Biomedical subjects
Publications and source records attributed to M Nakadate.
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.
1,1'-Ethylene-bis(1-nitrosourea) (EBNU) posesses antitumor activity against leukemia L-1210. Chemical stability, alkylating activity, and lipophilicity of EBNU and related compounds were compared. EBNU was the most unstable among several bis-N-nitrosoureas and mono-N-nitrosoureas tested. The alkylating activity of EBNU was the same as that of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), but higher than those of other bis- and mono-N-nitrosoureas except 1-methyl-1-nitrosourea. Lipophilicity of EBNU was extremely low compared with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and CCNU.
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N-Methyl-N'-nitro-N-nitrosoguanidine (MNNG), or its derivatives N-hexyl-N'-nitro-N-nitrosoguanidine (HNNG) and 1,6-bis(N'-nitro-N-nitrosoguanidinyl)-n-hexane (HxBNNG) were given to newborn ICR/JCL mice by a single subcutaneous injection in 1% gelatin suspension. In an acute toxicity study, the maximum tolerated dose of MNNG, HNNG or HxBNNG was 62 microgram/g, 555 microgram/g, or 500 microgram/g of body weight, respectively. In a chronic study, a single subcutaneous injection of MNNG to newborn mice at a dose of 62, 31, or 3 microgram/g of body weight induced tumors of the lung and hemangioendotheliomas in both sexes, and tumors of the liver in males. Other pathologic findings, such as deformities of the spine and alopecia of the skin, were frequently observed. The incidences of tumors in each group were clearly dose related. HNNG and HxBNNG were not tumorigenic within the observation period.
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Polymethylene-bis(1-nitrosourea), polymethylene-bis(1-nitroso-3-nitroguanidine), and polymethylene-bis(1-nitroso-p-toluenesulfonamide) derivatives were tested for antitumor effect against rat ascites hepatoma AH-13 and mouse leukemia L-1210. Bisnitrosoureas were effective against AH-13 and L-1210, bisnitrosoguanidines were effective against AH-13 alone, and bisnitrosotoluene-sulfonamides were ineffective against both tumor lines. Of all these compounds, 1,1'-ethylene-bis(1-nitrosourea) (EBNU) was the most effective. The antitumor effect of EBNU was compared with that of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). Intraperitoneal administration of EBNU according to the schedule, day 1, days 1 and 5, and days 1, 5, and 9 after intraperitoneal inoculation of L-1210 showed marked prolongation of host survival, although the effective doses used were a few times higher than those used in BCNU to obtain a similar effect. The minimum effective dose (MED) of EBNU on AH-13 cells was estimated as 1 mg/kg, which was 10 times less than that of BCNU, suggesting that EBNU was more effective than BCNU against AH-13.
Groups 1, 2, and 3 of female Donryu rats were given continuously 400, 200, or 100 ppm solution of 1-methyl-1-nitrosourea (MNU) as their drinking water. The incidence of neurogenic tumors was 12/27 (44%), 39/33 (91%), and 33/36 (92%) in Groups 1, 2, and 3, respectively. Among the neurogenic tumors, neurinomas developing from the spinal nerve roots were the most frequent. In addition, tumors of the digestive tract were found in 12, 1, and 2 rats in Groups 1, 2, and 3, respectively, and tumors in hematopoietic tissues developed in 6 rats. Tumors in other organs were infrequent.
Three groups of ACI/N rats of both sexes received continuous administration of 66 (Group I), 30 Group II), or 13(Group III) ppm solution of 1-methyl-3-acetyl-1-nitrosourea (Ac-MNU) in their drinking water. Tumors were found most frequently in the stomach and nervous system. The former was more frequently found in the male than in the female. The incidence was highest in males of Group II, 28/30 (93%), and lowest in females of Group I, 4/30 (13%). Histologically, all epithelial tumors of the stomach were benign adenomas except 5 adenocarcinomas. Neurogenous tumors were more frequently seen in the female than in the male. The incidence was highest in females of Group I, 29/30 (97%), and lowest in males of Group III, 6/28 (21%). The tumors were predominant in the central nervous system, especially in the hemispheres. Transplantation studies were done in some of these tumors. Although gastric tumors failed to get positive transplantation, all the neurogenous tumors transplanted were positive.
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Three groups of female Donryu rats were given continuously 1-ethyl-1-nitrosourea, 400, 200, or 100 mg/liter, in their drinking water. Leukemias developed in 94 of 104 (92%) rats surviving more than 6 experimental weeks. Of the leukemias, the erythroleukemias were induced most frequently, rapidly, and selectively. Other types of leukemias were found in a few rats of the high-dose group and, in some cases, in rats of the low-dose group. Tumors were also induced in the digestive tract, mammary glands, ear duct, and other organs, but their incidences were lower than 24%.
Three groups of female Donryu rats were given a single gastric intubation of 800, 400, or 200 mg/kg body weight of 1-propyl-1-nitrosourea and one group of female Donryu rats was given a single subcutaneous injection of 1-propyl-1-nitrosourea. The incidence of tumors was highest for mammary tumors and leukemia, and next for tumors of the ovary, thyroid, and adrenal glands, and in the digestive tract in rats given the chemical by oral administration. There were also scattered tumors in various other organs. Mammary and subcutaneous tumors were found in some rats given a subcutaneous injection of 1-propyl-1-nitrosourea.
Three groups of female Donryu rats were continuously given 600, 300, or 150 ppm solution of 1-propyl-1-nitrosourea in their drinking water. Leukemias developed in 62 of 109 (57%) rats surviving for more than 17 weeks and tumors developed in the digestive tracts of 31 (28%) animals. Of the leukemias, the differentiated myelocytic type was the most frequent, followed by myeloblastic leukemia and erythroleukemia. Tumors in the digestive tract, predominantly in the glandular stomach and duodenum, were both epithelial and nonepithelial. The other induced tumors were mainly in the mammary glands, ear ducts, and thymus, though the incidence was less than 15%.
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