Aqueous solution of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was given orally for 15 months in 4 dogs and follow-up examination of their stomach was made successively by radiography, endoscopy, and biopsy. Double-contrast photography revealed fine gastric mucosal damages. Dogs were sacrificed when they became moribund during the follow-up period. Eight cancers and one leiomyosarcoma were found histologically in the cardiac and pyloric portions of the stomach. Seven of these 9 lesions were visualized clearly in radiographs. Diagnosis of the lesions was 6 cancers or suspected cancers, and one polyp. The progress of these lesions was followed by radiographic examination.

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Bleomycin in various concentrations was added to cultures of peripheral lymphocytes for various periods during culture in order to elucidate quantitatively the cytogenetic effect of the antibiotic on human cells. The antibiotic induced chromatid-type aberrations in G₁ cells and the incidence of these aberrations showed a peak in rather low concentration of the antibiotic. Contrarily, the incidence of acentric fragments and dicentrics induced in G₁ cells was increased in linear proportion to the concentration of Bleomycin. The mechanism of the induction of these aberrations remains to be elucidated but the present results imply the possibility for estimating the severity of damage due to Bleomycin in vivo by following the incidence of aberrations.

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Persistence of histological and enzymic alterations induced by subcarcinogenic doses of 3'-methyl-4-(dimethylamino)azobenzene (3'-Me-DAB) was studied in the rat liver. When the animals were fed with a diet containing 0.06% of 3'-Me-DAB for 2 weeks, marked degeneration of hepatocytes occurred and, when dye-diet was given for 4 or 6 weeks, a large number of original hepatocytes were replaced by hepatocytes which seemed to have been transformed from proliferating cholangiolar cells. In accordance with degeneration of the original hepatocytes and proliferation of renewed hepatocytes, activities of glucose-6-phosphatase (G-6-Pase) and acid phosphatase decreased markedly, but cathepsin activity increased and isozyme pattern of aldolase altered. Twenty-four weeks after cessation of the dye feeding for 6 weeks, these biochemical alterations nearly returned to normal, while slight but evident histologically recognizable changes remained. These livers had a focus consisting of altered liver cells which usually showed decreased G-6-Pase activity with occasional decrease in adenosine triphosphatase (ATPase) activity. Such altered cells contained a large amount of glycogen within the cytoplasm which did not disappear even after 12hr of fasting. When these animals were partially hepatectomized for induction of liver cell regeneration, abnormality in mitosis was found in a considerably high frequency. These persistent alterations were more prominent in rats fed the dye for 4 or 6 weeks than those treated for 2 weeks.

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An attempt was made to enhance the extravasation of antitumor agents administered by way of the vascular route. When the portal vein was clamped, the levels of Mitomycin-C, Bleomycin, and 5-fluorouracil in tissues such as the stomach and the small intestine were markedly increased. Tumor growth was strikingly suppressed by the combined use of Mitomycin-C and portal vein clamping. Of particular interest is a significant decrease in the number of foci of lymphatic metastasis and of peritoneal dissemination after clamping. These results suggest that clamping of the portal vein simultaneously with intravenous injection of antitumor agents may induce an increased extravasation of the drugs thereby producing an enhanced suppressive effect on tumor growth.

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The effect of various carcinogenic and non-carcinogenic substances on the development of urinary bladder tumors in rats induced by N-butyl-N-(4-hydroxybutyl)nitrosoamine was examined histologically.
Pre- or post-treatment with N-nitrosopiperidine, N-nitrosomorpholine, diethylnitrosoamine, or N-2-fluorenylacetamide inhibited the incidence of urinary bladder tumors in rats induced by N-butyl-N-(4-hydroxybutyl)nitrosoamine, but the production of hyperplasias and papillomas in the urinary bladder epithelium was not inhibited by pre- or post-treatment with several carcinogens. On pretreatment with various hepatotoxic and nephrotoxic substances, 4-chloroacetanilide and 1-naphthyl isothiocyanate were found to inhibit the production of urinary bladder cancer induced by N-butyl-N-(4-hydroxybutyl)-nitrosoamine, the latter especially inhibiting not only the development of cancer but also hyperplasia and papilloma of the urinary bladder epithelium in rats induced by this carcinogen.
When the two carcinogens, N-butyl-N-(4-hydroxybutyl)nitrosoamine and N-2-fluorenylacetamide, were administered together, their action of inducing urinary bladder cancer was synergistic. Moreover, DL-tryptophan promoted their actions in producing urinary bladder tumors in rats.

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The effect of the nephrotoxic substance, N-(3, 5-dichlorophenyl)succinimide, on the histological pattern and incidences of kidney tumors in rats induced by dimethylnitrosoamine was studied histologically.
Post-treatment with N-(3, 5-dichlorophenyl)succinimide markedly increased the induction of tumors, especially renal cell tumors, by dimethylnitrosoamine, but pretreatment with this substance clearly inhibited the induction of tumors, especially embryonal cell tumors in the kidney. Oral administration of N-(3, 5-dichlorophenyl)succinimide alone caused severe interstitial nephritis but not development of kidney tumors. Thus, treatment with N-(3, 5-dichlorophenyl)succinimide changes the histological type and incidence of kidney tumors in rats induced by dimethylnitrosoamine.

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The humoral inhibitor, which may play a primary rôle in the regulatory mechanism of cell division in the regenerating rat liver, was investigated by isolating the active principle from the F-fraction, which was found to be α₁-globulin fraction, separated from the ethanolprecipitate (P-3 fraction) of normal rat plasma and to contain the hepatocyte-specific mitosis-inhibiting protein. Ampholine isoelectric focusing was utilized to isolate the active principle, with which the P-3 fraction was divided into four areas, a, b, c, and d, and the F-fraction, into three areas, a, b, and c.
Intraperitoneal injection of a-area, b-area, and c-area proteins into partially hepatectomized rats suggested that the mitosis-delaying effect may be present in the a-area protein and b-area protein, but absent in the c-area protein.
These results suggest that the humoral inhibitor or hepatocyte-specific mitosis-inhibiting protein may be present in the a-area protein and b-area protein. The nature of these proteins is briefly discussed.

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Effect of intratumor injections of BCG was examined on primary tumors induced by 3-methylcholanthrene and early transplant generation of syngeneic tumors in a group of mice previously injected with BCG and in that of non-injected mice.
1) The therapeutic effect of intratumor injection of BCG on established intradermal tumors of early transplant generation of tumor was as follows: Intratumor injection of BCG into the third transplant generation of 3-methylcholanthrene-induced growing tumors led to regression of tumor growth in 6 of 32 mice (19%), and induced systemic tumor immunity in 5 of these 6 mice.
2) Intratumor injection of BCG on primary tumors led to tumor retardation in 3 of 22 mice (14%) with tumor nodules of 3 to 10mm in diameter, and survival period of animals treated with BCG was longer than that of saline-treated controls.

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The distribution in tissues and excretion of cyclocytidine (2, 2'-anhydro-1-β-D-arabinofuranosylcytosine hydrochloride) and its metabolites in urine and feces of macaca monkeys (Macaca irus, Macaca fuscata, and Macaca mulata) and in beagle dogs were examined by the spectrophotometric assay. Distribution of cyclocytidine in plasma and tissues of rats was also examined.
The administered cyclocytidine showed a half-life of 22min in plasma of dogs and monkeys, whereas the half-life of aracytidine (1-β-D-arabinofuranosylcytosine hydrochloride) was 47min in plasma of dogs and less than 5min in plasma of monkeys, because of rapid deamination of the comvound to arauridine (1-β-D-arabinofuranosyluracil) in the latter species. Cyclocytidine exhibited maximum concentration in tissues of rats and monkeys at 20 to 40min after the administration, but its metabolites, aracytidine and arauridine, were not detected in these tissues. Cyclocytidine levels in tissues diminished thereafter but were detected within the next 40 to 80min, Neither cyclocytidine nor its metabolites could be detected in the brain. When cyclocytidine was administered intravenously in dogs and monkeys, 65-85% of it was excreted in urine, almost all as intact cyclocytidine, and small amounts of aracytidine and arauridine were detected. On the other hand, the administered aracytidine was excreted only as arauridine in urine of monkeys, and aracytidine and arauridine in dogs. Cyclocytidine and its metabolites were not detected in feces of both species.
It might be suggested that the distribution and elimination rate of cyclocytidine after its intravenous administration is not affected by the presence of cytidine deaminase in plasma and tissues.

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By using a solution of the carcinogen, N-ethyl-N'-nitro-N-nitrosoguanidine, with a device to contact the chemical long-lastingly to mucosa of the stomach in dogs, period of carcinoma production, which was confirmed by radiography, endoscopy, and biopsy, was strikingly shortened, without development of any sarcomatous lesion. The metastases to pancreatic and thoracic lymph nodes were observed to prove the effectiveness of this device, which is an improvement of an earlier method by administration of N-methyl-N'-nitro-N-nitrosoguanidine as a drinking water solution to produce stomach carcinoma in dogs.

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Oil-attached mycobacterial cell walls and peptidoglycolipid fraction suppressed the growth of asrcoma-180, mastocytoma P815, and EL-4 leukemia in mice, and regressed preëstablished tumor of melanoma B16 in mice.

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2-Deoxy-D-glucose transport into various cells was tested. In mouse the transport of "brain cells" and "embryonic (2-week) fibroblasts" was similar to that of transformed cells and markedly different from that of "embryonic (full-term) fibroblasts"; in rat that of "brain cells" and "embryonic (full-term) fibroblasts" was similar.

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The fluorescence of DNA in acid solution was found to decrease by the presence of quinolines. The quenching effect decreased in the order of 4, 6-dinitroquinoline 1-oxide>6-chloro-4-nitroquinoline 1-oxide>4-nitroquinoline 1-oxide>2-methyl-4-nitroquinoline 1-oxide>4-nitroquinoline.

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A water-soluble nitrosourea, 1-(4-amino-2-methylpyrimidin-5-yl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU), was found to be highly active against mouse leukemia L-1210 in vivo. The leukemic mice could be rescued by intraperitoneal or oral administration of ACNU.

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