To further understand gastric mucosal alterations caused by E3810, anovel proton pump inhibitor, in parietal cells, morphometry was applied to gastric tissue of rats administered E3810 subcutaneously at doses of 5, 10, and 20 mg/kg/day for 2 or 5 weeks. Plasma gastrin levels in the 2-week treatment groups were significantly elevated at all doses of E3810, whereas in the 5-week treatment groups, a significant increase in the level was found in rats administered 20mg/kg E3810 only. By light microscopy, the fundic mucosal thickness dose-dependently increased in the 5-week treatment groups. The number of chromogranin-immunopositive enterochromaffin-like (ECL) cells also increased at the dose of 20mg/kgin the 2-week treatment groups and at all doses in the 5-week treatment groups. By electron microscopy of parietal cells, no distinct vacuolization appeared in parietal cells even in rats administered 20mg/kg E3810 for 5 weeks. Morphometrically, the volume and surface density of tubulovesicles did not change in both the 2- and 5-week treatment groups, whereas those of microvilli on secretory canaliculi significantly decreased in the 5-week treatment groups. These results suggest that the increases in mucosal thickness and number of ECL cells after treatment with E3810 are due to hypergastrinemia induced by its prolonged pharmacological effects. Moreover, the changes in morphometric parameters of microvilli on secretory canaliculi in parietal cells may result from the inhibitory effect of E3810 on H⁺/K⁺-ATPase. However, the morphologic and morphometric changes in parietal cells after E3810 treatment were slight, compared with those reported previously for omeprazole at the same dose levels.

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Lactose-positive bacteria facilitate the colonization in the intestine in mono-associated quails fed a lactose-containing diet, because the quail does not possess intestinal lactase. We examined the influence of the overgrowth of various human intestinal lactose-positive bacteria on pathological change of mono-associated quails fed a lactose-containing diet. The strains used in this study included Bacteroides fiagilis Bifldobacterium breve, Clostidium butyrwwn, Esherichia coll. Enterococcus faecaliss, and Lactobacillus casei. Gas cysts, hemorrhage, and erosion were observed in the cecum of the quails mono-associated with E. coil or C. butyricum Necrotic areas were not observed in the lesion. These lesions were diagnosed as typical pneumatosis cystoides intestinalis (PCI), and the findings were benign, neither fulminant nor fatal. Weak-gas-producing mutants (gas^w) derived from C. butyricum were compared as to incidence of lesion with parent strain. The biochemical characters of the mutants were consistent with the parent strain except for less than half gas production. The incidence of lesion was significantly lower in the quails mono-associated with gas^w mutant than in those of mono-associated with the parent strain. These results suggest that a large amount of gas produced by C. butyricum might be mainly related to the onset of cecal PCI.

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In addition to mutagens and/ or carcinogens many modulators in carcinogenesis exist in our environment. Some of them are contained in our regular foods and therefore dietary factors play a role in the development of some types of cancers including colon cancer. There are still many unknown constituents and/ or factors in foods that could either enhance or reduce the possibilities for developing cancer. Recent research indicated that in addition to the macro- and micronutrients, many common foods contain nonnutritive components, belonging to different chemical groups, that may protect against certain type of cancer including colon neoplasm. These chemicals are knows as “chemopreventive agents”. The mode of action of most chemopreventive agents is still unknown, although many of them are antioxidants. With increasing the incidence of colon cancer rising certainly, there is an ever increasing need to determine the most effective means to prevent colon cancer and to understand the mechanism(s) underlying successful prevention. Previous studies in our laboratory demonstrated protective effects of several naturally occurring and synthetic compounds against rat colon tumorigenesis. This article will introduce our recent studies in search for the chemopreventive effects of some flavonoids and other naturally occurring products in edible plants on colon carcinogenesis.

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Changes in the kidneys were studied histopathologically and biochemically in F344 rats treated for long periods with 2-amino-4, 5-diphenylthiazole (DPT), with and without prior application of the renal carcinogen N-ethyl-N-hydroxyethylnitrosamine (EHEN). Experiment I: A total of 45 male 6-week-old F344 rats were divided into two groups; one receiving DPT at 1.06% in the diet (n=30) and the other being untreated (n=15). The observation period was 52 weeks. DPT caused cystic changes in the corticomedullary border, which were seen from the 4th week, progressed with time. Urine osmolarity began to decrease from the 6th week, however no biochemical signs of renal failure were noted before the 32nd week. High-performance liquid chromatography (HPLC) revealed 6 fractions, representing metabolites of DPT, in urine from DPT-treated rats. Experiment II: A total of 132 male 6-week-old F344 rats were divided into four groups: Group 1 (2-weeks 1, 000 ppm EHEN treatment followed by 1.06% DPT treatment), Group 2 (1.06% DPT treatment), Group 3 (2-weeks 1, 000 ppm EHEN treatment), and Group 4 (untreated controls). They were observed for 60 weeks. Cystic changes in the kidneys, as seen in Experiment I, were noted in Groups 1 and 2. Preneoplastic changes were seen only in Group 1, at incidences of 20% and 75% at weeks 48 and 60, respectively. Adenomas were seen in Groups 1 and 3, at incidences of 20% and 0%, and 25% and 20% at weeks 48 and 60, respectively. A carcinoma was diagnosed in 1 (20%) of the 5 rats from Group 1 in the 48th week. These results suggest that the DPT-treated rat can serve as a valid experimental model of congenital cystic kidney disease and chronic renal failure, and that DPT may promote EHEN-induced renal carcinogenesis.

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The carcinogenicity of monosodium aspartate (MSA), an amino acid, was examined in Fischer 344 rats of both sexes. MSA was added to the drinking water of groups of 50 male and 50 female rats at levels of 2.5% or 5.0% for 100 wk. There was a dose-dependent reduction in the mean final body weights of rats treated with MSA. Body and organ weights, urinalysis, and hematological evaluations revealed no evidence of adverse effects associated with the test chemical. However, hyperplasias of the renal papillae and hyperplasias of the urinary bladder were observed in MSA-treated groups, but not in the controls. In the kidneys, hyperplasias were found in 24% (10/41) and 7% (4/44) in males fed 5% MSA and 2.5% MSA, and 22% (9/36) and 3% (1/40) in females, respectively. Hyperplasias of the urinary bladder occurred in 5 of the male rats and 3 of female rats receiving the 5%-dose. No calcification or necrosis of the renal papillae was observed. While many other tumors developed in all groups, including the controls, the organ distribution of these neoplasms and their histological characteristics did not differ significantly from those known to occur spontaneously in this strain. These results suggest that development of hyperplasias of the urinary tract may occur due to a direct-action of MSA.

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Effects of high-fat diet on urinary bladder tumorigenesis in male Syrian golden hamsters caused by 3, 2'-dimethyl-4-aminobiphenyl (DMAB) were analyzed. DMAB was administered i. g. suspended in corn oil at a dose of 100mg/kg b. w. once a week for 20 weeks. Diet supplemented with 5% corn oil was administered throughout the experiment (50 weeks) or for 30 weeks after DMAB treatment. Incidences of DMAB-induced urinary bladder carcinomas were 27% (3/11 animals) in the basal diet group, and 58% (7/12) and 57% (4/7) respectively in the 50 and 30 week high-fat diet groups. The enhancement of bladder carcinogenesis by the high-fat diet was statistically significant by the cumulative chi-square test applied for the sequence of hyperplastic and neoplastic lesions. Thus, corn oil added to the diet increased DMAB-induced bladder carcinogenesis in hamsters.

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The promoting effect of nalidixic acid (NA), an old quinolone antibacterial agent, was investigated in a two-stage preputial/clitoral gland carcinogenesis model in F344 rats initiated with 3, 2'-dimethyl-4-aminobiphenyl (DMAB). 3, 3'-Dimethoxybenzidine dihydrochloride (DMOB) was used as a genotoxic carcino-gen for the preputial/clitoral gland. After that, ofloxacin (OFLX), a new quinolone antibacterial agent, was examined. Male and female rats were given weekly subcutaneous injections of DMAB at a dose of 50mg/kg body weight, for a total of 8 times. Ten weeks after the commencement of DMAB treatment, rats were given 4, 000ppm NA in the diet, 330ppm DMOB in the drinking water or 4, 000ppm OFLX in thediet for the next 26 or 42 weeks. Upon histopathological investigation at experimental weeks 36 and 52, preputial/clitoral gland adenomas and carcinomas, respectively, were found in rats given DMAB alone. NA or DMOB administration after DMAB treatment enhanced the incidences of adenomas or carcinomas of the preputial/clitoral gland whereas OFLX did not. Meanwhile, NA is known to be a non-genotoxicagent. The present results indicate that NA is a tumor promoter in the preputial/clitoral gland of rats.

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The efficacy and clinical safety of chlormadinone acetate (CMA) in preventing estrus were assessed in queens on condition that CMA was subcutaneously implanted in silastic silicon rubber. Thirteen queens were divided into the following four groups according to dose of CMA-administered: group 1 (n=3), control; group 2 (n=3), 2.5 mg/kg; group 3 (n=3), 5 mg/kg; group 4 (n=4), 20 mg/kg. The implants were left in these queens for 12 months after implantation. All control animals showed signs of estrus during the experiment, with periods of anestrus of normal duration. In contrast, estrus was completely inhibited in the CMA-treated groups. Plasma concentrations of CMA had started to decrease by l month after implantation and continued to decrease gradually thereafter. Histopathologically, the uterus from group 4 had coiled branched glands with little secretion in the endometrium. Mammary glands from the CMA-treated groups showed mild lobular development with acinar proliferation and secretion. Sections through the other organs (pituitary gland, adrenal gland, ovary, and implant site) had no distinct or consistent changes that could be related to the CMA-treated. It was concluded, therefore, that low, stable levels of CMA maintained in plasma by subcutaneous implantation could be the main reason for few changes due to the antigonadotropic and glucocorticoid-like activities and less serious condition in the uterine and mammary glands due to progestagenic activity.

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The present study was designed to examine the effects of a low iodine diet (LID) on tumorigenesis in F344 rats treated with N-methyl-N-nitrosourea (MNU). Four-week-old male F344 rats were exposed to 100 ppm MNU in their drinking water for 15 weeks. Thereafter Group 2 animals received a low iodine diet LID while Group 1 received no further treatment after MNU. Non-carcinogen control animals received the LID without prior initiation (Group 3). At sacrifice, 36 weeks after starting MNU administration, nerve tumors were present in 16 of 20 (80%) animalls, and 19 of 32 (59%) in Groups 1 and 2, respectively, mostbeing malignant schwannomas. Thymic lymphomas appeared in 7 of 20 (35%) rats in Group I and 15 of 32 (47%) in Group 2, and also gastric tumors were present in 6 of 20 (30%) in Group I and 10 of 32 (31) in Group 2. There were no significant intergroups differences regarding these lesions. However, the incidence of thyroid carcinomas in Group 2 was significantly higher than that in Group I (P<0.01). Also cumulative incidence curves indicated a significantly earlier appearancein Group 2 and the number of rats bearing 3 different tumors was significantly increased in this group (P<0.01). Moreovar, administration of the LID was itself associated with a small incidence of thyroid lesions.

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The potential for endogenous formation of N-nitrosobis(2-hydroxypropyl)amine (BHP) and car-cinogenicity were investigated in male Wistar rats administered tris (2-hydroxypropyl) amine (THPA) mixed in powdered diet at a concentration of 2% and sodium nitrite dissolved in distilled water at concentrations of 0.15% and 0.3% for 102 weeks. Endogenous formation of BHP was demonstrated by its presence in the urine of rats given 2% THPA and 0.3% nitrite, but not in the groups receiving either of these precursors alone. However, significant induction of tumors was not observed in BHP target organs in groups given 2% THPA together with 0.15% or 0.3% nitrite, nor in groups given precursors alone. In BHP non-target organs, various tumors developed in all groups at levels similar to those previously reported for spontaneous lesions in male Wistar rats. The present results indicate that BHP is endogenously formed in rats given 2% THPA and 0.3% nitrite, but that its amount is not high enough for significant induction of tumors in the target organs of BHP in rats. However, since man is exposed to various precursors for the entire lifespan, we can not exclude the possibility that endogenously formed nitrosamines are a potential risk factor in human cancer development.

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