Shigeyoshi Odashima

Antitumor activity of 4-nitropyridazine 1-oxides and related compounds for AH-13.

Antitumor activity of 4-nitropyridazine 1-oxides and related compounds was tested with AH-13 system. Among these nitro compounds, 3, 6-dimethoxy-4-nitropyridazine 1-oxide (III) and 4-nitrocinnoline 1-oxide (XIII) were the most effective. 4-Nitropyridazine 1-oxide (I), 3, 6-dimethyl-4-nitropyridazine 1-oxide (II) and 3-alkoxy-4-nitro-6-chloropyridazine 1-oxides (VI, VII) were effective to some extent.

Carcinogenicity of N-alkyl-N-(acetoxymethyl)nitrosamines after subcutaneous injections in F-344 rats

SummaryAs model compounds for metabolically activated N,N-dialkylnitrosamines, five N-alkyl-N-(acetoxymethyl)nitrosamines were synthesized and their carcinogenicy was testet in F-344 rats of both sexes. Compounds used in this study are N-methyl-(MAMN), N-ethyl-(EAMN), N-propyl-(PAMN), N-butyl-(BAMN), and N-isobutyl-N-(acetoxymethyl)nitrosamines (i-BAMN). All chemicals were dissolved in olive oil and rats received 10 weekly subcutaneous injections of these chemicals (10×5 mg MAMN or equimolar amounts of other chemicals) at the interscapular region. Subcutaneous tumors were detected in many rats of all groups treated with the chemicals, although no tumor was detected in the control group. Lung and/or thyroid tumors were also observed in many rats in the experimental groups. The incidence of subcutaneous tumors was highest in EAMN, followed in order by MAMN, PAMN, BAMN, and i-BAMN. On the contrary, the incidence of lung and thyroid tumors was highest in MAMN and decreased as the length of the alkyl chain of the chemicals increased. Histologically, almost all subcutaneous tumors were malignant fibrous histiocytomas. The results indicate that the chemicals possess systemic as well as local carcinogenicity in F-344 rats. The potent carcinogenic effects at the injection site of the α-acetoxy nitrosamines, coupled with their direct mutagenic activity reported previously, support the notion that these derivatives are useful as models for the ultimate form in the metabolic activation of N,N-dialkylnitrosamines.

Induction of tumors in the small intestine and mammary gland of female Donryu rats by continuous oral administration of N-carboxymethyl-N-nitrosourea

SummaryThe carcinogenicity of N-carboxymethyl-N-nitrosourea (CMNU), a naturally occurring N-nitroso compound, was tested in female Donryu rats. Four groups of female Donryu rats were given 400, 200, 100, or 0 ppm of CMNU solution continuously as drinking water. The incidence of tumors was highest and the mean survival time shortest in the 400 ppm group. A dose-effect relationship was observed in the tumor incidence and the mean survival time and the incidences of tumors in all experimental groups were significantly different from those in the control group. In the 400 ppm group, tumors were detected most frequently in the small intestine, followed by the mammary gland. In contrast, most tumors were observed in the mammary gland in the other two experimental groups, although dose-dependent induction of tumors of the small intestine was also detected in these two groups. The organ specificity of CMNU is compared with that of other N-alkyl-N-nitrosourea derivatives.

Leukemias Induced by 1-Butyl- and 1-Propyl -1-Nitrosoureas in the Rat

The leukemogenic effect of 1-propyl- and 1-butyl-1-nitrosourea (PNU and BNU) was studied in Donryu and Sprague-Dawley rats, which received the chemical in their drinking water. BNU produced leukemia in 42 out of 46 (91%) of the Donryu rats, and the majority of the induced leukemia were myeloblastic type. In the Sprague-Dawley rats, the incidence of leukemia was 70% (47/67), of which 37%(13/35) were myelocytic leukemia, although the development of myeloblastic leukemia was still predominant (54%, 19/35). The leukemogenic activity of PNU was slightly lower than that of BNU; it produced leukemia in 64% (61/95) of the Donryu rats. The predominant type of induced leukemia was myelocytic leukemia (59%, 36/61). Therefore, it was demonstrated through the series of experiments using BNU and PNU that the strength of leukemogenic activity has a close relationship to the types of leukemia induced in animals. Both BNU and PNU, however, provide excellent disease models of myelogeneous leukemia in the human being.

Induction of digestive-tract tumors in F344 rats by continuous oral administration of N-butyl-N-nitrosourea.

SummaryMale and female F344/DuCrj rats were administered N-butyl-N-nitrosourea at a concentration of 400 ppm in their drinking water. By the 50th week of the experiment, the cumulative incidence of upperdigestive-tract tumors was as high as 35/39 (90%) and 34/39 (87%) in male and female rats, respectively. Among these, esophageal and forestomach tumors occurred most frequently. Except one female rat with fibroma, upper-digestive-tract neoplasms were of the epithelial type—papilloma, squamous-cell carcinoma or adenocarcinoma. In female rats, vaginal tumors were induced in 16 (41%) animals. Ear-duct tumors and hematopoietic neoplasms were also induced in both sexes of rats, with incidence of less than 21%.

Induction of tumors in female Donryu rats by a single administration of 1-propyl-1-nitrosourea.

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.

Mammary tumorigenic effect of a new nitrosourea, 1,3-dibutyl-l-nitrosourea (B-BNU), in female Donryu rats

SummaryFour groups (groups 1-4) of female Donryu rats were given continuously 400, 200, 100, or 0 ppm solution of 1,3-dibutyl-1-nitrosourea (B-BNU) as their drinking water, and were studied for the development of tumors. The incidence of mammary tumors was 15/19 (79%), 20/24 (83%), 21/26 (81%), and 8/25 (32%) in groups 1, 2, 3, and 4, respectively. In addition, hematopoietic neoplasms, uterine tumors, and vaginal tumors developed in 13, 11, and six rats, respectively in 69 treated rats. Other tumors were infrequent.

Antitumor effect of pyridine N-oxides having 1-(2-chloroethyl)-1-nitrosoureidoalkyl and 1-methyl-1-nitrosoureidoalkyl groups.

Pyridine N-oxides having 1-(2-chloroethyl)-1-nitrosoureidoalkyl or 1-methyl-1-nitrosoureidoalkyl groups were evaluated for their antitumor activity against AH13 hepatoma and L1210 leukemia. Among them, 1-(2-chloroethyl)-1-nitroso-3-(2-pyridylmethyl)urea N-oxide (1), its tosylate (2), 1-(2-chloroethyl)-1-nitroso-3-(2-pyridylethyl)urea N-oxide (4), and 1-(2-chloroethyl)-1-nitroso-3-(3-pyridylmethyl)urea N-oxide (6) were highly active against both tumors in ip-ip system. These compounds were also active in ip-iv and ip-po systems of L1210. On the other hand, pyridine N-oxides having 1-methyl-1-nitrosoureidoalkyl group were all inactive against AH13 and weakly active against L1210. Effect on blood cells in Donryu rats bearing EDEN-5 erythroblastic leukemia cells was tested with these 1-(2-chloroethyl)-1-nitrosoureidoalkylureas. These compounds caused leucopenia and compound (4) was only slightly effective against EDEN-5.