A large amount of hydrogen peroxide was generated in a neutral buffer solution through which cigarette smoke was bubbled. Superoxide anion radical also appeared. The hydrogen peroxide may be formed by the autoxidation of polyphenols such as catechol and hydroquinone in the cigarette smoke.

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Transmission of adult T-cell leukemia virus (ATLV) was demonstrated from human lymphoid cell lines carrying ATLV to various non-lymphoid cells accompanied with syncytium formation, which was specifically inhibited by human anti-ATLV sera, indicating that ATLV has cell membrane fusion activity.

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The expression of adult T-cell leukemia virus (ATLV/HTLV) antigen was demonstrated by the indirect immunofluorescence method in phytohemagglutinin-cultured mononuclear cells of milk samples from 3 out of 22 sero-positive mothers after delivery. This result raises the possibility that milk might be the source of ATLV/HTLV infection of infants.

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A monoclonal antibody reactive with gastric carcinomas of the stomach was established. This antibody reacted with 88% (15/17) of the scirrhous carcinomas, and 75% (6/8) of the well differentiated adenocarcinomas of the stomach tested, but did not react with normal gastric mucosa or various other normal tissues, with the exception of the mucosa of the large intestine.

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When human milk was examined for the presence of transforming growth factor (TGF) activity, high levels of the activity were found in milk collected in the early days after delivery. Fractionation of an acid-ethanol extract of colostrum by Bio-Gel P-60 column chromatography revealed that the activity was found in two molecular weight ranges; over 45, 000 and from 10, 000 to 20, 000 daltons. The activity of the milk TGF did not compete with epidermal growth factor (EGF) for EGF receptor and was potentiated by the addition of EGF when assayed using normal rat kidney (NRK) cells.

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Quercetin markedly suppressed the promoting effect of teleocidin on skin tumor formation in mice initiated with 7, 12-dimethylbenz[a]anthracene. This activity of quercetin may have some bearing on the fact that quercetin is not carcinogenic despite showing mutagenicity.

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The threshold level or minimum carcinogenic dose of N-ethyl-N-nitrosourea (ENU) and the effect of dose on organ specificity were examined by continuous oral administration to both sexes of F344 rats of low doses of ENU at four concentrations (0.3, 1, 3 and 10ppm) in the drinking water. ENU at 10ppm selectively induced neurogenic tumors and tumors of the digestive tract, including duodenal tumors. Even at lower doses it enhanced the spontaneous development of some other tumors. A high dose of ENU (400ppm) was previously found to induce duodenal tumors selectively. These results indicate that the organ specificity of ENU is influenced by the dose and that ENU has multi-potent carcinogenic activity in many organs and/or tissues. In this study, some specific tumors, such as those of the nervous system and digestive tract, seemed to require a minimum carcinogenic level of ENU (10ppm) for their appearance. However, it seems that ENU is carcinogenic at much lower dose levels than 10ppm because ENU enhanced the spontaneous development of some other tumors in many experimental groups. The so-called virtually safe doses inducing these specific tumors at a risk level of 10^-6 were calculated.

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The times of origin of fibrosarcomas induced with 3-methylcholanthrene in mice were analyzed mathematically. Histograms of the rates of formation of original single tumor cells plotted against the time after carcinogen treatment fitted a two-step exponential decay function. This model was named a radioisotope-decay model by analogy with the multistep decay of radioisotopes. The half-lives of the initial and intermediate transient states were determined for three tumor groups, and were found to be 23-29 days for both states. The present study indicates the involvement of at least two steps in the establishment of tumors, even with a complete carcinogen.

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The concentrations of N-terminal peptide of type III procollagen in the sera of patients with various cancers were measured by radioimmunoassay. The mean value (with standard deviation) in the control group was 9.9±2.6ng/ml. Serum levels exceeding 15ng/ml were defined as positive, and it was found that 94% of 18 patients with primary liver cancer with cirrhosis, 88% of 8 patients with primary liver cancer without cirrhosis, 77% of 13 patients with metastatic liver cancer, 86% of 7 patients with recurrent breast cancer, 86% of 8 patients with colonic cancer, 75% of 8 patients with pancreatic cancer, 70% of 23 patients with stomach cancer, 51% of 35 patients with lung cancer, and 54% of 28 patients with uterine cancer showed positive levels. The concentrations showed great intersubject variations, probably reflecting the activity of tumor growth and/or invasion. The concentrations in the sera of patients with primary liver cancer with cirrhosis were generally higher than those in patients with liver cirrhosis alone or primary liver cancer without cirrhosis. This result suggested that the growth of primary liver cancer complicated by cirrhosis might be detected by serial measurements of this peptide in the serum of patients with liver cirrhosis. Present data suggested that this peptide is not cancer-specific, but assay of the peptide might be of value as an auxiliary means of detecting and monitoring various cancers, especially liver cancer.

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The activation of DNA synthesis induced by growth factor from the cytosol of AH-130 tumor cells (AH-130GF) was inhibited by alkylamines (methylamine, ethylamine, and dansylcadaverine), which inhibit the intracellular processing of hormone-receptor complexes. Calmodulin inhibitors (trifluoperazine and W-7) also inhibited the mitogenic action of AH-130GF, suggesting that the Ca-calmodulin system and proteolytic processing in lysosomes are necessary for stimulation of DNA synthesis by AH-130GF after its binding to the cell surface. Membrane phosphorylation induced by AH-130GF or epidermal growth factor (EGF) was investigated by using rat liver plasma membranes and 3T3 cell membranes in vitro. EGF increased the phosphorylation of two protein components with molecular weights of 160K and 130K in rat plasma membranes, but AH-130GF increased the phosphorylation of only the 130K protein. No specific phosphorylation induced by AH-130GF was detected in 3T3 cell membranes, but EGF induced phosphorylation of the 160K receptor protein.

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The cytotoxic effect of pepleomycin (PEP), a derivative of bleomycin (BLM), was investigated and compared with that of BLM on cultured Chinese hamster V79 cells. The concentration-response curve of PEP was biphasic, like that of BLM: the D₀ values of the first and second slopes for PEP were 32μg/ml and 140μg/ml, while those of BLM were 60μg/ml and 140μg/ml, respectively. The ratios of D₀ for BLM to that for PEP were 1.88 for the first slope and 1.0 for the second one, suggesting that PEP is more cytotoxic than BLM on a unit concentration basis. The time-response curve for PEP showed that the surviving fraction dropped immediately, then rose gradually and finally declined slowly. Analysis of these curves together with the results of further experiments suggested the induction of two types of lethal damage by PEP; potentially lethal damage and non-reparable lethal damage. Potentially lethal damage was induced by PEP treatment, developed within a few minutes, was fixed as lethal damage by trypsinization and was repaired fully within 1hr if trypsinization was not applied. Non-reparable lethal damage was another type of damage induced by PEP and led to cell death without repair. The two types of lethal damage can account for not only the various shapes of survival curves, but also the differences in cytotoxicity of PEP and BLM.

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A chemically defined medium containing selenium was further improved, and the improved medium showed excellent ability to support growth and colony formation of a human hepatoma cell line, HuH-7. The improved defined medium (designated as IS-RPMI) contained small amounts of unsaturated fatty acids, inorganic trace elements including selenium, and HEPES buffer. Many of these additions exert only a small individual effect on the growth of cells, but their cumulative effects were substantial. HuH-7 cells replicated continuously with a doubling time of 47-51hr in IS-RPMI. A conditioned medium from a semiconfluent population increased the colony-forming ability of HuH-7 cells in IS-RPMI. The addition of insulin to the medium gave good colony growth, thus duplicating the effect of the conditioned medium. Although some alterations of morphological and growth characteristics of HuH-7 cells were observed, the differentiated liver functions, as revealed by production of plasma proteins including high levels of α₁-fetoprotein, were maintained for a period of more than 3 years and through 70 passages under the above culture conditions.

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A day-old testis was transplanted into the spleen of one-month-old castrated ACI male rats. For the first six months, diffuse hyperplasia of the interstitial cells was conspicuous with progressive deletion of spermatogenic cells in the seminiferous tubules. Then multiple foci of hyperplastic nodules started to appear, mainly near the tunica albuginea, in all castrated rats, but never in noncastrated rats. These nodular tissues gradually fused together (so-called Leydig cell tumors) and at about 12 months, other distinct tumor foci, morphologically indistinguishable from ovarian granulosa cell tumors, developed in and replaced the nodular tissues. The specific binding of follicle stimulating hormone to the “granulosa” cell tumor tissues was demonstrated. The hypothesis is presented that Sertoli cells were involved in the hyperplastic nodules and ultimately gave rise to the “granulosa” cell tumors.

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The occurrence of secretory component (SC), IgA, IgG and IgM within tumor cells was immunohistochemically examined in a total of 101 gastric carcinomas comprising 50 early cancers and 51 advanced cancers. In advanced cancers, the frequency of SC was significantly higher in well-differentiated adenocarcinoma than in poorly differentiated adenocarcinoma. The frequency of IgA did not differ with stage of cancer, but the frequencies of IgG and IgM were significantly higher in advanced cancer than in early cancer. The immunoglobulin-producing plasma cells in the stroma of advanced cancer were chiefly IgG, followed by IgA and IgM producers. The intensity of IgA plasma cell infiltration correlated with presence of IgA in tumor cells. No correlation was noted between serum immunoglobulin value and immunoglobulin in tumor cells. The survival rate indicated a tendency for IgG-containing advanced cancers which were infiltrated with many IgG plasma cells to have a better prognosis.

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Culture fluids of concanavalin A-stimulated rat spleen cells were purified by means of ammonium sulfate precipitation and Sephacryl S-200 column chromatography. Interleukin 2 (IL-2), which can promote the proliferation of mouse lymphocytes was distributed in the fractions of molecular weight of 22, 000 to 26, 000 daltons. Culture of C57BL/6 mouse spleen cells with the IL-2 fraction resulted in the induction of cells cytotoxic to syngeneic fibrosarcoma cells. Determination of the target specificity of the killer cells revealed that the killer cells could lyse a variety of syngeneic and allogeneic tumor cells in vitro. The results of cold target inhibition tests and cytotoxicity assay after treatment with antisera plus complement indicated that the killer cells mainly consisted of Thy 1.2⁺, Ly 2.2⁺, asialoGM₁^- T cells but included some asialoM₁^- natural killer (NK) cells. Although the cytotoxicities of both IL-2-activated killer T cells and NK cells were nonspecific in terms of the antigen specificity, their cytotoxic activities against syngeneic fibrosarcomas and NK-sensitive allogeneic lymphomas were complementary. The assay of interferon in culture fluid from IL-2-treated spleen cells suggested that generation of IL-2-activated killer cells was closely associated with the amount of immune interferon released from lymphocytes in the culture.

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By priming with Bacillus Calmette-Guérin (BCG) and subsequent immunization with L1210 leukemia cells to which purified protein derivative of tuberculin (PPD) had been coupled, a resistance to L1210 leukemia but not to syngeneic P388 leukemia was induced in DBA/2 and CDF1 mice. Separate injections of mitomycin C-treated L1210 cells and PPD also induced the resistance, but it was established only when they were administered simultaneously. PPD-coupled cells seemed to play a more important role than BCG, since the immunoprophylaxis was observed when L1210 challenge was made at the sites of PPD-L1210 immunization, but was not observed when L1210 challenge was made at the sites of BCG priming.

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Tumor metastasis was examined after iv inoculation of highly metastatic variants of mouse tumors. Highly metastatic variants, B16-F10 and B16-BL6, of B16 melanoma origin and colon 26 NL-17 of colon adenocarcinoma 26 origin were used in the experiments. Formation of pulmonary metastasis was influenced by the mouse strain and age. Based on the results, experimental metastasis systems of these tumors were established, and the effects of chemotherapeutic agents were examined. 5-Fluorouracil and adriamycin were significantly effective for the suppression of pulmonary metastasis. The degrees of suppression of metastasis by these drugs were different with different tumor variants, but the sensitivity of the metastasis to the drug was similar to that of the parent tumor. Several aspects of the chemotherapy of metastasis are discussed.

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