The ultrastructural changes of dividing hepatocytes, especially in respect to Golgi-lysosome system, were studied by electron microscopy. Obvious increase of small vesicles with or without coat and "rod-shaped bodies" was observed around the prophase nucleus. In metaphase, spherules in various sizes also occurred near the chromosomes. These structures were regarded as unusual forms of primary lysosomes. Golgi apparatus was hypertrophic and was observed within the perinuclear cytoplasm throughout the mitotic cycle, but it lost its lamellar components from early metaphase to late anaphase. It was suggested that this disappearance of Golgi lamellae might represent temporary cessation of its normal function, and lysosomes derived from Golgi might also appear in unusual morphological features.
It was strongly suggested that lysosomes might play an important rôle in the course of mitosis of hepatocytes.

View full abstract

Mice neonatally grafted with glandular stomach were continuously given N-methyl-N'-nitro-N-nitrosoguanidine (NG) dissolved in drinking water (50mg/L) for 10 months. This dose of NG did not induce gastric carcinoma, but gave rise to leiomyosarcomas in the wall of the gastric cysts in the subcutaneous tissue, in 5 out of 26 mice. Atypical hyperplasia of epithelial cells in the cysts was also found in 2 mice. A strengthened and remote action of this carcinogen in gastric cysts was suggested.

View full abstract

The antitumor activity of and enhancement for cyclophosphamide by the following 27 compounds were studied against ascites sarcoma-180: Trifluoperazine, perphenazine, fluphenazine, trifluperidol, perazine, chlorprothixene, prothipendyl, methotrimeprazine, diphenylhydantoin, acetylpheneturide, haloperidol, biperiden, opipramol, promethazine, chlorpromazine, prochlorperazine, 4-amino-3-hydroxy-butyric acid, thiethylperazine, benactyzine, mephenesin, styramate, amitriptyline, promazine, diazepam, chlordiazepoxide, imipramine, and desmethylimipramine.
As a result, thiethylperazine was found to be the most active among them, both in antitumor and enhancing activities. Fluphenazine, perphenazine, trifluoperazine, and methotrimeprazine were moderately active against the tumor. Methotrimeprazine and desmethylimipramine had a potent enhancing activity.
The relationship between antitumor activity and chemical structure was examined. In general, phenothiazine ring was found to be suitable for antitumor activity. The antitumor activity of and enhancement for cyclophosphamide by phenothiazines were increased by substitution with CF₃, SC₂H₅, OCH₃, or Cl at 2-position and by the introduction of piperazine in the side chain at 10-position.

View full abstract

Carbazilquinone, 2, 5-bis(1-aziridinyl)-3-(2-carbamoyloxy-1-methoxyethyl)-6-methyl-1, 4-benzoquinone, was tested for antitumor activity against four transplantable mouse tumors, methylcholanthrene-induced tumor, and spontaneous tumor in mice. The compound produced almost complete inhibition of tumor growth in four transplantable tumors. The growth of methylcholanthrene-induced tumor in ICR mice and spontaneous tumor in C3H mice was also apparently inhibited.

View full abstract

It was found that the photoinduced radical production from 4-nitroquinoline 1-oxide in a frozen aqueous solution at 77°K was promoted by the presence of DNA. The mode of action was examined at the nucleoside level. The extent of the promotive effect of deoxyribonucleosides on the photoinduced radical production decreased in the order of deoxyguanosine>deoxyadenosine>deoxythymidine>deoxycytidine. The spin densities of the mixed systems of 4-nitroquinoline 1-oxide and deoxyribonucleosides were found to run parallel with the formation constants of the charge-transfer complexes which had previously been obtained. On the basis of these experimental results, it was presumed that the electronic state of the N-oxide compound might have been so altered as a result of acceptance of an electron from the DNA base that a radical would be formed under photoirradiation more easily than before.

View full abstract

The Δ⁴-hydrogenase activity for hydrocortisone, testosterone, and progesterone of liver microsomes was markedly increased in male rats bearing Walker carcinosarcoma-256. In contrast, it was slightly decreased in the tumor-bearing female rats. On the other hand, the steroid Δ⁴-hydrogenase of liver supernatant in the tumor-bearing male and female rats was not significantly altered. The administration of testosterone to the tumor-bearing male rats did not prevent the increase of Δ⁴-hydrogenase activity in liver microsomes. Since the steroid Δ⁴-hydrogenase activity in microsomes was suppressed by androgen, these results suggested that the increase of Δ⁴-hydrogenase activity in tumor-bearing rats may be related to the impairment of androgen-induced suppression of Δ⁴-hydrogenase.

View full abstract

An attempt was made to transform NLW cells, derived from the liver of a newborn Wistar rat, by means of aflatoxin B₁ in vitro. After 161 days' cultivation through twelve subcultures in Eagle's minimum essential medium supplemented with 10% calf serum, the cells were exposed to aflatoxin B₁ for 5 to 7 days at the concentrations ranging from 10 to 0.01ppm in the medium, and further cultivation was carried out in the maintenance medium. Delayed cytotoxic effect was observed for several weeks after the exposure; most remarkable at two weeks, then survived cells gradually presented morphological transformation in all the experimental groups. Growth of fibrosarcoma was recognized in Wistar rats transplanted with the cells cultured for more than 87 days after the exposure. These results indicate that aflatoxin B₁ is a relatively potent carcinogen in vitro and able to produce malignancy in vitro at a moderately wide range of concentrations.

View full abstract

To elucidate the cause of discrepancies of growth rate in size during the growing period of sarcoma-180, analysis of the proliferation kinetics was carried out using ³H-thymidine by autoradiographic technique. Duration of the cell cycle and its components in the initial period of the growth were approximately the same as those observed in the later period of the growth in any portion of the tumor. In the growth fraction, however, there was significant difference between peripheral and central portions, and the reduction in proportion of cells engaged in the cell cycle was more markedly observed in central portion than in periphery, in the later period of tumor growth. As a result, the slowing down of the growth rate would be explained by this reduction.

View full abstract

A triazinylstilbene derivative, tetrasodium 4, 4'-bis(2-o-hydroxyanilino-4-m-sulfanilino-1, 3, 5-triazinyl-2-amino)stilbene-2, 2'-disulfonate (TC-17), showed a marked inhibitory effect on tumor spread, especially on the pulmonary spread of Ehrlich ascites tumor cells, inoculated intravenously, and of MH-134 mouse ascites hepatoma cells, transplanted subcutaneously in the tail of mice. Combined use of TC-17 with Mitomycin-C or cyclophosphamide showed no additive effect.
TC-17 has no stimulatory effect on the host resistance mechanism. Slight suppression of the hemolysin production to sheep erythrocytes, no decrease of survival days of skin allografts in mice, and no change of phagocytic ability in reticuloendothelial system in rats were observed.
TC-17 showed marked inhibitory effects on neuraminidase, hyaluronidase activities, and fibrinogen-fibrin transition system in vitro, while neuraminidase levels in the liver and kidney of tumor-bearing mice receiving TC-17 were markedly elevated.

View full abstract

Two new transplantable cell lines of ascites tumors were established in rats. The original tumors were produced by the intraperitoneal back-transplantation of the epithelial cells, cultured from rat liver and transformed in culture with 4-nitroquinoline 1-oxide. These tumors were diagnosed as poorly differentiated hepatoma. Some characteristics of the tumors are described.

View full abstract

An antitumor polysaccharide derived chemically from pachyman was labeled with tritium, and its distribution was studied by radioautographic technique. Intense reactions were detected over the cells of reticuloendothelial systems such as macrophages in red pulp of the spleen and Kupffer cells in the liver.

View full abstract

Metabolism of 4-hydroxyaminoquinoline 1-oxide was studied in mice. Concentrations of 4-hydroxyaminoquinoline 1-oxide and its metabolites in the injection site, blood, lung, and liver were quantitatively analyzed according to the reverse-dilution method.

View full abstract

History of development of four lines of transplantable leukemia originating in Donryu rats by N-nitrosobutylurea, and their cytological, biological, and pathological characteristics observed in the rats which received intraperitoneal transplantation with these leukemia cells during the past one Year are described.

View full abstract

The structure-cytocidal activity relationship was tested with the carcinogenic 4-nitroquinoline 1-oxide and related compounds. There was a close association between cytocidal and carcinogenic activities, and a complete parallelism in cytocidal activity between the nitro compounds and their corresponding hydroxyamino derivatives.

View full abstract

This work presented an experimental model of regression of Friend leukemia induced in vaccinated mice by parabiotic union with Friend virus-infected mice. Well established immune system of vaccinated mice seemed strong enough to regress their own Friend leukemia.

View full abstract