Aryl hydrocarbon hydroxylase activity in liver from the C3H/He strain of mice is apparently increased by the administration of 3-methylcholanthrene, but the enzyme activity from the DBA/2 strain of mice is not. The enzyme activity from female mice is higher than that from male mice, even 72hr after a single application of 3-methylcholanthrene into the mice. The control enzyme in the liver from both strains of mice has a pH optimum at 7.9 and the induced enzyme from C3H/He mice, at 8.2. There are approximately the same levels of the apparent K_m for benzo[a]pyrene, NADPH, or NADH in the liver enzyme from both strains of mice even after treatment with 3-methylcholanthrene. The induced enzyme is inhibited by 7, 8- or 5, 6-benzoflavone non-competitively, and nicotinamide inhibits both the constitutive and induced enzyme uncompetitively. Cyclohexene oxide and 1, 1, 1-trichloropropane oxide, known to be inhibitors of epoxide hydrase, inhibit the activity of the constitutive enzyme, but enhance the induced enzyme in the liver. The difference in the properties between the constitutive and induced enzymes from mouse liver is discussed briefly.

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The effect of feeding and lighting on the regulation of aryl hydrocarbon hydroxylase activity in liver, small intestine, and lung from C3H/He, DBA/2, and Swiss albino mice was investigated. A circadian rhythm of aryl hydrocarbon hydroxylase activity in the liver from DBA/2 mice was observed under the controlled lighting conditions, showing higher activity at the end of the light period of a day and lower activity in the dark period. Contrasting to the change of the enzyme activity in mice fed freely in the continuous dark period, inconsistent and variable results of the enzyme activity and its induction by 3-methylcholanthrene were observed in the mice that were not fed during the continuous light period, depending on the sex and strain of the mice used.
Different responses in the induction of aryl hydrocarbon hydroxylase to different routes of 3-methylcholanthrene administration were found between the liver and small intestine of the mice, but not in the lung. The higher levels of the enzyme activity induced in the liver and small intestine were detected after the intraperitoneal and intragastric administration of 3-methylcholanthrene.
The significance of controlled feeding schedules for obtaining reproducible experimental results in the regulation of aryl hydrocarbon hydroxylase activity in the mice was discussed.

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Male Wistar rats were divided into three groups for studying the chronic effect of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), in continuous dose of 50mg/L in drinking water, or 50mg/L MNNG and 0.4% Tween 60 in drinking water. From the 2nd to 50th week after the administration of MNNG, every 3 or 5 rats were sacrificed and autopsied after the intraperitoneal injection of 1μCi ³H-thymidine/g body weight at 2- or 3-week intervals. The resected stomachs were studied morphologically and autoradiographically. Six cases of experimental gastric cancer were produced that fulfilled Stewart's criteria. Autoradiographically, there was no significant difference in the flash labeling index in the normal antral mucosa, in the non-pathologic antral mucosa, and in the cancerous lesion, but generation time and DNA synthesizing time of the cancerous lesion were 2 or 3 times longer than those of the glandular stomach of normal rats reported by Galjaard. They were also longer than those of the non-pathologic antral mucosa of rats treated with MNNG. These experimental results were discussed, comparing with cell kinetics of the gastrointestinal tracts in man.

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A theoretical analysis was made on the optimum Bleomycin treatment regimen on the basis of the "binding-saturation model" which was proposed for the Bleomycin dose-cell survival relation. The surviving fraction of tumor cells decreased as a function of the number of fractionated treatments up to the optimum fractionation number if the tumor was treated with the same total dose. The effect of cellular sensitivity to the antibiotic, tumor doubling time, treatment interval, and total doses on the optimum regimen was analyzed. The importance of treatment interval and of tumor doubling time was emphasized and the short treatment interval was recommended for the clinical use of this antibiotic. The optimum number of fractions increased linearly with the increase of the total dose while the optimum single dose was independent of the total dose. A concept of the tumor control probability of tumors treated with the optimum fractionation regimen was introduced and implications of these analyses in the clinical cancer chemotherapy were discussed.

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A water-soluble nitrosourea, 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride (ACNU), was tested for antitumor activity against lymphoid leukemia L-1210 in BDF₁ mice. The results obtained were as follows:
(1) ip-ip system: By daily administrations optimal dose for 12 days, MED (ILS₄₀), and therapeutic ratio were found to be 18mg/kg, 1.3mg/kg, and 14, respectively, and by a single injection, those were found to be 46mg/kg, 4.2mg/kg, and 11, respectively. The therapeutic ratio of ACNU was the highest of all the drugs tested. At the neighboring dose level to optimal dose most of leukemic mice survived more than 60 days.
(2) ip-iv system: Remarkable prolongation of life-span was observed by a single injection. Majority of mice administered more than 32mg/kg of ACNU survived more than 60 days.
(3) ip-po system: Remarkable prolongantion of life-span was shown by a single administration and most of leukemic mice given more than 46mg/kg of ACNU survived over 60 days.
(4) iv-ip system: By a single administration of ACNU remarkable prolongation of life-span was seen and majority of leukemic mice were rescued at doses of 32mg/kg or more.
(5) iv-iv system: Result almost similar to iv-ip system was obtained.
(6) iv-po system: The result in this system was similar to that in ip-po system. Thus, the compound was highly effective in the leukemic mice by either its parenteral or oral administration.

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Change in immunosensitivity of various chemically modified cells to the specific antibody was investigated in the Donryu rat-Yoshida sarcoma system. Among various agents, Amphotericin-B and cetyltrimethylammonium bromide were effective in increasing the immunosensitivity. This effect was not due to the general damage of cell membrane but to the increase of antigen exposed on the cell-surface membrane.

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Sedimentation condition for DNA from various kinds of cultured mammalian cells lysed directly on the top of an alkaline sucrose gradient was examined after the lysis for various periods at 19° or 37°. When cultured normal embryo cells from human, mouse, and Syrian hamster were analyzed, "complex" and "main" peaks were demonstrated. The former, which had low sedimentation coefficient, was obtained after 1 or 2hr of lysis at 19° and resolved after a 4-hr lysis into the latter which had a higher sedimentation coefficient. When cultured cells with malignant history were analyzed, a sharp and high peak was observed after 1 or 2hr of lysis at 19° and this peak resolved into the "main" peak after a 4-hr lysis. When the cells were lysed at 37°, the "main" peak appeared after 1 or 2hr of lysis.
Metaphase cells in which the chromatin is condensed heterochromatically were also analyzed. Sedimentation profiles from normal human embryo cells and HeLa cells in metaphase were similar to those obtained from cells with malignant history in interphase during various lysis periods. From these data the difference in the sedimentation pattern between normal embryo cells and cells with malignant history could be interpreted as a phenotypic expression of the cells.

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Indirect macrophage migration technique was employed to study in vitro cellular immune response to autologous tumor extract in man. Cellular hypersensitivity to autologous tumor extract was detected in 21 (26%) of 80 patients with various carcinomas preoperatively by means of the in vitro production of macrophage migration inhibitory factor (MIF). The relative frequency of MIF production in these patients, varied inversely with progress of the diseases. The follow-up studies revealed postoperative decline of the cellular hypersensitivity after curative operation. These findings indicate that this assay can be applied for detecting cellular hypersensitivity to autologous tumor extracts in clinical situation.

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1-Butyl-1-nitrosourea (BNU), a strong leukemogen for rats and mice, was administered prenatally, neonatally, and to sucklings via maternal milk in the ACI/N rats. A high incidence of neurogenous tumor was obtained in the offspring of the mother rats that received 3 subcutaneous injections of 10mg/rat of BNU at the late stage of pregnancy and also in the animals that received one subcutaneous injection of 100mg/kg of BNU within 24hr after birth. Though in low incidence, the tumors also developed in the offspring of the mothers that received the BNU treatment at the middle stage of their pregnancy or in the rats that were nursed by the mother rats which received 3 subcutaneous injections of 300mg/kg of BNU during lactation.
Contrary to expectations, leukemia developed in only one rat of all the offspring of the mother animals that received the BNU treatment during their pregnancy.

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The tumorigenic effect of a diet containing the α-isomer of benzene hexachloride (α-BHC) on the liver of various animals was examined. It was found that α-BHC induced liver tumors in male and female mice but not in rats or hamsters in the present observations. Histological changes in the liver of mice induced by α-BHC were also much greater than those induced in rats or hamsters. Male animals were more susceptible to the tumorigenic action of α-BHC than females. Among different strains of mice, the DDY showed greatest susceptibility and the C57BL/6 showed the least. Induction of mouse liver tumors by α-BHC was not inhibited by concomitant feeding of 1-naphthyl isothiocyanate or p-hydroxypropiophenone. However, 3-methylcholanthrene slightly inhibited their induction by α-BHC.

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Murine sarcoma virus (Moloney) was found to be heat labile. Inactivation curve represents a first-order kinetics at temperatures between 30°and 60°. Inactivation constant analysis showed an inflexion at about 45°, and the activation energy was calculated as 67.6kcal/mol for higher temperature range and 7.95kcal/mol for lower temperature range. Nature of inactivation is also discussed.

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Production of rat α-fetoprotein by transplantable ascites hepatoma was studied by radioimmunoassay method. α-Fetoprotein was detected in sera-from rats bearing 22 out of 50 ascites hepatoma cell lines that were previously negative for the presence of α-fetoprotein by the Ouchterlony test. α-Fetoprotein was also detected with high prevalency in Morris hepatomas and sublines of Yoshida sarcoma by this assay system.

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Specific death rates for esophageal cancer by each city and county in Japan were calculated. Nara and Wakayama Prefectures formed a high death-rate area with some neighboring cities and counties in other prefectures. Inhabitants of these area are known by the custom of taking "Chagayu", tea-cooked rice gruel. According to this survey on the habit of taking hot tea-gruel, with over 5, 000 teachers and their families aged over 50 years old, the distribution of the percentages of taking tea-gruel among surveyed subjects by cities and counties was similar to that of the death rates for esophageal cancer. Also, in Yamaguchi Prefecture, western-most prefecture of the main island (Honshu), there was an area which showed a similar condition. The result of this survey suggests that taking hot tea-gruel is one of possible factors for esophageal cancer in these districts.

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A single intramedullary administration of 4-nitroquinoline 1-oxide (4-NQO) into the mandible in 32 rabbits induced 21 cases of osteogenic sarcoma (65.6%), 5 chondrosarcomas (15.6%), 2 fibrosarcomas, and 3 cementoblastomas. None of the tumors appeared until the 3rd month after the treatment. From the 4th to 6th month, early stages of osteogenic tumors were seen. In the late stadium, from 7th to 12th month, tumors showed prominent proliferation and invasion to the oral cavity and surrounding areas. Metastasis to the lung and liver was found in 2 cases of osteogenic sarcoma.

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The effect of vinblastine sulfate on the regeneration of hydra was examined. When the three segments of hydra (fore, mid, and hind segments) were treated with 0.01% vinblastine sulfate immediately after separation, transferred to normal culture medium, and observed for 7 days, various types of abnormal regeneration were observed, especially in the regenerates from the mid segments. Other segments of hydra did not reveal any abnormal pattern of regeneration, although incomplete regeneration or no regeneration of the segments was seen in the advanced period of the treatment.
In the case of treatment of the three segments with 0.01% vincristine sulfate, no abnormal regeneration was seen, in spite of marked inhibition of regeneration which was observed in the advanced period of the treatment.

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N-Hydroxy-4-(methylamino) azobenzene (I) which had been assumed to be an intermediate compound to ultimate metabolite of 4-(dimethylamino)azobenzene, and 4'-methoxycarbonyl derivative (II) of I were respectively prepared from N-benzoyloxy derivatives by alkaline hydrolysis in the presence of ascorbic acid. Reactivity of I and II, and acetates of I and II to several amino acids was recorded.

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