Biomedical subjects
Publications and source records attributed to T Kawachi.
Carcinogenicity of seven homologs of N-alkyl-N'-nitrosoguanidine (N-alkyl-NNG), namely, N-methyl-NNG, N-propyl-NNG, N-butyl-NNG, N-isobutyl-NNG, N-pentyl-NNG, and N-hexyl-NNG, was examined by injecting the compounds subcutaneously into rats. All of them except N-isobutyl-NNG and N-hexyl-NNG were carcinogenic, but N-ethyl-NNG followed by N-methyl-NNG were stronger carcinogens than those with longer alkyl chains.
The mutagenic activities of antitumor agents, including 5 antibiotics, 19 antimetabolites, 5 alkylating agents, 2 alkaloids, 1 enzyme, and 1 adrenal steroid hormone, were tested on Salmonella tyhimurium TA100, TA98, and TA92. Four of these, busulfan, carbazilquinone, 1-(4-amino-2-methylpyrimidine-5-yl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride, and pipobroman were shown for the first time to be mutagenic. Further, the known mutagenicities of five others, daunomycin hydrochloride, Adriamycin hydrochloride, mitomycin C, 6-mercaptopurine, and cyclophosphamide, were confirmed.
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Donryu strain male rats were administered a large amount of N-methyl-N-nitrosobenzylamine directly into the stomach through a tube. Ulcers were found to develop in the portion of the esophagus where esophageal carcinoma is known to develop. Autoradiography of the entire body of rats after an intravenous injection of N-methyl[U-3H]-N-nitrosobenzylamine showed specific incorporation of radioactivity in the esophagus. When N-methyl[U-3H]-N-nitrosobenzyl-amine was injected intravenously, incorporation of radioactivity in the esophagus was higher than in other parts of the alimentary canal, and remained at the same value even after 24 hr. Microautoradiography of rats injected with N-methyl[U-3H]-N-nitrosobenzylamine through the tail vein showed that the silver grains were dominant in the mucous membrane than in the muscle layer in the esophagus. These results suggest that N-methyl-N-nitrosobenzylamine accumulated specifically in the esophagus, resulting in the production of carcinoma.
The immunoreactivities of amylase from human saliva and pancreatic juice and rat parotid and pancreas were investigated. Antisera were prepared in rabbits against each of the human and rat amylase. Human salivary and pancreatic amylases reacted similarly with the antibodies to both human salivary and pancreatic amylases. Rat parotid and pancreatic amylases reacted differently with the antibodies to both rat parotid and pancreatic amylases.
In rats amylase activity in the pancreas increased greatly from day 15 of gestation to a maximum on day 21. Then it decreased to less than one-tenth of this maximum value on about day 5 after birth. It increased again about 15 days after birth and reached the adult level about 30 days after birth. No amylase activity was in the parotid gland before birth: it appeared about 12 days after birth and reached the adult level, which was higher than that in the pancreas, about 30 days after birth. The serum corticosterone level was as high as the adult level before birth. Then it decreased to less than one-tenth of the adult level 5 days after birth and increased again from 15 to 25 days after birth to the adult level. The developmental change in the serum corticosterone level seemed to influence amylase activity in the pancreas both before and after birth, and that in the parotid gland only after birth. The serum contained both pancreatic and parotid type isozymes of amylase until 1 day after birth but only the parotid type from 3 days after birth.
Sucrases were purified from human small intestine and from areas of intestinal metaplasia of the stomach mucosa surrounding stomach cancers. The kinetic constants and pH activity profiles of enzyme preparations from the two sources were similar. No blood group activity of sucrase was detectable in preparations from three cases of intestinal metaplasia, but preparations from two other cases showed activity like that of the small intestine. These results indicate that sucrase from areas of intestinal metaplasia has similar enzymatic properties to those of enzyme from the small intestine, but that the antigenic sugar moiety of the enzyme associated with blood group activity varies.
The carcinogenicity of a food additive, 2-(2-furyl)-3-(5-nitro-2-furyl) acrylamide (trade name, AF-2), was studied. A diet containing AF-2 at a rate of 0.25% was administered to male golden hamsters and male ddY mice. The hamsters developed squamous cell carcinomas in the forestomach after the 49th day from the start of administration. In mice fed a AF-2 diet for 308 days, squamous cell carcinoma was observed in the forestomach after the 381th day from the start of the experiment; in some cases the carcinoma metastasized to the lung and liver.
The carcinogenicity of sodium nitrite and methylguanidine singly and together were examined in rats. A hepatocellular carcinoma, a hemangiosarcoma and a spindle cell sarcoma were found in 3 of 15 rats fed continuously on pellet diet containing 0.16% sodium nitrite and 0.16% methylguanidine. Hemangiomas and bile duct adenomas of the liver were also found in 6 and 8, respectively, of the 15 rats in this group. Hemangiomas and bile ducts adenomas of the liver were found in 2 and 3, respectively, of the 4 rats fed on pellet diet containing 0.16% sodium nitrite. Only 1 of 5 rats fed on pellet diet containing 0.16% methylguanidine developed a hemangioma. No tumor was found in the control group. All the tumors were found in rats that survived for over 12 months. No significant changes were detected in the esophagus or stomach.
Smoke condensate obtained by pyrolysis of proteins, such as lysozyme and histone, was shown to be mutagenic to Salmonella typhimurium TA100 and TA98. In vitro metabolic activation by a mammaliam postmitochondrial enzyme preparation (S-9 Mix) was required. Smoke condensates obtained by pyrolysis of DNA, RNA, starch and vegetable oil were slightly mutagenic, whereas those from pyrolysis of L- and D-tryptophan and 5-hydroxy-D,L-tryptophan were very strongly mutagenic with metabolic activation by S-9 Mix. Because of the high correlation between mutagenicity and carcinogenicity, it is theorized that the cooking of proteinaceous foods might be an important cause of human cancers.
Three 6-month-old male beagle dogs were given a solution of 150 microng N-ethyl-N'-nitrosoguanidine (ENNG)/ml to drink ad libitum for 9 months. They all developed esophageal squamous cell carcinomas and gastric adenocarcinomas. The stomach adenocarcinomas were mostly in the antrum along the lesser curvature and were either well differentiated or poorly differentiated, with or without signet ring cells. The well-differentiated adenocarcinomas metastasized to the liver, and the poorly differentiated ones metastasized to the lymph nodes. The gastric mucosa in the antrum was atrophic, and the muscularis mucosae was fibrotic. Esophageal lesions were multicentric moderately differentiated squamous cell carcinomas, and they developed without diffuse hyperplastic changes of the epithelium. One dog with a large ulcerated carcinoma of the esophagus had metastases in the lung, liver, peritoneum, and abdominal lymph nodes. One dog also had a hemangiosarcoma with hepatic metastasis and spindle cell sarcoma in the stomach and duodenum, respectively.
The effect of a microbial protease inhibitor, leupeptin, on the induction of urinary bladder tumors in W rats by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) was examined. Three groups of animals were given 0.01% BBN in their drinking water for 12 weeks. A basal powder diet supplemented with 0.1% leupeptin was given to group A throughout the experiment and to group B when BBN administration was stopped. Group C was given the basal diet without leupeptin throughout the study. The total preservation period was 40 weeks. Results clearly showed that when leupeptin was given during the promotion step of bladder carcinogenesis (as in group B), it increased the size of tumors and the incidences of cancer and invasion. When leupeptin was given throughout the experiments, its effect was counteracted (as in group A).
The effect of leupeptin on the induction of lymphoblastic leukemia in ICR/JCL female mice by N-nitrosobutylurea (NBU) was investigated. NBU was given as a 0.02% solution in drinking water for 10 weeks. A 0.1% concentration of leupeptin was given in the diet. Group A was fed on the leupeptin diet from the beginning, Group B received it after the end of NBU treatment, and Group C was fed on a leupeptin-free control diet throughout. The average periods in the appearance of leukemia in groups A, B, and C were 115+/-50, 112+/-43, and 100+/-17 days (mean+/-SD), respectively, and there was a significant difference between groups A and B and Group C at P less than 0.001. In regard to this point, leupeptin might have the effect of retarding the rpocess of leukemogenesis. However, leupeptin showed no effect on the incidence and histopathological finding of leukemia.
A method was developed to isolate transitional cells from the mucous lining of the rat urinary bladder by treatment with ethylene diaminetetraacetic acid and sonication. The isolated cells were examined by phase contrast microscopy, Giemsa staining, and scanning electron microscopy. Two types of isolated cells were distinguished: large ones which were characterized as superficial cells and smaller ones which seemed to be intermediate basal cells.
Esophageal carcinomas were induced in three of five rabbits given 0.25% N-methylbenzylamine and 0.16% NaNO2 in their drinking water. The three rabbits with carcinoma had consumed more than 94 g of NaNO2 and had survived for more than 536 experimental days. The esophageal carcinomas were a slightly elevated type, and no polypoid lesions were seen. They were classified histologically as squamous cell carcinomas or adenosquamous carcinomas, or both. No metastases were found. The other two of the five rabbits died early in the experiment before any esophageal carcinoma had developed.
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