The electronic structure of 4-nitroquinoline N-oxide and related compounds were investigated. The frontier electron density and the approximate superdelocalizability for nucleophilic reaction at the carbon atom to which nitro group is attached had a definite correlation with the carcinogenic activity. This is a support for our proposition that the interaction with the nucleophilic center in the body might be primarily concerned with the production of cancer by all types of chemical carcinogens.

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Summation effect of two chemically unrelated carcinogens was investigated, using 4-nitroquinoline N-oxide and 20-methylcholanthrene. Doses of each of these two carcinogens that can be applied to the mouse skin without producing tumors (submanifestational doses) were first worked out, and then, in the main experiments, submanifestational dose of either one was given followed by that of the other and the rate of tumor production observed.
The results established that the submanifestational carcinogenic process started by 20-methylcholanthrene can be quantitatively brought to manifestation (tumor production) by 4-nitroquinoline N-oxide, and vice versa, showing that the effects of these two carcinogens, in spite of the striking chemical difference, are capable of summation, and suggesting that the immediate carcinogenic mechanism may be qualitatively identical for the two. It was also demonstrated that the submanifestational effect produced by the first treatment with either carcinogen persisted without any recognizable loss for at least 200 days, and was capable of summation with the effect of the second treatment, just as quantitatively as when the second treatment immediately followed the first.
These results definitely support the postulate that cancerization results from the summation of a multiple of alterations in the self-replicating cell subunits (duplicants), each alteration being irreversible, and add an important fact that the alterations caused by a carcinogen of one type can summate with those that are due to another of different kind.

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4-Nitroquinoline N-oxide was painted only once on the skin of 213 dd strain mice at four different concentrations in acetone, and the subsequent development of skin lesions followed for 200 days. Fifteen papillomas were induced, of which nine disappeared spontaneously and four persisted, and two of these latter eventually became squamous cell carcinoma.
The known prompt chemical reaction of this carcinogen in biological milieu and the non-carcinogenicity of the entire reaction products suggest that even a single hit of the force of a chemical reaction is at least at times capable of inducing all the intrinsic alterations in the cell that are necessary for cancer production.

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1. A comparative autoradiographic and electronmicroscopic study was performed on the fibrosarcoma and benign granulation tissue induced by subcutaneous injection of 20-methylcholanthrene to mice.
2. Although a definite parallelism was noticed between the proliferative activity and S-³⁵sulphate fixation in the benign fibroblastic tissue, this appeared not true in conjunction with the malignant tissue.
3. The abundance of immature collagen fibrils in the granulation tissue was assumed to be consistent with the active synthesis of sulphomucopolysaccharide as revealed in the autoradiographs.
4. Electronmicroscopy revealed no direct evidence of sulphomucopolysaccharide production in the tissue.

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1) Rats were fed on DAB-coated rice for about one month. DPNH dehydrogenation activities of the liver were determined in the presence of several electron acceptors.
2) DPNH-cytochrome C reductase in the liver of rats fed DAB was lower than normal.
3) TPNH-cytochrome C reductase was about one-tenth of that of DPNH-cytochrome C reductase, and was definitely reduced by DAB feeding.
4) Diaphorase activity was about fifteen times higher than DPNH-cytochrome C reductase in normal rat liver and not reduced by DAB feeding.
5) Lipoflavoprotein activity in the liver of rats fed DAB was slightly lower than normal.
6) The in vitro addition of FAD did not restore the reduced activities of cytochrome reductases or lipoflavoprotein.

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The behaviors of ⁶⁵Zn- and ²⁰³Hg-hematoporphyrins injected into Ehrlich ascites tumor-bearing mice were studied in comparison with that of the ⁶⁵Zn-glycine complex and the following results were obtained.
1. In both cases of the subcutaneous and intraperitoneal injections of ⁶⁵Zn-hematoporphyrin, the high radioactvity was found in the ascites plasma on the first day after the injections and then disappeared at fairly high rate with the lapse of days. A low or no radioactivity recovered in the ascites tumor cells did not so much vary in the course of days.
2. In both cases of the subcutaneous and intraperitoneal injections of ²⁰³Hg-hematoporphyrin, the high radioactivity was found in the tumor cells on the first day and then rapidly reduced to nearly zero on the third day after the injections. The ascites plasma and the liver contained no radioactivity during the period from the first to sixth days.
3. These behaviors can be understood from the point of view that the uptake of metal (zinc or mercury) by the tumor cells may be controlled by the natute of the chemical bond between the metal atom and its ligands in the complex compound.

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Using two strains of the ascites hepatoma, AH 13 and AH 7974, which are of epithelial nature, resistant sublines to methyl-bis-(β-chlorethyl)-amine N-oxide were established by passing tumor cells through animals treated with the agent. There was no significant difference in ascitic findings and histological features of tumor tissues between the original strain and resistant subline of AH 13 which is composed of single free tumor cells. However, in AH 7974 in which tumor ascites is composed of cell aggregates and single isolated tumor cells, a significant difference was observed in both ascitic findings and histological features between the original strain and resistant subline. These differences were attributed to changes in motility and mutual adhesiveness of tumor cells.

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The action of RC4 on the glycolysis, respiration, hexokinase and phosphatase of the Ehrlich ascites tumor cells and on ChE of human blood has been examined in comparison with the actions of o-RC4, TEPA and NMO.
It was observed that, while NMO and o-RC4 displayed strong inhibitorya ctivity against glycolysis and stimulating activity for alkaline phosphatase immediately after dissolution, RC4 or TEPA were scarcely active on such condition, and, they acquired equal activity to the former two, only after their aqueous solutions were preserved at 2°C.
It might be expected that the clarification of the characteristics of the latter agents will help elucidate those of alkylating agents containing ethyleneimino rings.

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