Tubercidin (7-deazaadenosine) is a strong inhibitor of cell proliferation in mouse L5178y cells. Radioactive tubercidin is incorporated into DNA and RNA. Poly(A)-containing RNA shows the highest specific radioactivity. The amount of low molecular weight 4S and 5S RNA is diminished to some extent under the influence of the compound.
Tubercidin triphosphate is a potent inhibitor of DNA-dependent DNA polymerases α and β, and the DNA-dependent RNA polymerases I, II, and III, although the efficiency of its incorporation is lower than that of dATP and ATP. Tubercidin triphosphate also seems to be a good substrate for the Mg²⁺-dependent poly(A) polymerase.

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Oral administration of N, N-dimethylamino-{p-(p'-guanidinobenzoyloxy)}-benzilcarbonyloxy glycolate depressed induction of breast tumors in rats by a single intravenous injection of 7, 12-dimethylbenz[a]anthracene. The latent period was delayed in the group fed on a diet supplemcnted with N, N-dimeth-ylamino-{p-(p'-guanidinobenzoyloxy)} benzilcarbonyloxy glycolate, Administration of this compound for 40 days after 7, 12-dimethylbenz[a]anthracene also significantly reduced the average weight of tumors per rat. These findings suggest that protease may play an important role in the process of mammary tumorlgenesis.

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Metabolism of antipyrine was studied in 12 patients with gastric carcinoma and 5 control subjects with peptic ulcer matched for sex, body weight, height, and smoking history. The mean antipyrine half-life was significantly longer (21.5±1.5hr) in 3 patients with disseminated gastric carcinoma compared to control subjects (9.3±1.5hr) (P<0.001). There was no significant difference in the mean antipyrine half-life between 9 patients with localized gastric carcinoma and control subjects. Similarly, the mean metabolic clearance rate of antipyrine was significantly lower (22.8±5.0ml/hr/kg) in patients with disseminated gastric carcinoma compared to control subjects (52.6±13.4ml/hr/kg) (P<0.02). Thus, the presence of gastric carcinoma in humans might alter antipyrine elimination. Significant negative correlation was observed between antipyrine half-life and albumin concentration (r=-0.786, P<0.01). These observations indicate that the decrease in antipyrine half-life is not primarily due to the presence of tumor but rather to the nutritional status of an individual.

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Metabolites of 3'-methyl-4-(dimethylamino) azobenzene (3'-Me-DAB) in the rat bile and urine were investigated by the use of a tracer technique. ³H-3'-Me-DAB in cottonseed oil was administered orally by a stomach tube. The dye metabolites in the bile and urine collected during 24hr after the administration were hydrolyzed with β-glucuronidase/arylsulfatase, The hydrolyzed metabolites were then extracted with chloroform or separated by chromatography on Amberlite XAD-2 using methanol as a solvent. The metabolites in the chloroform or methanol eluates were identified by the reverse isotope dilution analysis, before or after separation by thin-layer chromatography.
The N-demethylated, aryl hydroxylated, and their azo-reduced products were detected in the bile, in addition to the products oxidized at the ring methyl group as the new metabolites. On the other hand, the metabolites retaining the azo-linkage were scarcely detected in urine and instead 3-amino-benzoic acid, 3-amino-6-hydroxytoluene, and their N-acetylated products were major metabolites in urine. These results indicate that the metabolism of 3'-Me-DAB in the rat involves oxidation of the ring methyl group. Significance of the ring methyl group in the carcinogenic action of aminoazo dyes is also discussed.

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Uracil prevented the growth inhibition of Staphylococcus aureus 209P by 5-fluorouracil (5-FU). However, uracil did not reverse the growth inhibition by 5-FU in mammalian FM3A/B and HeLa cells even at 1, 000 times the concentration of 5-FU. These findings suggested that co-administration of uracil or its derivatives with 5-FU or the 5-FU derivative, 1-(2-tetrahydrofuryl)-5-fluo-rouracil (FT-207), might prevent the degradation of 5-FU released from FT-207 and thus increase the antitumor activity of FT-207. It was found that the antitumor activity of FT-207 on sarcoma-180 and AH-130 tumor was enhanced by oral administration of uracil, dUrd, or Urd. This enhancement of the antitumor activity of FT-207 increased with the dose of uracil. Uracil caused more enhancement than did dUrd or Urd.
The correlation between the doses of FT-207 and uracil, and the 5-FU levels in the tumor and blood was studied. When appropriate dose of uracil was co-administered with ³H-FT-207, 5-FU levels in the tumor became much higher than when FT-207 was administered alone and reduced very slowly, while that in the blood rapidly decreased. Consequently, the ratio of 5-FU level in the tumor to that in the blood increased markedly.
Co-administration of 5-FU and uracil increased the 5-FU levels in the blood and tumor to almost the same extent and the ratio of these levels was less than that after administration of 5-FU. These findings suggest that, in contrast to the results with FT-207, co-administration of uracil with 5-FU increased its antitumor activity and also the toxicity of 5-FU.

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The effect of azathiopurine and OK-432 on bladder carcinogenesis in rats was evaluated using the carcinogens, N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) and N-[4-(5-nitro-2-furyl)-2-thiazolyl] formamide (FANFT). Azathiopurine did not affect FANFT bladder carcinogenesis in any treatment. By contrast, when azathiopurine was fed simultaneously with BBN there was a significant increase in the incidence of bladder tumors, although it had no effect if administered before or after BBN. Short-term administration (8 weeks) of OK-432 subcutaneously before, during, or after BBN did not affect bladder carcinogenesis, but if OK-432 was begun after BBN and continued until the end of the experiment, the incidence of BBN-induced bladder tumor was significantly reduced. No bladder lesions were observed in control rats or in rats receiving only azathiopurine or OK-432.

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Various types of leukemias were induced by 1-alkyl-1-nitrosoureas in 242 Donryu rats. There were 90 erythroleukemias, and 23 myeloblastic, 74 myelocytic, 27 lymphoblastic, and 28 aleukemic or unclassified leukemias.
Survival period of the rat with myeloblastic leukemia was longer than those with erythroleukemia and shorter than those with myelocytic leukemia. The white blood cell (WBC) count was slightly greater than the normal level, anemia and hepatosplenomegaly were marked, and leukemic cells invaded diffusely, widely, and extensively into the liver lobules.
In the rat with myelocytic leukemia, the WBC count was very high, anemia and hepatosplenomegaly were marked, and leukemic cells were found in the periportal area in the liver.
In the case of erythroleukemia, although anemia, splenomegaly, and increase of the WBC count were slight, hepatomegaly was very marked. In the liver, leukemic cells invaded into sinusoids forming small cell-clusters.
In the case of lymphoblastic leukemia, survival period of the rat was similar to those with myeloblastic leukemia. The WBC count was very high, anemia was prominent, and hepatosplenomegaly was slight. Invasion of leukemic cells into the liver was found in the periportal area.

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The effect of presensitization with X-irradiated tumor cells on the development of host's immune resistance against the tumor-associated transplantation antigens (TATA) was investigated in two syngeneic tumor systems with distinct effector mechanisms.
When X5563 plasmacytoma, to which immune resistance was mediated exclusively by killer T lymphocytes, was intravenously inoculated into syngeneic C3H/He mice with lower number after 7000 R X-irradiation, the mice failed to exhibit any protective immunity against the subsequent challenge with viable tumor cells. Moreover, these mice lost their capability to develop any immune resistance even after an appropriate immunization procedure. The immunodepression induced by such a pretreatment regimen was specific for X5563 tumor. While no suppressor cell activity was detected in the above pretreated mice, serum factor(s) from these mice was virtually responsible for this suppression. When the serum factor mediating this tumor-specific suppression was fractionated on the Sephadex G-200 column, the suppressive activity was found in albumin-corresponding fraction, free of any immunoglubulin component.
In contrast, in MM102 mammary tumor system, in which immune resistance is solely mediated by tumor-specific antibody, the pretreatment with X-irradiated MM102 cells augmented the induction of anti-tumor immunity.
These results indicate that while tumor antigens given in the form of X-irradiated tumor cells suppress the induction of killer T cell-mediated immunity in one system, the same presensitization regimen of tumor antigens augments the antibody-mediated immunity in another system, thus giving a divergent effect on the distinct effector mechanisms of syngeneic tumor immunity.

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When N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was orally intubated to conventional newborn rats by the catheter technique, the rats were found with tumors almost exclusively developed in the glandular stomach, mostly until 280 days after the first intubation. Tumor incidence was about 50% in both sexs of rats that survived the intubation of a single dose of MNNG in rats of less than 24hr after birth and almost 100% in both sexes of rats that survived the intubation of three consecutive daily doses of MNNG on 5th day after birth. Out of 52 rats treated with MNNG, 40.4% developed carcinomas (20 adenocarcinomas and 1 squamous cell carcinoma), three of them having metastatic lesions. The predilective localization of tumors in the glandular, especially fundic, portion of the stomach, might be attributed to the use of newborns and to the catheter technique devised here.

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Properties of insulin receptor on plasma membranes isolated from AH-66 ascites hepatoma cells and liver of tumor-bearing rats were studied. Specific binding (total binding minus nonspecific binding) of ¹²⁵I-labeled insulin to plasma membranes from AH-66 tumor cells and liver of normal and tumorbearing rats were 33, 31, and 16% of a fixed amount of labeled insulin (1×10⁵cpm) added to each membrane preparation, respectively. Using Nisonoff plot, these membranes were found to possess at least two types of insulin receptors with a high affinity-low capacity and a low affinity-high capacity, as has been shown in normal liver. Total number of binding sites (high affinity plus low affinity sites, 8.4×10^-12mol/mg protein) in hepatoma cells was more than that (7.0×10^-12mol/mg protein) in normal rat liver. However, kinetic constants of binding in receptors of two types on tumor cells and tumor-bearing rat liver were similar to those of membrane receptors from normal rat liver.
Insulin receptors of the hepatoma cells were considered to be highly specific for insulin from the results of competition with other peptide hormones. Inhibition of insulin binding with the tumor cell membranes by concanavalin-A, a competitive inhibitor for insulin receptor sites, did not differ very greatly from that of normal liver.

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The effect of radiotherapy on peripheral blood lymphocytes (PBL) of lung cancer and the effect of BCG cell-wall skeleton (BCG-CWS) on recovery of impaired PBL were examined. A remarkable depression of the absolute number of E- or EAC-rosette cells and of the response of PBL to mitogens were observed immediately after radiotherapy, and these continued for several months. With BCG-CWS immunotherapy, the response of PBL to phytohemagglutinin recovered rapidly, compared with non-vaccinated patients. The response of PBL to pokeweed mitogen seemed to give similar results. These results suggested that BCG-CWS injection to the patient receiving radiotherapy was effective for recovery of T-cell response.

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A spontaneous tumor was obtained from a hen of White Leghorn stock raised in a local farm in Yamaguchi City, in December 1973. The tumor had characteristics of fibro- or myxofibro-sarcoma and could be maintained by transplantation in chickens of similar flocks. This tumor was proved to produce sarcoma virus at 33rd passage and the transforming virus was designated as Y73 sarcoma virus.
Biological studies suggested that the virus recovered from the tumor belonged to avian leukosis-sarcoma complex having subgroup A specificity. The possibility of defectiveness of this virus will be discussed.

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Peritoneal exudate cells (PEC) induced by oil-attached cell-wall skeleton of Mycobacterium bovis BCG (BCG-CWS) in ACI/N rats were tested for their effect on both in vivo and in vitro growth of syngeneic fibrosarcoma cells (AMC-60). Treatment of rats with intraperitoneal injections of BCG-CWS induced regression of syngeneic ascites tumor and increased the number of survivals. Whole PEC and adherent PEC from rats injected intraperitoneally with BCG-CWS inhibited the uptake of tritiated thymidine into the fibrosarcoma cells in an in vitro cytostasis test. This in vitro cytostatic effect was more marked as the ratio of effector to target cells increased. In addition, when tumor cells were inoculated subcutaneously with BCG-CWS activated PEC, tumor takes decreased markedly. Oil-stimulated PEC and normal peritoneal resident cells were inactive in inhibition of tumor growth in vivo and in vitro.

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4-(N-Hydroxy-N-methylamino) quinoline 1-oxide (N-Me-4-HAQO), the structure of which consists of a quinoline 1-oxide moiety involved in carcinogenic 4-nitroquinoline 1-oxide and an N-hydroxy-N-methylamino group involved in N-hydroxy-N-monomethylaminoazobenzene, was sythesized and proved to be potently carcinogenic in mice by its subcutaneous injection.

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A prolonged-release derivative of cytosine arabinoside (Ara-C), cytosine ara-binoside-agarose bead conjugate (Ara-C-AB), was synthesized and its pharmaceutical and pharmacological characteristics were examined. Ara-C was released successively for considerably long period from Ara-C-AB in vitro. Following intraperitoneal injection of ³H-Ara-C-AB, radioactivity could be detected in plasma and urine of BDF₁ mouse for four days, while ³H-Ara-C administered as a free form was excreted completely in the first 24hr. Increase in lifespan of L1210 leukemia-bearing mice was demonstrated after intraperitoneal injection of Ara-C-AB with both the dosage schedules of three days before and one day after inoculation of L1210 cells at the dose of 30mg equivalent Ara-C/kg.

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The effect of vitamin A acetate on the urinary bladder carcinogenicity of N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) was determined in male Wistar rats. Vitamin A acetate at the dose administered induced no changes in the urinary bladder or other organs when administered without the carcinogen. However, hypervitaminosis A inhibited keratinization and squamous metaplasia in bladder lesions induced by BBN, and the incidence of transitional cell carcinoma and papilloma of the urinary bladder was significantly reduced at a dose greater than 100IU/g diet (P<0.02). The present experiment suggests that for the urinary bladder epithelium of rats hypervitaminosis A reduced susceptibility to the tumorigenicity of BBN.

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The typing of human major histocompatibility antigens (HLA) of two cases of invasive hydatidiform mole showed that the fibroblast-like cells as well as trophoblasts from the mole selectively expressed paternal HLA haplotype specificity but not maternal HLA on the surface. This result was completely in agreement with the notion of androgenetic origin of hydatidiform mole from the aspects of HLA specificity. Immunological implication of this finding and development of chorionic tumor were discussed in the light of fetomaternal relationship and host immune surveillance against the tumor.

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Lung carcinoma was induced by a single intraperitoneal injection of 3g/kg and 4g/kg body weight of DHPN in male Wistar rats. The incidence of adenomas was 100%, and that of adenocarcinomas was 82% and 75%, respectively, after 52 weeks.

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A replication defective virus having transforming capacity for chick embryo fibroblast was isolated from R strain of avian erythroblastosis virus. The virus rescued as pseudotype of RAV-1 possessed genomic RNA of 30S in addition to 35S RNA of RAV-1.

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Out of over 200 autopsied nude mice, so far, there was one mouse with normal thymus-like tissue which had many Thy-1.2 positive cells in the spleen. Histologically, it was proved to be the enlarged embryonal thymus. Heterotransplantation study in the nude mouse was discussed.

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Squamous cell cancers developed in the male reproductive tract, mostly confined to the coagulating glands and ejaculatoryducts, of neonatally castrated, not of non-castrated Wistar rats that were given diethylstilbestrol (DES) for the first 30 postnatal days. This may suggest higher risk of cancer in the prenatally DES-exposed human males.

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Various Pt(II) complexes of 1-amino-2-aminomethylcyclohexane isomers were prepared and tested against leukemia P388. They were found to be better, than Pt(II) complexes of 1, 2-diaminocyclohexane isomers in antitumor activity. Water-soluble dinitrato, sulfato, and n-glucuronato Pt(II) complexes are markedly active and promising.

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Mechanism of metabolic activation was investigated for carcinogenic aromatic hydrocarbons lacking the bay region. Semiquinone radical of anthanthrene and 6-oxy-10-aza-benzo[a]-pyrene radical were formed enzymically with rat liver microsomes. These free radicals were active enough to bind covalently with poly(G), retaining the radical forms.

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