The multiple combination therapy against solid tumors prevailing in Japan is presented and the meaning of its methodology is discussed. Some multiple combinations have shown excellent therapeutic effect in some cases of advanced cancer, so large and wide-spread that any single drug could not be effective, and prolonged the life span.

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Two human cell lines, THE-2 and THE-3, established from the foci of morphologically altered cells of embryonic culture exposed to human leukemic culture fluid in vitro were studied by means of electron microscopy and chromosome analysis. The herpes-type virus particles, morphologically identical with those known to exist in Burkitt lymphoma cell lines and in other cultured human leukemic cell lines, were demonstrated in both cell lines. Studies on metaphase cells of THE-2 and THE-3 revealed the presence of the C10 chromosome marker which also has been reported in Burkitt cultured cells. The implications of these findings were discussed.

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The gastric region of twenty-one 82- to 88-day-old CF₁ strain female mice in Group I was irradiated with 1, 500 rads of X-ray at 1-week intervals for a total of 6 exposures (total radiation dose, 9, 000 rads) and of twenty-four 59-day-old CF₁ strain mice of both sexes in Group II was irradiated with 2, 000 rads of X-ray at 1-week intervals for a total of 5 exposures (total radiation dose, 10, 000 rads).
In Group I, 17 of 21 mice survived for more than 16 weeks after the initial irradiation; mucosal atrophy of the glandular stomach was seen in 100% of the mice, ulceration in 88%, atypical hyperplasia or precancerous change in 35%, and gastric adenocarcinoma in 12%. In Group II, 18 of 24 mice survived for more than 14 weeks after the initial irradiation; mucosal atrophy of the glandular stomach was seen in 100% of the mice, ulceration in 78%, atypical hyperplasia or precancerous change in 44%, gastric adenocarcinoma in 28%, and squamous cell carcinoma in 6%. A total of 7 cases of gastric adenocarcinoma was observed, two of which had metastasis to the pancreas or mesentery.

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Early events of in vitro carcinogenesis with 4-nitroquinoline 1-oxide, particularly the effect of carcinogens on macromolecular synthesis and cell life cycle were investigated. 4-Nitroquinoline 1-oxide and its proximate carcinogen, 4-hydroxyaminoquinoline 1-oxide, were added at an effective concentration for cancerization on hamster embryonic cells, a target of the carcinogens. The results are as follows.
(1) 4-Nitroquinoline 1-oxide and 4-hydroxyaminoquinoline 1-oxide markedly inhibited DNA and RNA syntheses, while protein synthesis was inhibited by the former.
(2) Degradation of DNA was not observed when treated with these carcinogens.
(3) The cell life cycle was blocked markedly by 4-nitroquinoline 1-oxide, which blocks the flow of the cells into S period and M period. 4-Hydroxyaminoquinoline 1-oxide largely induced block of flow of the cells at S period into G2, and seemed to prolong the S period.
(4) Recovery from inhibitions induced by 4-hydroxyaminoquinoline 1-oxide took place within 48 hours after treatment.
(5) There was a striking contrast between the carcinogens and a noncarcinogenic derivative, 4-aminoquinoline 1-oxide, by which no interruption of the cell cycle and macromolecular synthesis was induced.

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The purified mannan prepared from baker's yeast (Saccharomyces cerevisiae) was examined for its antitumor activity against sarcoma-180 solid tumor. Four glucan preparations, one water-insoluble and three water-soluble fractions, were also examined for their activities against the same tumor. The pure mannan showed the strongest activity; its intraperitoneal administration in a dose of 150mg/kg/day for 10 days brought about a complete regression of sarcoma within 4 weeks after implantation. Among the four glucan preparations, the water-insoluble fraction showed 88.6% inhibition of tumor growth, whereas three water-soluble fractions gave less than 70% inhibition. These results indicate that not only the glucan but also the mannan behaved as tumor-growth inhibitors, though many workers who investigated the antitumor activities of the whole cells of yeasts or their water-insoluble polysaccharide components have focussed their attention only on the glucan.

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1) RNase and inhibitor of alkaline RNase were assayed on C-1498 leukemia cells of C57BL/6 mice, SN-36 leukemia cells of dds mice, and their liver and spleen.
2) RNase activities were determined in a range of pH 5.0-9.0. RNase activities of leukemia cells at pH 5.9 and 7.6 were very much lower than those of liver and spleen.
3) The titer of proteinous inhibitor of RNase in SN-36 leukemia cells was much higher than that in liver, spleen, or C-1498 leukemia cells.
4) Most of alkaline RNase was masked by an inhibitor in leukemia cells as well as in liver and spleen.
5) The liver of C57BL/6 mice bearing C-1498 leukemia showed a systemic effect, depressed RNase activity, and decreased titer of inhibitor. In the case of dds mice bearing SN-36 leukemia, systemic effect was observed only on titer of inhibitor.

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A hot-water extract of the yeast (Candida utilis) composed mostly of mannan was found, in serial studies on plant polysaccharides, to have the most striking antitumor activity against a subcutaneously implanted sarcoma-180 in mice by 10 daily intraperitoneal injections (100mg/kg/day) started 24hr after the tumor implantation. Approximately 7% of nitrogen found in the extract was characterized to be attributable mainly to RNA which was confirmed not to be essential for the antitumor activity of the extract, substantially separated from the effective sugar components by means of Cetavlon. The hydrolysate of the effective subfraction (Cetavlon-pH 10-precipitate) gave the following constituents: Approximately 70% of mannose, 10% of glucose, 2.5% of nitrogen, 1.0% of ash, and 0.3% of phosphorus. The specific rotation was determined as [α]²⁰_D+73° (c=1.0, H₂O). The nitrogen remaining in the subfraction was found to be attributable to some protein (possibly peptide moiety) which was thought to be bound to the sugar component(s).
The cell fractionation studies revealed that the final supernatant (105, 000g, 2hr) gave an equivalent hot-water extract to that of the whole cell in its chemical constituents and antitumor activity.

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Examinations have been made on the new absorption bands which appeared in the visible difference spectra of mixed systems of 4-nitroquinoline 1-oxide with DNA and with deoxyribonucleosides (deoxyadenosine, deoxyguanosine, deoxythymidine, and deoxycytidine). It was revealed that complexes of 1:1 stoichiometry were formed between each of the four deoxyribonucleosides and 4-nitroquinoline 1-oxide. A linear relationship was found between absorption maxima of the complexes and energy levels of the highest-occupied molecular orbitals of nucleobases, which was indicative that π-π type charge transfer was involved in the interaction. On the other hand, sigmoidy of the difference absorbance-pH profiles found in the mixed systems of deoxyribonucleosides, other than deoxythymidine, and 4-nitroquinoline 1-oxide indicated that n-π type charge tranfser was involved. From these results, it was presumed that complexes are formed by simultaneous participation of charge transfer of π-π and n-π types. The magnitudes of ε, K, and ΔH values were compatible with this presumption. It was observed that spectral changes exhibited at the monomer level were well reflected on the spectral change of the DNA-4-nitroquinoline 1-oxide system, and it was presumed that the carcinogen might be bound to DNA through the base moieties by the driving forces mentioned above. Reference has also been made to the behavior of non-carcinogenic 4-nitropyridine 1-oxide.

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Investigation has been made on the interaction of the carcinogenic 4-nitroquinoline 1-oxide with proteins, such as albumin and ribonuclease, and aromatic amino acids, such as L-tryptophan, L-histidine, L-tyrosine, and L-phenylalanine. Reference has also been made to the behavior of non-carcinogenic 4-nitropyridine 1-oxide in comparison with the quinoline compound. From the analysis of difference spectra of mixed systems, it was revealed that charge transfer complexes are formed between 4-nitroquinoline 1-oxide and each of the four aromatic amino acids. In the case of tyrosine, hydrogen bonding was also presumed to participate in the interaction. It was shown that charge transfer through the aromatic amino acid residues plays an important part in the interaction of the carcinogen with proteins. From the results of equilibrium dialysis experiments, it was revealed that 4-nitroquinoline 1-oxide is bound more firmly to protein than 4-nitropyridine 1-oxide.

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Wistar male rats were subjected to eight different treatments: (1) Unilateral nephrectomy followed by administration of N-nitrosodimethylamine (DMN); (2) unilateral nephrectomy without DMN treatment; (3) DMN administration followed by unilateral nephrectomy; (4) no DMN administration but later unilateral nephrectomy; (5) sham-operation followed by DMN administration; (6) sham operation without DMN treatment; (7) DMN administration followed by sham operation; (8) no DMN but later sham operation, Rats were given a diet containing 500ppm of DMN for 2 weeks. Animals were examined for kidney tumor 30 weeks after various treatments.
There was an increase in the incidence of kidney tumors when unilateral nephrectomy preceded treatment with DMN. However, unilateral nephrectomy had no effect after administration of DMN. The histological features of rat kidney tumors induced by DMN were not influenced by unilateral nephrectomy but tubular epitheliar proliferation and infiltration of undifferentiated cells into the interstitial areas in the groups subjected to unilateral nephrectomy were more significant than that in groups receiving a sham operation. A kidney tumor of one animal in group 1, subjected to unilateral nephrectomy followed by DMN treatment, was a hemangioendothelioma. The mechanism of the effect of unilateral nephrectomy on the incidence of tumor is still obscure.

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A mouse ascites tumor was intraperitoneally transplantable not only to mice of 11 different strains but to Wistar rats with high rate of lethal takes. The karyotype of the original tumor cells persisted unaltered throughout the heterologous transfer passages in rats.

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One to two mg of 7, 12-dimethylbenz[a]anthracene dissolved in olive oil was injected into the luminal space of the subcutaneous gastric cysts, which were created by neonatal grafting of the gastric mucosa of litter mates. Eight of 14 C57BL/6Ms and 14 of 18dd/I mice developed leiomyosarcomas originating from the cyst wall.

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Antibody titer against EB virus in sera of patients with various neoplastic diseases as well as some infectious diseases and normal controls was determined by immunofluorescence technique. The sera of nasopharyngeal cancer patients both of Taiwan and Japan exhibited extremely high anti-EB virus titer in majority of cases examined.

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Effect of insect-moulting hormones, ecdysterone and inokosterone, on tumor cells was examined, using Yoshida sarcoma and HeLa cells. Results obtained in this experiment, in which a sufficient dose of crystalline preparation was used, revealed that these insectmoulting hormones are ineffective on tumor cells.

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The report deals with the type-specific leukemia mortalities in Japan by 5-year age groups. It clarifies also for the first time that the leveling-off of mortalities in under 5 years of age and consistently low rate of increase in the young are the current trends of leukemia deaths.

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What is believed to be the first case of Burkitt tumor ever reported in Japan is described. Tumor developed on the left upper jaw of a girl aged 2yrs. and 8mo. Histology showed uniform proliferation of immature lymphocytes with "starry sky" appearance. Its cytomorphology was identical with that of African Burkitt tumor.

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Tumor cells inoculated subcutaneously at the inside of the right thigh metastasized to various lymph nodes. Chemotherapy was applied to the animals with marked lymph node metastasis and reduction in the size of lymph nodes was observed. A possible screening model for the chemotherapy of lymph node metastasis was presented.

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N-Nitrosodibutylamine is a potent carcinogen in mice, producing carcinomas of the forestomach, esophagus, and liver, and lung tumor in mice by oral administration.

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