The effects of 3-methylcholanthrene and 5, 6- and 7, 8-benzoflavones on aryl hydrocarbon (benzo[a]pyrene) hydroxylase in the liver, small intestine, lung, and skin tissues from C3H/He and DBA/2 strains of mice under the controlled lighting conditions were examined. Apparent differences were observed in the inducibility of the hepatic enzyme by the inducers between the two strains of mice, showing that the enzyme in the C3H/He mice is inducible but not in the DBA/2 mice. Comparison of the results on the enzyme induction by 3-methylcholanthrene in the liver among the parent, intercrossed, and backcrossed mice suggested that the inducibility may be inherited as a single autosomal dominant trait. However, different genetic responses to 3-methylcholanthrene and benzoflavones in the enzyme of small intestine might be considered, because a discrepancy in the inducibility of the enzyme between the liver and the small intestine from the identical mice was demonstrated when the progeny of F₂ and (DBA/2× F₁) backcross were used. On the other hand, no apparent difference was found in the inducibility of the enzyme in the lung and skin between the C3H/He and the DBA/2 mice. It is assumed that the genetic regulation of the induction of aryl hydrocarbon hydroxylase was separately controlled in the respective tissues from the identical mice.
By the repeated topical applications of benzo[a]pyrene, the incidence of skin cancer was higher in the DBA/2 mice than in the C3H/He mice. The relationship between the induction of aryl hydrocarbon hydroxylase and carcinogenicity in the skin is briefly discussed.

View full abstract

The humoral inhibitor, which may play a primary rôle in the regulatory mechanism of cell division in the regenerating rat liver, was investigated by isolating the active principle from the ethanol-precipitate (P-3 fraction) of normal rat plasma by isoelectric focusing, and determining the exact nature of the active principle by physicochemical analysis, and studying its localization in the liver by immunofluorescence method.
The active principle was demonstrated to be α₁-acid glycoprotein by physicochemical analysis and by the immunohistological examination to be synthesized in the cytoplasm of the hepatocyte and excreted from it before its mitosis.
These results show that the humoral inhibitor or the hepatocyte-specific mitosisinhibiting protein is α₁-acid glycoprotein itself. Based on these findings, a new hypothesis concerning the regulatory mechanism of cell division in general is proposed.

View full abstract

A hypoalbuminemic substance (F-3), which was obtained from Ehrlich ascites carcinoma cells, showed a marked vascular permeability-increasing action in mice. The highest increasing effect was produced 20min after an intradermal injection of F-3. This action was inhibited by diisopropyl fluorophosphate, soybean trypsin inhibitor, and indomethacin but not by hydrocortisone or D-2-bromolysergic acid diethylamide. The inhibition of F-3 by diisopropyl fluorophosphate was observed in partial even after the excess diisopropyl fluorophosphate was removed from the diisopropyl fluorophosphate-treated F-3. The hypoalbuminemic and hypoproteinemic actions were not subjected to any inhibition by the diisopropyl fluorophosphate treatment. The decrease in albumin produced 3hr after the injection of F-3 would be due to the leakage of albumin from blood vessels. F-3 might contain at least two components, one being a vascular permeability-increasing substance and the other a hypoalbuminemic one.

View full abstract

A method for producing solid tumors in rat liver or spleen by local inoculation of Yoshida sarcoma or Hirosaki sarcoma was developed by careful selection of rat strains. After development of the tumor, the liver was isolated and perfused with a mixture of calf serum and fluorocarbon. Addition of corticoid hormone to the perfusion fluid induced tyrosine aminotransferase in normal tissue of the liver and to a lesser degree in the tumor tissue. Corticoid did not cause any detectable induction of thymidine kinase in normal tissue of the liver, but caused slight but definite induction of the enzyme in the tumor tissue. Ornithine decarboxylase was induced in the normal tissue by perfusion with serum alone, even without corticoid, but no enzyme induction was observed in the tumor tissue. The low level of this enzyme found in solid tumor tissue might be due to the fact that the enzyme was measured in the late period of tumor growth, because, in experiments with ascites tumor cells, higher enzyme activities were observed in the early period of growth.

View full abstract

The induction of concomitant immunity was studied in Donryu strain rats with Yoshida ascites sarcoma cells. The changes of enzyme activity in spleen lymphocytes were also examined in normal and tumor-bearing rats. The concomitant immunity was detected 1 week after transplantation of tumor cells. Extended metastases were found 2 weeks after transplantation. The enzyme activities of ATPase and acid phosphatase were definitely higher than that of normal rat 1 week after the transplantation but decreased to lower level than normal 2 weeks later. On the other hand, alkaline phosphatase activity increased 3 times at 1 week after the transplantation and remained at the same level even at 2 weeks later.

View full abstract

The oral administration of 0.01% potassium 1-methyl-1, 4-dihydro-7-[2-(5-nitrofuryl) vinyl]-4-oxo-1, 8-naphthyridine-3-carboxylate (NFN) in ICR/JCL mice resulted in the development of tumors in the lung, forestomach, thymus, and other areas. Special attention was directed to the incidence and growing processes of the pulmonary tumors, which usually exhibited multicentric occurrence. Adenomatous hyperplasia and adenoma were observed in 22.2% of group A (15-30 weeks), 81.3% of group B (30-38 weeks), and 91.2% of group C (38-54 weeks). One case of carcinoma in group B and 5 cases in group C were also found. Most of adenomatous hyperplasia and adenomas developed around 30 weeks after the beginning of administration, whereas the carcinomas developed after 36 weeks. The incidence of tumors was much earlier in females than in males.
Further, the tumors were observed to have originated from type B alveolar epithelial cells. The growth of type B alveolar epithelial cells was first noted as an adenomatous hyperplasia along the original alveolar walls, disintegrating and virtually replacing type A alveolar epithelial cells. Accordingly adenoma noduli was formed by these proliferated type B alveolar epithelial cells. Atypical, basophilic cell clusters were found to be present within the adenomas. It was suggested that carcinomas might have originated from these atypical type B alveolar epithelial cells.

View full abstract

Effect of various sugars related to cell membrane on the aggregation of HeLa-S3 cells was examined in a rotation culture by adding each sugar to the culture medium. Some specific sugars among those tested induced (1) greater size of aggregates and (2) higher synthesis of hyaluronic acid than that of the control. Since the addition of hyaluronidase inhibited the aggregate formation, both in the test and control cultures, with HeLa-S3 cells of both groups forming only small aggregates, it was presumed that the hyaluronic acid synthesized might be of cardinal importance for the formation of aggregates.
The specific sugars producing the effect mentioned above were N-acetyl-D-glucosamine, bis (N-acetyl) chitobiose, N-acetyl-D-galactosamine, α-methyl-D-glucopyranoside, and N-acetyl-D-mannosamine, while D-glucosamine, β-methyl-D-glucopyranoside, L-fucose, D-glucose, and a commercially available hyaluronic acid were ineffective. The findings obtained in the present study interestingly ran parallel with the results of previously reported study on the induction of specific biological phenomena by the cell membrane-related sugars.

View full abstract

Two cases of neurocutaneous melanosis with development of malignant melanoma in the Japanese are presented. The first case was a 4-year-old boy in whom a retroperitoneal melanoma appeared with giant nevi, and cerebral and spinal melanosis. The second case was a 39-year-old man, in whom a primary leptomeningeal melanoma developed with leptomeningeal melanosis and smaller pigmented nevi. Microspectrophotometric and electron microscopic studies were made on the neoplastic and non-neoplastic melanotic tissues to elucidate the histogenesis of this rare disorder. Two different patterns of nuclear DNA histograms, corresponding to melanosis and melanoma, were obtained by microspectrophotometry. Considerable variation in the ultrastructure of the melanocytes was seen by electron microscopy.

View full abstract

The survival time of animals, inhibition of the incorporation of thymidine-[6-³H] (³H-TdR) into DNA, and histopathological observation were made after the injection of Mitomycin-C, Bleomycin, cyclophosphamide, Daunomycin, Actinomycin-D, or 5-fluorouracil into mice transplanted with sarcoma-180 to their liver, kidney, and lung. The most prolonged survival time was obtained by the injection with cyclophosphamide and a moderate prolonged survival by Bleomycin and Actinomycin-D. In the case of 5-fluorouracil and Daunomycin, there were extreme variations in the survival time depending on the site of tumor growth. Cyclophosphamide and 5-fluorouracil showed greater and longer lasting inhibition of the incorporation of ³H-TdR into DNA of the tumor tissue, whereas the remaining agents caused transient inhibition on the tumor tissue. Inhibitory ratio and duration of the incorporation of ³H-TdR into DNA of normal site of the tissue of tumor-bearing organ were found to be more increased or almost the same compared with those of the tumor tissue. The most rapid recovery of the incorporation of ³H-TdR into DNA was observed in the small intestine among various organs and tumor in any treatment groups. From the histopathological observation, the degree of tumor cell damage by the agent was almost in agreement with inhibition of the incorporation of ³H-TdR up to 72hr after the treatment.

View full abstract

The urinary excretion of steroids was determined in premenopausal patients with advanced breast cancer in the non-menstrual phase and in control women in the follicular phase, ovulatory stage, and luteal phase. The estrone level in the urine of cancer patients was higher than that in the urine of control women at any phase. Excretion of 17β-estradiol in the follicular and luteal phases was similar in the urine of control women and cancer patients, but estradiol and estriol levels in the ovulatory stage of control women were higher than those of cancer patients. The estriol level in the urine of control women in the luteal phase was also higher than that of cancer patients. Total 17-ketosteroid was lower in the urine of cancer patients than in that of controls at any phase. Among the fractions of 17-ketosteroids, only dehydroepiandrosterone was excreted at a higher level by cancer patients than by control subjects.

View full abstract

Respiratory tumor induction was tested for the tumorigenic activity of benzo-[a]pyrene alone. A group of 32 male and 28 female Syrian golden hamsters were given weekly intratracheal instillation of 1mg of benzo[a]pyrene suspended in isotonic saline, for 30 weeks. Squamous cell carcinoma, adenocarcinoma, anaplastic carcinoma, adenoma, papilloma, and polyps were induced in the respiratory tract of hamsters. Tumor incidences were 42.3% in males and 57.7% in females. Respiratory carcinomas were inducible in hamsters by simple instillation of a low dose of benzo[a]pyrene without using a surface-active agent or carrierdust. These findings may be useful as a standard data for cocarcinogenesis studies when using other modality combined with benzo[a]pyrene in experimental studies.

View full abstract

A lipopolysaccharide (serratigen) and a polysaccharide (serratimannan) were isolated from Serratia marcescens, red strain No. 51. They were different from any other polysaccharides previously reported. The antitumor activity of these polysaccharides was determined. Serratimannan showed 63% tumor inhibition and serratigen 38%, at a dose of 150mg/kg, against solid tumor of sarcoma-180 using ICR mice. The fraction obtained by removal of proteins from the crude extract by the Sevag method showed a high antitumor activity against solid tumor of sarcoma-180 using Swiss albino mice, but did not show so high an activity using ICR mice. In total packed cell volume method, these polysaccharides exhibited a high rate of antitumor activity against ascites tumor of sarcoma-180.

View full abstract

Four cases of ameloblastic odontomas were found in the Long-Evans rats treated with multiple oral administration of a heavy dose of N-butylnitrosourea. The tumor was found as an expansive enlargement over the mandible and was roentgen-opaque. The tumor was histologically characterized by various elements such as odontogenic epithelium, stellated reticulum tissue, enamel, and/or dentine, and was classified as ameloblastic odontoma.

View full abstract

Considerable number (8.2-10.7%) of ovarian tumors were produced in Sprague-Dawley adult rats treated with multiple oral or intramuscular administration of heavy doses of N-butylnitrosourea. Histologically the tumor was a clear-cell adenoma which reminded of embryonal testicular tissue. Electron micrograph revealed secretory function of the tumor cells. It was not possible to find histogenesis in the normal ovarian components.

View full abstract

A bone-inducing factor was detected in murine osteosarcoma and its cultured cells. The factor was partially purified from the osteosarcoma and its biological properties were examined. The ectopic formation of the bone with hematopoietic marrow was observed in situ histologically 4 weeks after inoculation of the cell-free material intramuscularly or subcutaneously. Non-osteogenic tumors do not produce this factor. This factor seems to be a protein which is relatively resistant to heating yet labile to mechanical shaking.

View full abstract

Cytochalasin-B was found to inhibit the transport of uridine, but not leucine, in cultured fibroblastic mammalian cells. The inhibition of cellular protein synthesis by 5-fluorouracil is also lessened by the addition of Cytochalasin-B to the culture.

View full abstract

Fifteen rabbits were administered cycad extract by gastric intubation, 1ml/rabbit, once a week for 27 or 33 weeks. The extract contained 16.6mg of cycasin/ml. Out of 9 rabbits surviving over 200 days, 7 animals had malignant neoplasms developing in the liver. Histological and electron microscopic examinations of the developed tumors revealed that they were malignant hemangioendotheliomas. The animals showed no proliferation of hepatic cells or any tumor development in other organs.

View full abstract

The present study was undertaken to determine the mucopolysaccharide content of cells, AH-100B, and in the ascites, liver, and kidney of a rat bearing this hepatoma. AH-100B is similar to other mixed-type cells in having heparan sulfate as the main component in its mucopolysaccharides but its minor component was different in containing heparin. The main mucopolysaccharide in the ascites of AH-100B bearing rat was hyaluronic acid, which was similar to that of control ascites induced by injection of polypeptone, but minor component contained heparin derived from the cells. The content of hyaluronic acid in the liver of a rat bearing this hepatoma was higher than those of control liver and liver of a rat bearing other tumors. There were no significant differences between control kidney and kidney of a rat bearing this hepatoma.

View full abstract

3-(Methyl-α-D-glucopyranos-2-yl)-1-(2-chloroethyl)-1-nitrosourea, when administered at a dose of 2.0-12.5mg/kg/day, exhibited marked activities against Nakahara-Fukuoka sarcoma, adenocarcinoma-755, ascites sarcoma-180, Ehrlich ascites carcinoma, and leukemia L-1210. It exhibited neither diabetogenic nor antibacterial activities.

View full abstract