Carcinogenic activities of potassium 1-methyl-7-[2-(5-nitro-2-furyl)vinyl]-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxylate (NFN) and 1-ethyl-7-methyl-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxylic acid (nalidixic acid) were examined histopathologically using 134 ICR/JCL mice. NFN was fed to 60 mice evenly divided by sex at a dose level of 0.02% by weight for 9 weeks, followed by 5 weeks of basal diet, 0.01% for 7 weeks and 15 weeks of basal diet, with mean cumulative doses of 115mg in males and 125mg in females (Group A). Forty control mice received only basal diet for 36 weeks and were evaluated. Because of suddenly occurred gastric hemorrhage after 7 weeks, 20 mice in Group A survived 20 weeks or longer and were evaluated. Then, 14 mice were supplementally fed 0.015% dose level of NFN for 26 weeks, followed by 10 weeks of basal diet (Group B).
Papillary growths with hyperkeratosis in the squamous epithelium of the forestomach were observed in most of the treated mice and became marked with progress of the experiment. Squamous cell carcinomas of the forestomach were induced in 6 mice (1 male and 5 females) out of 14 Group A animals surviving 31 weeks or longer, but no tumor was produced in the glandular stomach. Pulmonary adenomas, often multifocal, were induced in 19 mice after 21 weeks with one exception. Other tumors also noted were 1 lymphatic leukemia, 1 subcutaneous fibroma, and 1 uterine myosarcoma in Group A, and 1 squamous cell carcinoma of the forestomach, 8 lung adenomas and 2 lung adenocarcinomas, and 2 lymphatic leukemia out of 10 mice surviving 16 weeks or longer in Group B.
Nalidixic acid was fed to 20 mice at a dose level of 0.05% for 36 weeks throughout. No tumor or tumorigenic alteration was induced in any organs, except for 1 hepatic adenoma.
In control group, 1 pulmonary adenoma and 1 lymphatic leukemia were detected during the 36-week period of observation.

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Carcinogenicity of four new N-nitrosoamines related to butyl(4-hydroxybutyl)nitrosoamine, a potent and selective urinary bladder carcinogen, was investigated in male ACI/N rats by their administration in the drinking water. They were butyl(3-hydroxypropyl)nitrosoamine, propyl(4-hydroxybutyl)nitrosoamine, butyl(2-hydroxyethyl)nitrosoamine, and butyl(2-oxopropyl)nitrosoamine. These compounds were chosen principally on the basis of the in vivo metabolic study of butyl(4-hydroxybutyl)nitrosoamine, in order to elucidate a possible relationship among the structure, metabolism, and organotropic specificity of the nitrosoamine. Propyl(4-hydroxybutyl)nitrosoamine which has a 4-hydroxybutyl group like butyl(4-hydroxybutyl)nitrosoamine was found to be a potent and selective urinary bladder carcinogen, while its counterpart, butyl(3-hydroxypropyl)nitrosoamine, did not induce any tumors in any organs. Butyl(2-hydroxyethyl)nitrosoamine induced hepatoma as well as papilloma in the esophagus. Histopathological changes were observed only in the liver with butyl(2-oxopropyl)nitrosoamine and development of hepatoma was demonstrated. Elevated level of serum glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, and alkaline phosphatase activities was observed with butyl(2-hydroxyethyl)-nitrosoamine and butyl(2-oxopropyl)nitrosoamine.

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Estimation of leukemic cells in various tissues of L-1210 leukemia mice treated with Carbazilquinone was attempted. A semiquantitative bioassay for L-1210 cells was developed on the basis of the direct relationship between the number of leukemic cells inoculated into BDF₁ mice and their respective life-spans. This bioassay method was applied for the detection of leukemic cells and the presence of a large number of leukemic cells was found in every tissue of mice inoculated L-1210 cells 5-6 days earlier. Administration of Carbazilquinone caused a marked reduction in the number of leukemic cells in every tissue (brain, thymus, lung, heart, spleen, liver, kidney, lymph node, bone marrow, and blood).

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To study the action of 4-nitroquinoline 1-oxide (4-NQO) on yeast mitochondrial DNA, synchronous cell cultures of yeast were used. The induction rate of cytoplasmic respirationdeficient (RD) mutants of yeast by 4-NQO was closely correlated to the yeast cell cycles, especially to mitochondriogenesis, such as the number of mitochondria in the cells, activities of some respiratory enzymes in mitochondria, and the replication of mitochondrial DNA.
Hydroxyapatite column chromatography of DNA preparations from intact cells or mitochondrial fraction of RD mutant yeast strain N-1, which was induced by the treatment of normal yeast with 4-NQO, showed that mitochondrial DNA had disappeared in this mutant.

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Electronic interaction between DNA and 2-anthramine, which induces skin tumor, and its related compounds was studied. Combined systems of calf-thymus DNA with 1-, 2-, and 9-anthramines and N, N-dimethyl-2-anthramine were found to produce hypochromism of a certain degree in the ultraviolet region when in low concentration. The orderly secondary structure of DNA was indispensable in the production of hypochromism, and there was an optimum salt concentration for the spectroscopic change. The degree of hypochromic change expressed by the integrated intensity and the degree of spectral overlapping of perturbants were in parallel. Among the compounds examined, the carcinogenic 2-anthramine gave the largest value of percentage hypochromicity at 260nm. Some discussions were made on the molecular action mechanism of 2-anthramine from the point of electronic perturbation of DNA by the carcinogen, and on the molecular specificity of 2-anthramine.

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In view of a potent gastric carcinogenicity of the well-known mutagen, N-methyl-N'-nitro-N-nitrosoguanidine, a screening of compounds related to it was attempted by examining the mutagenicity of various nitrosated guanidine derivatives for a strain of Salmonella typhimurium at neutral pH. Among naturally occurring guanidines so far tested, nitrosated methylguanidine was the most mutagenic, and nitrosated agmatine and γ-guanidinobutyric acid were moderately mutagenic, while nitrosated L-arginine and acetyl-L-arginine were weakly mutagenic. Regarding synthetic guanidines, nitrosated benzoyl-L-arginineamide, acetyl-L-arginineamide, and γ-guanidinobutyric acid amide showed a powerful mutagenic activity and were as active as or more so than nitrosated N-methyl-N'-nitroguanidine. Nitrosated L-arginineamide, β-guanidinopropionic acid, homoarginine, and benzoyl-L-arginine ethyl ester were weakly active. Some arginine-containing di- or tri-peptides and salmine hydrolysate, when nitrosated, also showed moderately or weakly mutagenic activity. Some urea derivatives revealed weak or slight mutagenicity after nitrosation. Several amino acids except arginine, which were treated with nitrite in the same manner, failed to show mutagenic activity. The mutagenic principle of nitrosated acetyl-L-arginineamide was identified as N-nitroso-4-acetamido-4-carboxamidobutylcyanamide. Based on these findings, the structural specificity involved in the mutagenicity of nitrosated guanidine derivatives is discussed.

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Interaction of antitumor agents in activity and in toxicity was examined separately. Ascites sarcoma-180 and ddN mice were used as the tumor system.
Interaction was evaluated on the concept of pharmacological synergism and not of therapeutic synergism. In activity, 18 out of 91 combinations provided synergism and most of them contained alkylating agents and antibiotics. Antitumor agents were therefore classified into two groups from the point of drug interaction. Synergism was observed in combinations of agents in Group I, alkylating agents, antibiotics, and alkaloids. In combination of agents in Group II (antimetabolites and others), additive action was observed. As a result, 18, 65, and 8 combinations provided synergism, additive action, and antagonism, respectively.
On the other hand, in toxicity, 13, 27, and 38 out of 78 combinations provided synergism, additive action, and antagonism, respectively. The combination that provided synergism in activity and antagonism in toxicity were 8 out of 91 combinations tested. In general, fortunately, combinations of antitumor agents were more than additive in activity and less than additive in toxicity.

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Bleomycin-sensitive mutants were isolated from Escherichia coli by mutagenesis with N-methyl-N'-nitro-N-nitrosoguanidine. All the mutants isolated are as resistant to ultraviolet (UV) radiation as the parental strain. Genetic analysis of one of these mutants revealed that a Bleomycin-sensitive gene is located near the locus lac, i.e., in the so-called membrane cluster region. From this strain, UV-sensitive substrains were derived. Double mutants possessing Bleomycin-sensitive and recombination-deficient genes were extremely sensitive to Bleomycin but those possessing Bleomycin-sensitive and host cell-reactivation deficient genes were not. Single mutants possessing recombination-deficient gene alone were not Bleomycin sensitive. From these facts, the following possibilities are strongly suggested. (1) Bleomycin damage on DNA may be repaired by recombination function, and (2) Bleomycin-sensitive gene may enhance the permeability of the cell membrane to Bleomycin molecules.

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Papillomas and carcinomas of urinary bladder of female ACI/N rats were induced by the intravesicular instillation of butyl(4-hydroxybutyl)nitrosoamine or its major urinary metabolite, butyl(3-carboxypropyl)nitrosoamine. Possible direct carcinogenic action of these potent urinary bladder carcinogens to the bladder epithelium was discussed in connection with the calculus formation by the treatment.

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Free radical concentrations per 10⁵ cells of normal rat liver, carcinogen-fed rat liver, AH-13, AH-7974, and AH-602 were 2.02, 0.73-0.45, 0.04, 0.05, and 0.08×10¹³ spins, respectively. The decrease in free radical of regenerating liver cells was observed from 2 to 5 days after operation.

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An α-fetoprotein-producing clone of Yoshida sarcoma was cultivated in vitro in a medium containing various concentrations of cyclic AMP. The growth of Yoshida cells was lowered, accompanying depressed DNA and RNA syntheses but increased protein synthesis, and the production of α-fetoprotein in the growth-depressed cells was accelerated.

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Using cultured transformed fibroblasts (RFL-T), an antitumor agent, 5-fluorouracil, was found to be potentiated in its inhibitory action on RNA formation by vitamin A as well as Amphotericin-B. 5-Fluorouracil in combination with vitamin A or Amphotericin-B enhanced more effectively the cellular sensitivity to cobalt radiation than when 5-fluorouracil was used alone.

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The treatment of spontaneous mammary adenocarcinoma of mice with cyclocytidine showed some perceptible delay in the onset of local recurrence and a slight prolonagtion of the survival period.

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