The present results suggest the occurrence of change of phenotypic expression of tumor cells from the gastric type to the intestinal type during growth of tumors.

Adenocarcinoma↗

PubMed1990

Effects of sodium nitrite and catechol or 3-methoxycatechol in combination on rat stomach epithelium.

The effects of sodium nitrite (NaNO2) and catechol or 3-methoxycatechol in combination were examined in male F344 rats. Animals were treated with 0.3% NaNO2 in the drinking water and 0.8% catechol or 2% 3-methoxycatechol in powdered diet for 24 weeks. While catechol or 3-methoxycatechol alone induced low incidences of mild or moderate hyperplasia, simultaneous administration of NaNO2 markedly enhanced the degree of hyperplasia and papilloma formation. In contrast, induction of submucosal hyperplasia and adenomas in the glandular epithelium was reduced. Thus, the results indicate that NaNO2 can modulate the metabolism of antioxidants, so that, possibly via production of new active moieties, targeting of forestomach epithelium is enhanced.

Adenoma↗

PubMed1990

Inhibitory effects of antioxidants on N-bis(2-hydroxypropyl)nitrosamine-induced lung carcinogenesis in rats.

Potential second-stage modifying effects of 8 antioxidants on lung tumorigenesis initiated by N-bis(2-hydroxypropyl)nitrosamine (DHPN) were examined in male F344 rats. After an initial 2-week treatment with DHPN (0.1% in drinking water), rats were administered one of the antioxidants supplemented in the diet for 30 weeks. Although the incidences of lung adenomas were not affected, those of carcinomas were lowered by 2% butylated hydroxyanisole (BHA, 2 rats/20 rats), 1% butylated hydroxytoluene (BHT, 1/20), 0.8% ethoxyquin (EQ, 3/20) and 1% a-tocopherol (a-TP, 2/20) treatments as compared to the control level (9/20), while 5% sodium L-ascorbate (SA), 0.8% catechol (CC), 0.8% resorcinol (RN), and 0.8% hydroquinone (HQ) did not exert any significant effect on incidence. Quantitative analysis of adenomas and carcinomas (numbers and areas of lesions per unit area of lung section) revealed obvious inhibitory effects of SA, CC, and RN as well as BHA, BHT, EQ, and a-TP. Among the antioxidants, BHT exerted the strongest inhibitory activity. In contrast, DHPN-induced thyroid tumorigenesis was significantly enhanced by BHT (14/20) and EQ (20/20) treatments (control = 5/20). Thus the antioxidants showed opposite effects on lung and thyroid carcinogenesis in the rat.

Adenoma↗

PubMed1990

Expression of transforming growth factor-beta 1 mRNA in human hepatocellular carcinoma.

We investigated the expression of transforming growth factor beta 1 (TGF-beta 1) mRNA in tumor tissues surgically removed from ten patients with hepatocellular carcinoma (HCC). All HCC tissues expressed TGF-beta 1 mRNA at different levels, indicating the presence of activated transcription of TGF-beta 1 gene in human HCC tissues in vivo. The level of TGF-beta 1 mRNA expression showed no relationship to main tumor size of plasma alpha-fetoprotein level. Some HCC tissues presenting a relatively low grade of histological differentiation showed the highest levels of TGF-beta 1 mRNA expression.

Aged↗