The antitumor activities of 4, 5-bis(ethyleneimino)-1, 2-benzoquinone (OBE), 2, 5-bis(ethyleneimino)-1, 4-benzoquinone (PBE), and 4-ethyleneimino-1, 2-naphthoquinone (NQE) were investigated in Ehrlich carcinoma. OBE was effective not only in prolonging the life-span of mice bearing Ehrlich ascites carcinoma but also in retarding the growth of the solid form of the same tumor. This compound was proved to be effective even in a smaller dose than the minimum effective dose of PBE, with lower toxicity than the latter. With NQE, the mice bearing the same ascites tumor did not survive longer than the control.
Ratio of the number of neutrophils to lymphocytes (N/L) in the peripheral blood was compared with the non-treated and the treated groups of animal bearing the tumor. Generally speaking, the more progressed the growth of the ascites tumor was, the greater the value of N/L, but such increase of N/L was eventually observed in case of leucopenia induced by these agents. It may therefore be said that the observation of change of N/L should be considered as an element for evaluation of the result of screening experiment.

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With the aid of vital staining with Trypan Blue, acini and hyperplastic alveolar nodules present in the same mammary gland of female C3H/HeMs and (A/Jax× AKR) F₁ hybrid mice carrying the mammary tumor agent were removed and submitted to electron microscopic studies. Both types of tissues always showed the presence of virus-like particles which in ultrastructure and in mode of proliferation were identical with those frequently found in mammary tumors. Normal mammary gland tissue at different stages of development could not be consistently distinguished from the hyperplastic nodules on the basis of presence of virus-like particles.
In addition, mammary tumors and lactating mammary glands were examined under the electron microscope. The ultrastructure of the four types of tissues, acini, hyperplastic alveolar nodules, lactating glands, and mammary tumors, were compared. It was impossible to demonstrate at the submicroscopic level any characteristic component or feature in any of these tissues. Alterations such as disorganization, disapearance, distortion, and disruption of many types of organelles in cells of normal, precancerous, and cancerous tissues may be only quantitative rather than qualitative.

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Results of the quantum biological study of an interaction of potent carcinogens such as 4-nitroquinoline 1-oxides and aromatic hydrocarbons with tissue components, especially with deoxyribonucleic acid (DNA), are presented and chemical carcinogenesis is discussed in connection with charge transfer phenomenon. An equation is derived to obtain the charge transfer quantity between two constituent molecules in the charge transfer complex, and distinct parallelism is found between the quantity of charge transfer and carcinogenic activity. From this result, it is suggested that the quantity of charge transfer is more important in the genesis of tumor than the charge transfer force. Summation of an alteration of base paring in Watson-Crick stereo-model of DNA resulting from the charge transfer between DNA and the carcinogens is deemed to be the cause of tumor.

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Cancers of the lung were induced by the repeated subcutaneous injections of 4-nitroquinoline 1-oxide in three groups of rats receiving a total amount of 15, 11, and 7.25mg, respectively. The lung cancer was found in 16 (37.2%) out of 43 effective rats that survived more than 223 days. These cancers were usually adenocarcinomas (30.2%), but there were also some epidermoid carcinomas (7.0%). Both adenocarcinoma and epidermoid carcinoma gave rise to metastases in distant organs. Almost all the rats had multicentric pulmonary adenomas. Various degrees of hyperplasia and metaplasia of bronchial epithelia or alveoli were also observed. Subcutaneous sarcomas often arose in the area of application of the carcinogen. A transplantable strain of the epidermoid carcinoma was separated successfully.

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Five of eight inbred Swiss mice given repeated injections of a small amount of benzene in olive oil developed subcutaneous sarcomas. One of the three tumors transplanted grew and is now maintained as transplants. Morphology of these tumors and histological changes in other organs are described. The present results indicate that benzene is capable of inducing solid malignant tumors in mice. No leukemia or lymphoma was observed among these experimental mice.

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The activity of glucose-6-phosphate dehydrogenase was determined by a histochemical procedure on 180 cases of human tumors. In squamous cell cancer, enzymatic activity was confined to the neoplastic epithelium and usually varied. Enzymatic intensity surrounding the keratinized portion was generally higher than that of the peripheral layer of neoplastic foci. Adenocarcinoma in the gastrointestinal tract, pancreas, breast, ovary, and uterus corpus exhibited a varying degree of activity of glucose-6-phosphate dehyrogenase in malignant epithelia. Metastatic cancer in the lymph node and ovary (Krukenberg) generally showed a higher enzymatic activity than primary malignant epithelium. Tumor cells of adrenocortical adenoma were most intensely reactive for glucose-6-phosphate dehydrogenase.

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From the fact that 4-hydroxyaminoquinoline 1-oxide (4-HAQO) as well as 4-nitroquinoline 1-oxide (4-NQO) have λ-phage inducing ability in lysogenic Escherichia coli K12 and from the studies of Okabayashi, showing that not only 4-NQO but also 4-HAQO are mutagenic and able to produce the phenotypically same mutants in Aspergillus niger, similarity between these two substances in their biological actions was examined on (1) carcinogenicity, (2) growth-inhibiting action, and (3) intranuclear inclusion-forming action.
1) 4-HAQO•HCl in peanut oil and cholesterol mixture was injected into the subcutaneous tissue of rats. Subcutaneous tumors were induced in 8 of the 15 effective rats (53%) in the first group and in 16 of 17 rats (94%) in the second group.
2) Three groups, consisting of 10 mice each, were inoculated with Ehrlich ascites tumor cells intraperitoneally. Twenty-four hours after the inoculation, the first group was treated daily with 0.5mg/kg body weight of 4-HAQO•HCl dissolved in physiological saline containing 0.4% carboxymethylcellulose, the second group with 7mg of 4-NQO, and the third with solvent alone. The treatment was continued for 10 days. All the mice of the first group and all but 2 mice of the second survived over 50 days, whereas the third (control) group survived only 15 days.
3) When the Chang's liver cells were incubated for 24 hours at 37° in a culture media containing 4-HAQO•HCl in the final concentration of 7×10^-5M, intranuclear inclusions phenotypically identical with those induced by 4-NQO were produced in about 60% of all the cells.
These results were discussed in relation to the carcinogenic mechanism of 4-NQO.

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Following previous experiments on the dye-protein binding in in vitro system, the dye-protein binding in in vivo systems is reported, in which 4-dimethylaminoazobenzene amine-N-oxide was administered intragastrically or intramuscularly to rats, mice, and guinea pigs. The binding took place at the site of injection as well as in the liver in the case of intramuscular administration. Amount of the protein-bound dye increased with the dose. LD₅₀ values of 4-dimethylaminoazobenzene amine-N-oxide were compared with that of 4-dimethylaminoazobenzene, using rats and mice, both by intragastric and intraperitoneal administration. The highest toxicity was observed in the intraperitoneal injection of 4-dimethylaminoazobenzene amine-N-oxide. The toxicity decreased to 1/5 (mice) and to 1/15 (rats) in the case of intragastric injection. Addition of 4-dimethylaminoazobenzene amine-N-oxide in the drinking water (0.03%) to rats and mice caused malignant hepatomas in rats, but only adenomatous growth in mouse liver.

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A systemic experiment to induce malignant tumors in mice with N-nitrosodimethylamine is reported for the first time.
Twenty-seven ddN mice were fed a diet containing N-nitrosodimethylamine in a concentration of 50p.p.m., After 5 months of feeding, adenocarcinomas of the lung in 4 cases, multiple adenomas of the lung in 21 cases, an anaplastic carcinoma of the kidney, malignant hemangioendotheliomas of the liver in 2 cases, and a hemangioendothelioma of the spleen were observed.

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Yoshida sarcoma cell acquired resistance to methyl-bis(2-chloroethyl)amine hydrochloride by a mere contact in vitro with a very dilute solution of this agent at 37° only for 30 minutes.
Resistance index was rapidly increased by repetition of contact with increasing concentration of the contact agent, and, in one case, a tumor line acquired resistance as high as 25, 000-fold of the original after 22 contacts.
Such a high resistance could never be induced or assayed for its grade by the usual animal experiment.
The resistance was slso induced by contact in vitro with Mitomycin C.

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Unusual structures which suggested viral etiology of human leukemia were revealed by electron microscopy in bone marrow leukemic cells of a patient with chloroleukemia. These structures were as follows:
1) Intranuclear inclusion bodies essentially composed of relatively electron-dense fine granules and demarcated from the surrounding nucleoplasm by a clear zone.
2) Intracytoplasmic virus-like particles, 100mμ in diameter, composed of an electrondense, ring-shaped double membrane, 100Å in thickness.

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Repeated subcutaneous injections of 4-hydroxyaminoquinoline 1-oxide produced tumors with a high incidence in mice and rats.
During the observation period of 8 or 9 months, tumors were found in about 70% of the mice which received 10 or 15 subcutaneous injections (0.05 or 0.1mg per time) of the chemical into the same site. Besides sarcomas in the majority, tumors of epithelial origin occurred in several of the mice.
Five of ten rats which received 3 subcutaneous injections (1mg per time) at the same site developed sarcomas within 8 months.
Negative results of carcinogenic experiments employing other related derivatives are briefly described.

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The stainability with Eosin has often been used as an indicator of certain types of cell injury. However, the previous technique was time-consuming and gave results of low reproducibility. In order to overcome these disadvantages, a colorimetric method which gave reproducible results for estimating Eosin uptake by cells was established.

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Biological and pathological features of a new transplantable strain of ascites leukemia established in ddOM mice were briefly described. The original tumor cells were obtained from a spontaneous same lymphatic leukemia in a mouse of the strain.

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Out of rat ascites tumors, Yoshida sarcoma and hepatomas, a few strains kill the host animals much earlier than expected from the pathological findings. It may suggest that these tumors excrete some toxic principles, but no parallelism was found between their catalase- and cholinesterase-inhibiting effect and length of life-span of animals bearing these tumors.

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