Biomedical subjects
Publications and source records attributed to K Imaida.
Male Syrian golden hamsters were given a pellet diet containing 2.0% butylated hydroxyanisole (BHA) or a powdered diet containing 1.0% BHA for 24 weeks. Papillomas of the forestomach were induced in all hamsters given either of these diets.
The effects of the antioxidants, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethoxyquin (EQ), and sodium L-ascorbate (SA) on two stage chemical carcinogenesis were investigated in male F344 rats initiated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), N-ethyl-N-hydroxyethylnitrosamine (EHEN), N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) or N-methylnitrosourea (MNU). BHA was given in diet at a dose level of 0.5 or 2.0%, BHT at 1.0%, SA at 5.0% and EQ at 0.8% for 29-51 weeks. Complete autopsy was performed at sacrifice and organs were examined histologically for the presence of preneoplastic and neoplastic lesions. All of the antioxidants tested exerted a positive influence on the development of BBN- or MNU-initiated bladder carcinogenesis. Similarly, these chemicals tended to enhance the appearance of forestomach tumors although the data gained after BHT administration were not significant. In clear contrast, no effect was observed on glandular stomach carcinogenesis and, with the exception of SA, the antioxidants all showed inhibition of the development of preneoplastic and neoplastic lesions in the liver. EQ increased the occurrence of renal adenoma in EHEN-treated rats. Clear differences were observed with respect to the modification of thyroid carcinogenesis after MNU initiation, BHT demonstrating strong promotion activity whereas BHA and SA had no effect. Thus organ specificity, with regard to both direction of modification and to the effects of individual antioxidants was apparent, this intriguing finding offering hope for the development of future experimental approaches for elucidation of the mechanisms underlying chemical carcinogenesis.
Tumor-promoting effects of phenobarbital (PB) and sodium saccharin (SS) were tested in rats pretreated with N-nitrosomethylurea (NMU) with special reference to the site of their action. Male F344 rats were initially given injections of NMU (20 mg/kg i.p.) twice a week for 4 weeks, then given basal diet containing 0.05% PB or 5% SS for the next 32 weeks, and then killed. Appropriate control studies were also done. Histological examination of whole organs of the rats showed that PB promoted thyroid carcinogenesis whereas SS did not. A significant increase in the incidences of total tumors as well as papillary adenocarcinoma of the thyroid was observed in the group given PB after NMU (p less than 0.001). The incidence of papillary adenoma with or without papillary adenocarcinomas was also high in the NMU-PB-treated group. The organ-specific promoting effect of PB in the induction of preneoplastic lesions, as demonstrated by development of gamma-glutamyl transpeptidase-positive foci in the liver and of SS in papillary or nodular hyperplasia in the urinary bladder, as reported previously, was also confirmed. The incidences of papillomas in the forestomach were similar in groups treated with NMU-PB, NMU-SS, or NMU alone. The results indicate that PB is a tumor promoter in the liver and thyroid and that SS is a tumor promoter in the urinary bladder of rats.
The promoting effect of sodium L-ascorbate on two-stage urinary bladder carcinogenesis in F344 rats initiated with N-butyl-N-(4-hydroxybutyl)nitrosamine at levels of 0.01 and 0.05% in drinking water was studied. Administration of 5.0% but not of 1.0% sodium L-ascorbate in the diet significantly increased the incidence and number of preneoplastic lesions, papillary or nodular hyperplasia, papilloma, and cancer of the urinary bladder. In groups given 5.0% sodium L-ascorbate, the urine was characterized by an apparent elevation of pH, a decrease of osmolality, and an increase of MgNH4PO4 crystalline. Addition of sodium L-ascorbate to the diet also resulted in increase in the content of ascorbic acid and its metabolite, dehydroascorbic acid, in the urine. These results show that an extremely high dose of sodium L-ascorbate (5.0%) promotes urinary bladder carcinogenesis under the present experimental conditions, while a high dose (1.0%) does not.
Effects of NaCl, Tween 60 and N-ethyl-N'-nitro-N-nitroso-guanidine (ENNG) on gastric carcinogenesis were investigated in male Wistar rats. Animals received a single dose of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) at 250 mg/kg body weight by gastric tube followed one week later by either 10% NaCl in their diet, twice-weekly applications of 1 ml of saturated NaCl solution by gastric tube, 1.0% Tween 60 in their drinking water or 0.0005% ENNG in their drinking water. One group of rats were given MNNG 24 h after a single application of 1 ml of saturated NaCl solution to investigate the effect of NaCl on initiation. A single dose of MNNG to rats resulted in development of multiple epithelial tumors in the forestomach and no epithelial tumors in the glandular stomach after 52 weeks. There were no differences in tumor incidences of the forestomach and glandular stomach between experimental groups which were given a subsequent treatment with NaCl or Tween 60 and the control group with MNNG alone. ENNG significantly enhanced the tumor induction in the glandular stomach, while ENNG alone did not induce any tumors in the stomach. The NaCl treatment prior to MNNG administration also increased tumor development in the glandular stomach but not in the forestomach.
Two cases of neuroblastoma in situ incidentally found in young infants at autopsy are reported. One was an 8-day-old female infant of large for dates clinically diagnosed as fetal erythroblastosis. Histologically, several foci of tumor were scattered within the medulla of the left adrenal gland. This case was thought to be multiple neuroblastoma in situ. The other was a 34-day-old male infant who was born premature and associated with patent ductus arteriosus (PDA). Grossly, a solitary small nodule was seen in the right adrenal gland. Microscopically, the lesion was located within the medulla. In both cases, the tumor was composed of lymphocyte-like small and dark cells with rosette formations. Local infiltrations were observed, but not metastasis. The review of 611 autopsy cases of neuroblastoma reported in the Annual of the Pathological Autopsy Cases in Japan, vol. 11 (1968) to vol. 20 (1977)2 revealed 7 cases of neuroblastoma in situ including one of our cases. The peculiar features of neuroblastoma were described.
The ability of four steroids and three bile acids to promote the appearance of hyperplastic foci and hyperplastic nodules initiated by diethylnitrosamine (DEN) in the liver of male Fischer rats was tested and compared with that of the known promoter phenobarbital (PB, 0.05%) as a standard value. Two weeks after a single dose of 200 mg of DEN per kg, the animals were exposed to test chemicals for 10 weeks. At 4 weeks following DEN, all treatment groups were subjected to partial hepatectomy. Of the steroids tested at the maximum tolerable doses, as determined in preliminary experiments, ethinyl estradiol was the most potent promoter, inducing more hyperplastic nodules than did PB and almost 50% less gamma-glutamyl transpeptidase-positive foci. However, gamma-glutamyl transpeptidase-positive foci induced by ethinyl estradiol were twice the average size as those induced by PB. The steroids testosterone, cortisone, and dexamethasone induced more foci than did DEN alone, but few if any hyperplastic nodules. Deoxycholic acid was the most potent promoter of the bile acids tested, including 3 to 4 times more hyperplastic nodules than did PB and more gamma-glutamyl transpeptidase-positive foci, which were 5 times larger on the average than those induced by PB. The other bile acids tested, lithocholic acid and taurine, induced slightly more foci than did DEN alone but no hyperplastic nodules. These findings suggest that ethinyl estradiol and deoxycholic acid are relatively strong promoters of the appearance of preneoplastic lesions in hepatocarcinogenesis.
The histochemistry of mucin in normal large intestine and in experimental colorectal cancers induced in Wistar rats with 1,2-dimethylhydrazine was analyzed by modifications of the concanavalin A-horseradish peroxidase method (paradoxical concanavalin A-staining) and high-iron diamine-Alcian blue (pH 2.5) staining (HID-AB). Quantitative analysis of each mucin reaction was done by the use of an image analyzer. Regional variations in the percentage area of "labile class III mucin" were 1 to 50% in the distal colon and 50 to 90% in the proximal colon. Regional variations in the percentage area of sulfated sialomucin were 80 approximately 100% in the distal colon and under 20% in the proximal colon. The percentage area of "labile class III mucin" in primary colorectal cancers showed region-specific variation and that in metastatic colorectal cancers also showed similar region-specific variation of colorectal mucosa where primary tumors were located. In contrast, there were no region-specific mucin reactions for sulfated sialomucin in almost all primary and metastatic colorectal cancers.
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Using the Solt and Farber model (Nature, 263 (1976) 701), dose-response relationships between initiating agents and the induction of hyperplastic nodules in rat liver were investigated. Male Fischer 344 rats were initiated by a single application of 1 of 5 carcinogens at 3 doses: 200.0, 50.0 and 12.5 mg/kg of diethylnitrosamine (DEN); 1.00, 0.25 and 0.062 mg/kg of aflatoxin B1 (Af-B1); 60.0, 15.0 and 3.75 mg/kg of N-2-fluorenylacetamide (2-FAA); 600.0, 150.0 and 37.5 mg/kg of 3'-methyl-4-dimethylaminobenzene (3'-me-DAB); 40.0, 10.0 and 2.5 mg/kg of dimethylnitrosamine (DMN) and their vehicles. Two weeks after initiation, animals were placed on a 0.02% 2-FAA diet for 2 weeks. Partial hepatectomy was performed at the end of the third week of the experiment. All rats were killed 4 weeks after the initiation, and the hyperplastic nodules of the liver were counted and their areas measured. Dose responses were observed in both numbers and areas of hyperplastic nodules per unit area of sections with all of the 5 carcinogens examined.
Factors enhancing renal carcinogenesis induced by formic acid 2-[4-(5-nitro-2-furyl)-2-thiazolyl] hydrazide (FNT) were studied. Five groups of rats were used. Groups 1 and 2 were subjected to right nephrectomy and 2 days late they were injected with 20 mg/kg body weight of dimethylnitrosamine (DMN). From one week after nephrectomy, group 1 was fed on 0.2% FNT diet continuously to the end of the experiment, and group 2 was given normal diet. In week 2, they were given 400 mg/kg body weight of chloroform (CHCl3) orally. Groups 3 and 4 were given ChCl3 first and 2 days later injected with DMN. Group 3 was then fed FNT diet and group 4 was fed basal diet continuously. In week 2, groups 3 and 4 were subjected to unilateral nephrectomy. Group 5 was given FNT diet without other treatment. The incidences of tubular hyperplasia in groups 1, 3 and 5 were 53.3%, 52.9%, and 0%, respectively, at week 16 and 100%, 94.9% and 94.1%, respectively, at week 32. Moreover, the incidences of renal cell tumors in these groups were 85.0%, 88.9% and 17.6%, respectively, at week 32. Thus, the inductions of tubular hyperplasia and renal cell tumor were markedly enhanced by combined treatment with CHCl3, DMN, unilateral nephrectomy and FNT in the initiating and promoting stages.
An autopsy case of Sandhoff disease in a 2-year-old boy is reported. Diagnosis was established by enzyme assay, which demonstrated total deficiency of hexosaminidase in the serum. Histochemical examination, using hematoxylin-eosin (H & E) and Luxol fast blue (LFB) stain, showed accumulation of LFB-positive material not only in cells of the cerebrum, cerebellum, spinal cord, and peripheral nervous system, but also in reticuloendothelial cells of the lymph nodes, spleen, thymus, and liver, in podocytes of renal glomeruli, in all types of renal tubular cells, in endothelial cells of small vessels, in fibroblasts, and in epithelial cells of the epididymis and ductus deferens. Electron microscopic examination showed that these deposits contained electrondense membranous bodies. Lipid analysis demonstrated a marked elevation of ganglioside GM2 and its asialo derivative in the brain and liver. Accumulation of globoside was found in the liver, kidney, and spleen. There was complete absence of hexosaminidase in the brain and liver.
The effect of partial cystectomy on induction of DNA synthesis in the urinary bladder epithelium was studied in a total of 147 male F344 rats. DNA synthesis started 12 hours after 75% or 50% resection of the bladder, and reached a maximum at 48 hours with a mean labelling index of 15.8% after 75% partial cystectomy and 13.8% after 50% partial cystectomy. In these two groups the proliferative activity of bladder epithelial cells returned to normal after 2 weeks and 1 week, respectively. Cytodifferentiation of epithelial cells, observed by transmission and scanning electron microscopy, remained normal during the regeneration process.
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The activities of pyrolysis products for initiating or promoting preneoplastic lesions were tested. In experimental series I, N-2-fluorenylacetamide (2-FAA) was used as an initiator or a promoter and 3-amino-1,4-dimethyl-5H-pyrido-[4, 3-b] indole (Trp-P-1), 3-amino-1-methyl-5H-pyrido [4, 3-b] indole (Try-P-2), 2-amino-6-methyldipyrido [1,2-a:3', 2'-d] imidazole (Glu-P-1) or 2-amino-dipyrido [1, 2-a:3', 2'] imidazole (Glu-P-2) was administered at a fixed dose and for the same period in the initiation stage or the promotion stage. Animals were subjected to partial hepatectomy or treated with carbon tetrachloride (CCl4) to increase the induction of gamma-glutamyl transpeptidase (gamma-GT) positive foci. Trp-P-1 and Glu-P-2 administered in either the initiation or promotion stage significantly increased the induction of gamma-GT positive foci (p less than 0.001). Glu-P-1 increased the induction of gamma-GT positive foci (P less than 0.001) when administered in the initiation stage but it was not effective when administered during the promotion stage. In experimental series II, animals were given a single dose of these chemicals at one of three different dose levels with partial hepatectomy and then were fed with 2-FAA and given a single dose of CCl4. Trp-P-1, Glu-P-1 and Glu-P-2 caused dose-dependent inductions of gamma-GT positive foci.
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The behavior of hyperplastic nodules following an in vivo short-term screening test for hepatocarcinogens was studied. Rats were injected ip with 200 mg/kg body weight of diethylnitrosamine (DEN), given basal diet containing 200 ppm of N-2-fluorenylacetamide (2-FAA) (group 1), 1000 ppm of the alpha-isomer of 1,2,3,4,5,6,-hexachlorocyclohexane (alpha-BHC) (group 2) or basal diet (group 3) from week 3 to week 8, and then given basal diet and tap water. They were subjected to partial hepatectomy at the end of week 3. Animals were killed at weeks 4, 6, 8, 10, 20, 30, 40, and 50. A significant disappearance of hyperplastic nodules following the cessation of carcinogen treatment was observed in group 1, but was not evident in groups 2 and 3. With gamma-glutamyltranspeptidase (GGTase) as a positive marker and adenosine triphosphatase (ATPase) as a negative marker, hyperplastic nodules were classified into 3 different phenotypic categories, i.e., (1) GGTase-positive and ATPase-negative, (2) GGTase-positive, and (3) ATPase-negative. The percentages of GGTase-positive and ATPase-negative hyperplastic nodules were almost 80 approximately 90% in group 1 and 70 approximately 80% in groups 2 and 3. Some of the hyperplastic nodules were necrotic from week 8 in groups 1 and 2, and from week 20 in group 3. Subsequently, the numbers of necrotic hyperplastic nodules increased with time. Hepatocellular carcinomas were found at weeks 30, 40, and 50 in group 1, and at weeks 40 and 50 in group 2. Significantly higher incidences of cancer were found in group 1 than in group 2. The hepatocellular carcinomas were also classified enzyme-histochemically into 3 different phenotypic categories as for hyperplastic nodules, but the percentage (20%) of GGTase-positive and ATPase-negative hepatocellular carcinomas was significantly lower than that (70 approximately 90%) of GGTase-positive and ATPase-negative hyperplastic nodules in each group.
Studies were made on the dose response of saccharin in the induction of bladder lesions. Inbred F344 rats of both sexes were pretreated with 100 ppm N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in the drinking water for 4 weeks. Sodium saccharin was given at 50,000, 10,000, 2,000, and 400 ppm in the diet for 32 weeks after BBN administration, and surviving rats were killed at the end of week 36 of the experiment. No increase in incidence of papilloma or cancer was noted in either sex at any dose of saccharin after BBN as compared to levels induced by BBN alone. The incidences of two types of hyperplasia and average number of papillary or nodular hyperplasias per 10 cm of basement membrane were significantly increased in the group receiving 50,000 ppm saccharin as compared to the group given BBN only. None of the incidences or numbers of these lesions were significantly different in any of the other saccharin-treated groups when compared to the group treated with BBN alone except for the incidences of two types of hyperplasias in the female rats dosed with 10,000 ppm saccharin. Dose-response curves showed enhanced hyperplastic responses in both sexes given 2,000--50,000 ppm saccharin. Administration of various doses of saccharin without BBN did not cause any changes in the urinary bladders of rats of either sex. These results show that saccharin enhances the induction of early-stage bladder lesions and that the biologic response demonstrates a dose-response effect.