Spread of tumor cells in linitis plastica type of gastric carcinoma was studied in relation to features of tumor cell aggregation which were classified into two types; free-cell type and small nest type. Free-cell type was accompanied by a larger amount of fibrous stroma in submucosal layers than in small nest type. In the gastric wall lymphatics and regional lymph nodes, small nest type was more prominent than the free-cell type. Lymphatic permeation was noted predominantly in the submucosa. In the mucosa, both free-cell and small nest types were frequently present. In carcinoma with free-cell type predominance, diffuse infiltration with infrequent lymphogenous spread was noted, while in carcinoma with small nest type predominance, spread via the lymphogenous route was observed more frequently. The mode of cancer spread in this type of carcinoma appeared to be affected by the type of tumor cell aggregation dominant in the mucosa.

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Pyridine N-oxides having 1-(2-chloroethyl)-1-nitrosoureidoalkyl or 1-methyl-1-nitrosoureidoalkyl groups were evaluated for their antitumor activity against AH13 hepatoma and L1210 leukemia. Among them, 1-(2-chloroethyl)-1-nitroso-3-(2-pyridylmethyl)urea N-oxide (1), its tosylate (2), 1-(2-chloroethyl)-1-nitroso-3-(2-pyridylethyl)urea N-oxide (4), and 1-(2-chloroethyl)-1-nitroso-3-(3-pyridylmethyl)urea N-oxide (6) were highly active against both tumors in ip-ip system. These compounds were also active in ip-iv and ip-po systems of L1210. On the other hand, pyridine N-oxides having 1-methyl-1-nitrosoureidoalkyl group were all inactive against AH13 and weakly active against L1210.
Effect on blood cells in Donryu rats bearing EDEN-5 erythroblastic leukemia cells was tested with these 1-(2-chloroethyl)-1-nitrosoureidoalkylureas. These compounds caused leucopenia and compound (4) was only slightly effective against EDEN-5.

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The antitumor activity of the cell-wall skeleton (CWS) of Propionibacterium acnes C7 was examined by using transplantable tumors in syngeneic mice and in guinea pigs, and autochthonous tumors in mice. P. acnes-CWS was shown to suppress the growth of fibrosarcomas, EL4 leukemia, and MH134 hepatoma in syngeneic mice, and to regress the established tumors of a fibrosarcoma (MC104) in C57BL/6J mice, and a hepatoma (line-10) in strain-2 guinea pigs. The oil-attached P. acnes-CWS mixed with fructose mycolate was effective for suppression of the autograft of fibrosarcoma in mice. The repeated intralesional injections of suspension of P. acnes-CWS in phosphate-buffered saline was effective for prolongation of survival period of mice bearing 3-methylcholanthreneinduced fibrosarcoma. The test results on the cell fractions of P. acnes indicated that the CWS, but not the cytoplasmic or glucan fraction, of P. acnes had antitumor activity. The activation of peritoneal macrophages of mice was observed when P. acnes-CWS, but not the cytoplasmic fraction, was injected intraperitoneally 4 days before. The relationship between the cytolytic activity of peritoneal macrophages and antitumor activities of P. acnes-CWS was also discussed.

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Benz[c]acridine and its 10 methyl-substituted derivatives were examined for chemical reactivity with osmium tetroxide and mutagenic activity on Salmonella typhimurium, and the results were contrasted with the electronic charge in the K region and the carcinogenic activity of benz[c]acridines. The addition of osmium tetroxide took place at the K region of benz[c]acridines. A linear relationship was established between the charge in the K region and the rate constant of the second-order reaction between osmium tetroxide and benz[c]acridines except the 5, 7-dimethyl derivative whose substituent in the 5-position sterically hindered the reaction. Benz[c]acridines showed mutagenic activity in the presence of S-9 Mix, but not in the absence of S-9 Mix. There was a corresponding relationship among the K-region reactivity, mutagenic activity, and carcinogenic activity in benz[c]acridines. The only exception for this was the 7, 11-dimethyl derivative in which the 11-methyl group had a steric effect on the ring-nitrogen atom. It was suggested that a common mechanism with regard to the reactivity of the K region is working in both carcinogenesis and mutagenesis. It was concluded that benz[c]acridines are activated, before they display a carcinogenic or mutagenic activity, to a proximate form such as 5, 6-epoxides, through a metabolic process in which the nucleophilic property of the K region to react with electrophilic reagents plays an important role.

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Splenic lymphocytes obtained from female ICR/JCL mice, which had received combined radiation and chemical treatment for induction of skin tumors on their back skin, were tested for their ability to undergo proliferative response to nonspecific mitogens as well as to allogeneic lymphocytes in vitro during 18 months after carcinogenic treatment. The treated mice, 168 in all, were divided into three groups: (a) 53 mice with no tumor, (b) 30 mice with skin papilloma, and (c) 85 mice with malignant skin tumor. Control mice, 39 in all, received no treatment. The local carcinogenic treatments used in this study induced a relatively long-lasting suppression of T-cell activities as detected by proliferative response to mitogens. Nevertheless, there was no significant difference in T-cell activities among the three groups of mice that developed (a) no tumor, (b) skin papilloma, or (c) malignant skin tumor. The results obtained with proliferative response to allogeneic lymphocytes were essentially similar. A preliminary study on the induction of cytotoxic T cells from splenic lymphocytes against allogeneic target cells in vitro also indicated that mice which developed tumors were not necessarily the ones which manifested reduced cytotoxic T-cell activity. These results suggest that reduced T-cell function was not a direct cause or not even a prerequisite for development of skin tumors in ICR mice.

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Three lines of rat leukemia, DBLA-1, -6, and -9, were studied serologically by complement-dependent cytotoxicity test. DBLA-1, -6, and -9 were killed by anti-lymphocyte sera, anti-Thy-1.1 sera, and rabbit anti-rat brain sera absorbed with AKR/J brain. However, anti-T and anti-B lymphocyte sera had no cytotoxic effect on DBLA-1, -6, and -9. Furthermore, DBLA-6 and -9 did not absorb the cytotoxic activity of anti-T serum on thymocytes, while DBLA-1 slightly absorbed the cytotoxic activity. These results indicate that DBLA-1, -6, and -9 are of lymphoid origin and possess rat Thy-1 antigens, but lack mature T-lymphocyte antigens. On the other hand, peroxidase-positive myelogenous leukemia L1005 failed to react with any of the antisera used.

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A cytotoxic antibody for L1210 leukemia cells was found in the (C57BL/6 × DBA/2) F₁ (BDF₁) mice immunized with L1210 leukemia cells infected with is mutant of HVJ (HVJ-pi) and challenged several times with uninfected L1210 leukemia cells. These immune mice fell into two categories; high and low responders regarding the titer of cytotoxic antibody produced. The antigen defined by this cytotoxic antibody was present on leukemia cells originating in DBA/2 mice but not on leukemia induced by passage-A Gross virus or spontaneous mammary tumors. This serological cross-reactivity among L1210, P388, and L5178Y leukemia cells has been substantially confirmed by the observation of cross protection against challenge with DBA/2 leukemia cells in immune BDF₁ mice. These findings strongly suggested the presence of a common DBA/2 leukemia-associated antigen different from known cell-surface antigens of murine leukemia. The results obtained in the present work also demonstrated the great efficacy of non-cytopathic, viable HVJ-pi-infected tumor cells as an immunogen for inducing tumor immunity.

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Three groups, each consisting of 36 male ACI/N rats, were fed a diet containing 10, 1, or 0.1ppm sterigmatocystin for life span. There was no dose-effect relationship on tumor incidence or mean survival time. Toxic and preneoplastic changes of the parenchyma such as hyperplastic foci were observed in the liver of experimental groups with dose-effect relation, but hepatocellular carcinoma was observed only in one rat of 10ppm group. In addition to these lesions, hemangiosarcomas of the liver were also observed in the highest and middle-dose groups, 3/26 and 1/29, respectively. There was no significant difference in the incidence of other tumors in experimental or control groups.

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A thermodifferential chemotherapy, consisting of systemic administration of antitumor drug and local hyperthermia combined with general hypothermia, was examined and gave satisfactory antitumor results. In search of basic optimal conditions required, this therapeutic system was tested on Ehrlich tumor implanted in the hind limbs of mice. The results obtained were as follows: (a) From the viewpoint of either the antitumor effect or the adverse effect of the therapy, local hyperthermia at 41° for 60min combined with general hypothermia at 20∼24° was found to be the best thermodifferential condition. (b) The thermodifferential treatment alone without drug administration displayed little antitumor effect. (c) General hypothermia applied not only enhanced the antitumor effect of the drug in loco but also reduced general toxicity of the drug. In the present therapy, carboquone displayed the best antitumor effect among the drugs tested. This suggests that the potentiation of tumoricidal activity of carboquone under the acidic condition produced by cancer cell metabolism in hyperthermia was deeply involved in the effectiveness of this therapy.

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Human leukemic B-cell (BALL-1), T-cell (TALL-1), and null-cell (NALL-1) lines were established from three patients with acute lymphoblastic leukemia (ALL). Intraperitoneal transplantation of these ALL cell lines into immunosuppressed newborn hamsters resulted in the development of invasive tumors in all recipients, except 4 of 10 implanted with NALL-1 line. BALL-1 and TALL-1 lines were serially transplanted for 10 and 9 passages, respectively.
In addition to a common in vivo feature of mesenteric and retroperitoneal tumors, BALL-1 line was characterized by infiltration of the skin, massive ascites, and bone marrow invasion. TALL-1 cells infiltrated various organs including the lymph nodes, liver, bone marrow, central nervous system, eyes, etc. NALL-1 line grew slowly, producing the least number of tumors. Leukemic cells were detected in the blood of 24 of 25 hamsters bearing BALL-1 and in the blood of 18 of 24 hamsters bearing TALL-1. Thus, these three ALL cell lines were found to exhibit a characteristic biological behavior in hamsters.

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Carcinogenicity and mutagenicity of 4-nitropyridine 1-oxide (4-NPO) and 7 kinds of its alkyl derivatives were tested on mice and on Salmonella typhimurium strains and Escherichia coli strains. 3-Methyl-4-NPO is the most potent carcinogen, followed by 3-ethyl-4-NPO and then 4-NPO. Mutagenicity was most potent in 3-methyl, 2, 3-dimethyl, and 2, 5-dimethyl derivatives, moderate in 4-NPO and 2-methyl and 2, 6-dimethyl derivatives, and to a least extent in 3, 5-dimethyl-4-NPO. Structure-mutagenicity relationship was discussed on the basis of molecular mechanism of the carcinogenesis of 4-nitroquinoline 1-oxide. Quantitative relationship between mutagenicity and carcinogenicity was not strictly found among the compounds examined.

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A cell line (KSNY) in vitro, which produces colony-stimulating activity (CSA) for human and mouse marrow cells, has been established. A biopsy was performed on the tumor mass of a lung cancer patient who had developed extensive leucocytosis. A piece of the tumor was transplanted to a nude mouse. The secondarily transplanted mice, in turn, developed extensive leucocytosis. The mouse tumor was then removed and placed in culture bottles. To date, the KSNY cells have been maintained in vitro continuously for 15 months. By the use of a methylcellulose bone-marrow colony-formation technique, a high level of CSA in the supernatant of the tumor cell culture was recognized. Doubling time of the cell line is 46hr. The modal chromosome number is 52, ranging from 45 to 106.

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A human lung cancer cell line (KSNY) produces a high level of human colony-stimulating activity (CSA) as shown by the dose-response relationship between the number of colonies and the concentration of conditioned medium (CM). The CM tends to induce markedly granulocytic colonies rather than other cell-type colonies. The medium conditioned by KSNY cells (KSNY-CM) is stable at 50°, but is completely inactivated at 70° for 30min. There is little binding of mouse CSA and/or human CSA in the CM to concanavalin-A-Sepharose. Fractionation of the CM by Sephacryl S-200 chromatography indicated that the maximum activity of KSNY-CSA for mouse and human marrow cells is eluted at approximately 20, 000∼25, 000 and at 45, 000∼48, 000 daltons.

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Administration of a diet containing 0.2% N-ethyl-N-hydroxyethylnitrosamine (EHEN) for 2 weeks induced hepatocellular carcinoma in 3 and renal tubular cell tumors in 7 of 9 Wistar rats. Diet containing 0.1% EHEN induced renal tubular cell tumors in 6 of 10 rats, but no hepatocellular carcinomas. Both diets induced atypical cell population of tubules in the kidney, but no nephroblastoma.

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Mixed lymphocyte-tumor cell cultures were made with materials from patients with various histological types of cancer. In 25 out of 89 patients, positive lymphocyte response to tumor cells was observed. There appeared to be an inverse relationship between the frequency of positive responses and extent of the disease. Patients with neuroblastoma, however, showed more frequent positive responses in cases of widespread disease. The data obtained may have valuable clinical implications, supporting the possibility of immunotherapy of cancer patients.

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Immunization of rabbits with rat leukemia DBLA-6 resulted in the production of antisera which upon absorption with hepatoma cells were specific for rat immature T lymphocytes. The antisera showed cytotoxicity against thymocytes and killed 75∼90% of them, whereas the antisera had no cytotoxic effect on peripheral lymphocytes from the spleen, lymph node, and bone marrow of rats. The antisera also showed cytotoxicity against rat lymphatic leukemia and lymphoma cells of all lines tested but not against rat myelogenous leukemia and erythroleukemia cells. The cytotoxic activity of anti-DBLA-6 serum was completely absorbed with rat brain or thymocytes.

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The superoxide anion-generating capacity of human blood monocytes was measured by a sensitive and rapid method established by taking advantage of the fact that the generation of superoxide anions by monocytes was markedly enhanced by the combined stimulaion of the cells with cytochalasin-E and wheat germ agglutinin. The activity was expressed by the initial rate of cytochrome c reduction after the addition of wheat germ agglutinin. The rate obtained with normal human monocytes was 0.73±0.19nmol/min/10⁵ monocytes (mean±SD, n=10). Because of its sensitivity, the method required only 10⁵ monocytes and can be used to follow the monocyte function in various patients. Preliminary data obtained with 15 cases of advanced cancer patients (0.29±0.10nmol/min/10⁵ monocytes) suggested a possible decrease of the superoxide-generating activity, at least in some state of cancer patients. It appears that measurement of superoxide-generating activity will be meaningful to monitor monocyte function.

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Studies were made in rats on the tumor-enhancing effect of phenobarbital, dichlorodiphenyltrichloroethane (DDT), and polychlorinated biphenyls (PCB), singly and in combination, after exposure to diethylnitrosamine (DEN). In sequential exposure to one of these three chemicals after DEN, liver tumor production was markedly enhanced by PCB, and moderately by phenobarbital sodium, but minimal by DDT. In combined administration of two to three of them, PCB took a dominant role in tumor enhancement, but their overall tumor enhancement did not exceed that of PCB alone.

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Tumor development was observed for 24 months in neonatally thymectomized (nTx) and normal (C3H/HeMs×129/J)F₁ mice. Thymectomy was performed at 3 days of age. Ovarian (29%, with significant difference from the control at P<0.001), pituitary (6%, P<0.08), and lymphoreticular tumors (16%, P<0.05) were observed in higher incidence in nTx females compared with normal controls, resulting in a significant increase in overall tumor incidence (99 tumors in 114 nTx females vs. 37 tumors in 71 normal females, P<0.01). No apparent difference in overall tumor incidence was observed between nTx and non-Tx males. Also, there was no higher risk for lung, liver, and mammary tumors in males and females after neonatal thymectomy. The finding that increased tumor incidence was limited to endocrine and lymphoreticular tissues does not support the concept of immune surveillance of carcinogenesis, but rather suggests the importance of tumor-prone conditioning of endocrine or immune systems as a result of neonatal thymectomy.

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Tuftsin, a physiological hormone-like peptide, has been shown to induce cytotoxicity in human granulocytes against established human malignant melanoma cell lines in vitro, but not against WI-38, a normal human embryonic lung cell line.

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The adjuvant and antitumor activities of quinonyl derivatives of N-acetylmuramyldipeptides were examined. QS₁₀-MurNAc-L-Val-D-Glu (OCH₃) NH₂ was shown to be active as adjuvant for the induction of killer T cells in allogeneic mice and suppression of tumor growth in syngeneic mice, when this adjuvant was administerd in the form of a suspension in phosphate-buffered saline.

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Potent mutagens, 2-amino-6-methyl- and 2-amino-dipyrido[1, 2-a: 3', 2'-d]imidazoles (Glu-P-1 and P-2, respectively) were identified in casein pyrolysate. The contents estimated by mass fragmentography were 2∼3μg and 30∼40μg per 100mg of the basic fraction of casein pyrolysate.

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