The oral administration of N-bis(2-hydroxypropyl)nitrosamine (DHPN) in drinking water induced lung tumors in high incidence in rats at 25 weeks. Histologically, they were adenoma, adenocarcinoma, squamous cell carcinoma, and combined squamous cell and adenocarcinoma. Metastases of adenocarcinoma were observed in regional lymph nodes. The development of tumors in other sites was seen in the liver, thyroid, kidney, ureter, urinary bladder, and pancreas. The incidence of lung tumor was distinctly higher than that of other sites. These results indicate that the target organ of DHPN was the lung and that oral administration of this chemical carcinogen was responsible for the development of lung carcinomas in rats.

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The effect of dimethylnitrosamine (DMN), ethionine, streptozotocin, N-methyl-N-nitrosourethan (MNUT), N-bis(2-hydroxypropyl)nitrosamine (DHPN), azaserine, and 4-hydroxyaminoquinoline 1-oxide (4-HAQO) on DNA synthesis after partial pancreatectomy was studied. Its results indicated that DNA synthesis of the residual pancreas occurred and reached the maximum value at 3 days and returned to the control value 12 days after the operation.
DNA synthesis, which was inhibited 96.7% by hydroxyurea 3 days after the operation, indicated that semi-conservative DNA synthesis had occurred in the residual pancreas. DMN and ethionine, non-pancreatic carcinogens, did not inhibit while DHPN, MNUT, azaserine, and 4-HAQO, pancreatic nonendocrine carcinogens, inhibited DNA synthesis in the rat pancreas by 57.9, 76.4, 71.7, and 82.1%, respectively. The effect of streptozotocin, pancreatic endocrine carcinogen, on DNA synthesis was not clear from the present experiment. Further effect on the inhibition of DNA synthesis by these carcinogens was obtained by dose-response studies and its results indicated that there was a correlation between pancreatic carcinogens and the inhibition of DNA synthesis after partial pancreatectomy in rats.

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Effect of BCG cell-wall skeleton (BCG-CWS) on the recovery of responsiveness of lymphocytes and the survival period was studied in patients with lung cancer. (a) Responsiveness of lymphocytes as demonstrated by proliferative response to phytohemagglutinin (PHA) or microcytotoxicity test with cultured cells of a bronchogenic carcinoma was depressed in the patients at later stages of cancer and it was restored by treatment with BCG-CWS in many of such patients. (b) Survival period of the patients at later stages such as III or IV was prolonged by treatment with BCG-CWS. Such an effect was detected even in the patients with carcinomatous pleuritis. (c) A close correlation was found between the reactivity such as PHA response or cytotoxicity and clinical course of the patients given BCG-CWS. Assay system with PHA response and microcytotoxicity test appears to be reliable in anticipating the prognosis and in following clinical course after the BCG-CWS treatment.

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Effect of Propionibacterium acnes on macrophage activation and antitumor activity was examined in ddN and SL mice. (1) Carbon clearance was enhanced to the same extent by P. acnes treatment in both strains. (2) Number of peritoneal macrophages increased to the same extent by P. acnes treatment in both strains. (3) Adhesiveness of peritoneal macrophages, as demonstrated by inhibition of migration or an increase in spreading cells, was enhanced more efficiently in ddN than in SL mice by P. acnes treatment. (4) Mice of both strains died in a similar pattern, when they were not pretreated in any way. The treatment with P. acnes conferred antitumor activity of a higher degree in ddN than in SL mice. (5) Peritoneal macrophages of ddN mice treated with P. acnes exhibited an antitumor activity in in vivo neutralization test.
These results suggest that strain difference in augmentation of antitumor activity by P. acnes is ascribed to distinct sensitivity of macrophage functions to a stimulative effect of P. acnes in the mouse strains.

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Comparison between Carbazilquinone and Mitomycin-C, both of which contain aziridinyl, carbamoyloxy, and quinonyl groups, was made for their therapeutic effect upon intravenous administration. Although both agents exhibited a significant effect on plasmacytoma X5563 in C3H/He mice to a similar extent, Mitomycin-C was not as effective on lympholeukemia L-1210 and on the lung metastasis of Ehrlich carcinoma in (C57BL/6 × DBA/2)F₁ (BDF₁) mice as was Carbazilquinone. Possible interpretations regarding this discrepancy are discussed.

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The molecular species and content of pepsinogen in regenerated mucosa over fundic ulcers induced in a rat stomach by iodoacetamide were found to be the same as those in normal pyloric mucosa, but different from those in normal fundic mucosa.

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The effect of simultaneous oral administration of dimethylamine or aminopyrine and sodium nitrite on the damage and repair of rat liver DNA was studied by the use of centrifugation in alkaline sucrose gradient. Fragmentation of the intact DNA was observed significantly shortly after combined treatment with aminopyrine and nitrite when no liver necrosis occurred yet and the damaged DNA at the lower dosage level of aminopyrine with nitrite was found to be repaired in contrast to the increased activity of serum aminotransferase.
The lowest effective dose on DNA damage at 2hr after administration was about 40mg/kg of aminopyrine and 80mg/kg of sodium nitrite. This effect was equal to that caused by single oral administration of 2 to 10mg/kg of dimethylnitrosamine, while dimethylamine at 160 or 320mg/kg together with 80mg/kg of sodium nitrite produced no pronounced DNA damage.
The significant damage of rat liver DNA by aminopyrine and nitrite correlates well with the easier nitrosation of aminopyrine and the occurrence of high incidence of malignant liver tumors in rats fed aminopyrine together with nitrite already reported by Lijinsky.

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Carcinogenic effect of 14 N-nitrosamines related to N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) and N, N-dibutylnitrosamine (DBN) was studied in ACI/N male rats by administration in the drinking water. BBN homologs having methyl, ethyl, or pentyl group selectively induced urinary bladder tumors, but a homolog with tert-butyl group did not have any carcinogenic effect. N-Ethyl-N-(3-carboxypropyl)nitrosamine, the principal urinary metabolite of the ethyl homolog of BBN, did also induce bladder tumors selectively, thus providing an additional evidence that N-alkyl-N-(3-carboxypropyl)nitrosamines are responsible for the selective induction of bladder tumors by BBN homologs. N-Butyl-N-(carboxymethyl)nitrosamine and BBN analogs having 3-hydroxypropyl chain together with ethyl or butyl group were found to be noncarcinogenic. N-Propyl-N-butylnitrosamine and DBN induced hepatomas, but simultaneous development of esophageal tumors was observed only with the former. N-Butyl-N-(3-hydroxybutyl)nitrosamine, one of the principal metabolites of DBN, did not induce any tumors, but its further transformation product, N-butyl-N-(3-oxobutyl)nitrosamine as well as N-butyl-N-(2-oxobutyl)nitrosamine, another metabolic intermediate of DBN, induced hepatomas. Possible correlation of structure and metabolism with organotropic carcinogenesis by N, N-dialkylnitrosamines is discussed, with special reference to selective induction of urinary bladder tumors.

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Cytotoxicity against tumor-specific antigen and allogeneic antigens in mice was raised by immunization with viable tumor cells in saline, but not by immunization with tumor cells in complete or incomplete Freund's adjuvant. On the other hand, strong delayed hypersensitivity as demonstrated by macrophage migration inhibition was detected in the mice immunized with tumor cells in complete Freund's adjuvant in both syngeneic and allogeneic systems. After immunization with viable tumor cells, delayed hypersensitivity was raised to a moderate degree in allogeneic, but not at all in syngeneic mice.
Cytotoxicity was retained after a booster with syngeneic tumor cells in complete or incomplete Freund's adjuvant in the mice which had been immunized with viable tumor cells. Cytotoxicity was raised after a booster with viable syngeneic tumor cells in the mice which had been immunized with tumor cells in complete or incomplete Freund's adjuvant. Thus, the development of cytotoxicity depended entirely on the presence of viable tumor cells as an immunogen.
Activation of helper T cells was not found in the syngeneic mice immunized with viable tumor cells or tumor cells in complete or incomplete Freund's adjuvant. In allogeneic mice, the activity was facilitated slightly by immunization with viable tumor cells or tumor cells in complete Freund's adjuvant but not with tumor cells in incomplete Freund's adjuvant.
This system may be useful for analytical studies on cellular immunity, since cytotoxicity, delayed hypersensitivity, and helper cell activation can be induced in dissociated forms.

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The inhibitory effect of sulfated polysaccharides on blood-borne metastasis was examined. As a model of blood-borne metastasis, the ascitic form of hepatoma AH-109A tumor was injected intravenously into Donryu strain rats. Examination of the pulmonary metastatic nodules developed 2 weeks later showed inhibitory effect of the five sulfated polysaccharides tested. Xylan sulfate was the most inhibitory, and exerted its inhibitory effect when the tumor cells were in the pulmonary capillary beds.
However, from the rapid disappearance of radioactivity from the lungs after injection of ¹²⁵IUDR-labeled AH-109A cells, tumor cells seemed to be retained in the lungs for only a very short time. Measurement of the anticoagulative and fibrinolytic activities of three sulfated polysaccharides showed that the inhibitory effect of these compounds on blood-borne metastasis was proportional to their anticoagulative and fibrinolytic activities, xylan sulfate showing the highest activities.
These results suggest that sulfated polysaccharides may inhibit blood-borne pulmonary metastasis by inhibiting the lodging of tumor cells in the pulmonary capillary beds.

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Newborn hamsters were inoculated intracerebrally with BK virus. Between 3 and 6 months after inoculation, they developed papillary ependymoma (8 hamsters, 42%) or functional malignant islet cell tumors of the pancreas (insulinoma, 8 hamsters), or both (1 hamster). Both tumors contained an antigen reactive to SV40 T-antibody, suggesting that at least a part of BK virus genome has been integrated into the tumor cells. No infectious virus was detected in the extract of these tumors.

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Immunological properties of synthetic 6-O-mycoloyl-N-acetylmuramyl-L-alanyl-D-isoglutamine (6-O-mycoloyl-N-acetylmuramyldipeptide) and 6-O-mycoloyl-N-acetylmuramic acid were examined in guinea pigs and mice in comparison with those of BCG cell-wall skeleton, N-acetylmuramyl-L-alanyl-D-isoglutamine, and 6-O-stearoyl-N-acetylmuramyl-L-alanyl-D-isoglutamine. 6-O-Mycoloyl-N-acetylmuramyldipeptide showed a potent adjuvant activity for the induction of delayed type hypersensitivity to N-acetyl-L-tyrosine-3-azobenzene-4'-arsonic acid (ABA-N-acetyltyrosine). It was also found that 6-O-mycoloyl-N-acetylmuramyldipeptide treated with oil droplets or suspended in phosphate-buffered saline was as effective as oil-attached BCG cell-wall skeleton for the generation of cell-mediated cytotoxic effector cells to mastocytoma P815-X2 cells in the spleen of C57BL/6J mice in vivo. However, 6-O-mycoloyl-N-acetylmuramyldipeptide was less active as adjuvant than BCG cell-wall skeleton and N-acetylmuramyldipeptide in enhancing the circulating antibody formation to Tindependent antigen, 2, 4-dinitrophenyl-lysyl (DNP-Lys)-Ficoll in vivo, and on the generation of helper function of carrier-primed T-cells, and was inactive as a mitogen on normal mouse spleen cells. On the other hand, although 6-O-mycoloyl-N-acetylmuramic acid was shown to be inactive as adjuvant on immune systems described above, it was active as a mitogen on normal mouse spleen cells.

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Liver tissue cells derived from rats fed 4-(dimethylamino)azobenzene (DAB) were maintained in vitro for several months. These cells showed higher malignancy after treatment with 4.8 or 19.2μg/ml of DAB. Subcutaneous back-transplantation of DAB-treated cells showed an earlier appearance of palpable tumors and a higher rate of "take" than the non-treated control cells. The tumor size at 60 days after back-transplantation was also significantly larger in the DAB-treated cells. Long-term treatment with DAB produced few morphological changes of the cells in vitro, but the plating efficiency and resistance to toxic effects of DAB were significantly higher in the treated cells than in the control cells. On the other hand, no definite differences in chromosome number were found between the treated and control cells. These findings suggested that cell malignancy could be promoted by long-term treatment with DAB in vitro.

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Yoshida ascites sarcoma and its variants, and several azo dye-induced ascites hepatomas of rats were examined by an immuno-peroxidase technique to demonstrate surface immunoglobulins. More than 60% of the tumor cells in 8 ascites tumors showed positive surface staining (Group A), whereas the other 9 tumors were less than 15% positive (Group B). One tumor showed 34% positive reaction. The staining did not show capping.
Six of the 8 Group-A tumors were single cell type, while 5 of the 9 Group-B tumors were island type. Intravenous transplantation rate was very low (less than 10%) in 2 of the 6 Group-B tumors, but only 1 of the 7 Group-A tumors showed moderately low (40%) intravenous transplantation rate. All of the 8 Group-A tumors showed survival period of less than 35 days after intraperitoneal transplantation, while the survival period was more than 45 days in 3 out of the 9 Group-B tumors.

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Measurement of the incorporation of iron into liver cells and liver ferritin of the rat revealed that both incorporated less iron under tumor-bearing condition than in the normal state.

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Amount of cytochrome P-450 in the hyperplastic liver nodules was measured during hepatocarcinogenesis with N-2-fluorenylacetamide in the rat. Amount of cytochrome P-450 in the liver microsome decreased in early stage of hepatocarcinogenesis. Concentration of cytochrome P-450 in the hyperplastic nodules and their surrounding tissues was examined, using homogenate from each of them. Its amount was significantly less in the hyperplastic nodules in the 13th week than in their surrounding tissues, and became more in hyperplastic nodules in the 19th week. The hyperplastic nodules of the animals treated with phenobarbital showed almost the same amount of cytochrome P-450 as that in the controls. Amount of cytochrome P-450 in hepatoma tissues also showed similar values as that in hyperplastic nodules.

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Effect of the administration of 4-hydroxypyrazolo[3, 4-d]pyrimidine (allopurinol) on the growth of Ehrlich ascites tumor cells was investigated in an in vivo system. Oral administration of allopurinol (0.1% in diet) suppressed the growth of both ascites and solid types of the tumor after the implantation of Ehrlich tumor cells in mice. The inhibitory action depended on the dose but was lost repidly when the administration was interrupted. Possible mechanisms involved in the inhibitory effect of allopurinol on tumor growth were briefly discussed.

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The Kasahara isoenzyme of alkaline phosphatase was found in cancer tissues from patients with gastric carcinoma, maxillary carcinoma, pulmonary carcinoma, and carcinoma of the urinary bladder, in addition to hepatoma. This fact suggests that the Kasahara isoenzyme may not be a specific marker protein of liver cancer but could occur in a variety of neoplasms.

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The growth of spontaneous mammary tumors and of tumors transplanted into the animals with different hormonal conditions was compared between SHN and SLN strains of female mice established from the same basal stock of Swiss albino as a high and a low mammary tumor strains, respectively. There were little differences between strains in the growth of spontaneous mammary tumors of multiparous mice which appeared first. The growth of transplanted mammary tumors was not affected by the hormonal conditions of the hosts in either strains. However, the tumors became palpable one week after transplantation in SHN, which was 2 weeks earlier than in SLN.
These findings indicate that the selection of animals for mammary tumorigenesis is effective on the time and frequency of malignant transformation of mammary cells and on the "take" of transplanted tumor cells, but not on the growth potentiality of already established tumors. They further suggest autonomy in the growth of mammary tumors in both strains of mice.

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Color reaction of leucine aminopeptidase is available for macroscopic demonstration of the distribution of intestinal metaplasia. Preliminary examinations revealed that areas showing positive reaction coincided with zones of intestinal metaplasia revealed histologically. The new approach is simple to apply and never interferes with subsequent histological examination.

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Carcinogenesis with a single injection of 4-hydroxyaminoquinoline 1-oxide (4-HAQO) after partial pancreatectomy in rats was studied. Pancreatic carcinoma developed only in rats given 4-HAQO at DNA synthetic phase after the operation. This result indicated that the pancreatic carcinogenesis initiated by 4-HAQO was enhanced by regeneration induced by partial pancreatectomy.

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Antitumor activity of diehloro-, oxalato-, malonato-, methylmalonato-, and uracil-platinum-(II) complexes of 1, 2-diaminocyclohexane isomers, cis, traps-d, and trans-l, was examined and they were markedly active against either L-1210 or P-388 leukemia.

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A method was established for in vitro assay of catalase-depressing activity of toxohormone using cultured liver cells with equal sensitivity to the in vivo assay method. The assay requires microgram order of toxohormone and takes only 20hr.

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