Biomedical subjects

T Ogiu

Publications and source records attributed to T Ogiu.

At least 37 records · Page 2Linked to original sources

PubMed1989

Leukocytosis in mice following therapy with a novel antitumor agent, RA-700.

Nine daily intravenous (iv) injections of RA-700 (an antitumor cyclic hexapeptide) at doses of 2 to 6 mg/kg/day caused increases of WBC counts at 4-6 days after treatment in normal C57BL/6 X DBA/2 (BDF1) mice. The percentages of neutrophils and lymphocytes were modified. There was a decrease of colony-forming units in culture (CFUc) in bone marrow to 40% of the control value on day 1 but CFUc rapidly returned to normal values on day 3. The colony-forming units in spleen (CFUs) in bone marrow decreased during treatment. On the other hand, CFUc and CFUs in spleen were increased from the initiation of treatment to the time prior to the increase of WBC count. Spleen weight increased after treatment, and histologically, increases of immature and also mature granulocytes and megakaryocytes were observed. However, RA-700 did not stimulate the progress of hematoprogenitors in vitro. The results indicated that RA-700 stimulates the progress of hematoprogenitors in the spleen, but this effect is probably indirect.

Animals↗

PubMed1989

Thymic lymphomas induced by N-propyl-N-nitrosourea (PNU) in the BUF/Mna rat, an inbred strain with a high incidence of spontaneous thymoma.

N-Propyl-N-nitrosourea (PNU) is known to be a strong leukemogen, inducing myelogenous leukemia or thymic lymphoma in some strains of rat. The thymic lymphomagenic effect of PNU has been demonstrated in F344 rats. On the other hand, the BUF/Mna rat has been established as an inbred strain that develops spontaneous thymomas after one year of age. In the present experiment, PNU was continuously administered in drinking water to male and female BUF/Mna rats starting at 5 weeks of age. Thymic lymphomas were induced in all PNU-treated rats with an average latent period as short as 14 experimental weeks. These results show the high susceptibility of the BUF/Mna rat to the lymphomagenic activity of PNU. The BUF/Mna rat is an ideal strain for studies on epithelial cell-lymphocyte interaction, not only in the development of thymic lymphomas but also in that of spontaneous thymoma. Karyotypes of twelve primary thymic lymphomas induced by PNU were analyzed for chromosomal abnormalities. Chromosomal abnormalities were often found in chromosomes 11 and 2. In some types of abnormality, dup (11q) and del(2q) were most frequently observed. In addition, trisomy of chromosome 7, on which the c-myc gene is mapped, was observed in five lymphomas, and monosomy of chromosomes 20 and X in six and five cases, respectively, though these changes were generally observed in a minor cell population in each case.

Animals↗

PubMed1988

Induction of lung tumors and peritoneal mesotheliomas in F344 rats given intragastric N-propyl-N-nitrosourea and histochemical, immunohistochemical, and ultrastructural characteristics of induced mesotheliomas.

N-Propyl-N-nitrosourea is a strong leukemogen that induces myelogenic leukemia in Donryu rats and thymic lymphoma in F344 rats when administered in drinking water. In the present study, a single or multiple doses of PNU (total 500 mg/kg body weight) was given to young male and female F344 rats via a stomach tube. The results demonstrated that the percentage of tumor-bearing rats was 100% in all PNU-treated male groups, while that of the control group was 46%. Predominant tumors induced by PNU in male rats were lung adenoma/adenocarcinoma followed by peritoneal mesothelioma, and forestomach papilloma. In females, the tumor incidence of PNU-treated groups varied between 58% and 92% while that of the control group was 42%. Although pituitary tumor was the most frequent tumor in PNU-treated female rats, it was thought to be spontaneous since its incidence in each experimental group was not statistically different from that of the control group. Lung tumors and forestomach papillomas were also induced by PNU in female rats. No thymic lymphoma, however, was found in any of the PNU-treated groups of either sex. Lung tumors developed in almost all PNU-treated male rats and in about one-third of PNU-treated female rats. Mesothelioma was induced only in male rats, and its incidence depended on the treatment schedule. Induced mesotheliomas were extensively examined histologically, histochemically, immunohistochemically, and electron microscopically.

Animals↗

PubMed1988

Cytogenetic studies on rat thymic lymphomas induced by N-propyl-N-nitrosourea.

N-Propyl-N-nitrosourea (PNU) was proved to be a strong leukemogen, which induces myelogenous leukemia or thymic lymphoma in rats. BUF/Mna rats and F344 rats were the strain most susceptible to thymic lymphomagenic activity of PNU. In addition, F1 rats between BUF/Mna and WKY rats were also susceptible to PNU-lymphomagenic activity. In the present experiment, karyotypes of 31 thymic lymphomas induced by PNU in BUF/Mna rats and in F1 rats between BUF/Mna and WKY rats were analysed for chromosomal abnormalities. Although no specific chromosomal abnormalities were observed throughout all lymphomas, del(11q) and dup(2q) were observed frequently in BUF/Mna rat lymphomas. Breakpoints and/or fusion-points were frequently observed in chromosome 11, followed by chromosomes 2, 5 and 6. Trisomy of chromosome 7, on which c-myc oncogene is mapped, was observed in seven cases, and monosomy of chromosomes 12, 18, 19, 20 and X was seen in seven or eight cases each, though these changes were generally observed in minor cell population in each case.

Animals↗

PubMed1988

Nodular development of spontaneous epithelial thymoma in (ACI/NMs x BUF/Mna)F1 rats.

The BUF/Mna strain is a high thymoma line of rats, and virtually all rats develop overt thymomas by the age of 40 weeks. To reveal the early morphologic changes in this thymomagenesis, thymuses and thymomas were studied in (ACI/NMs x BUF/Mna)F1 (ABF1) rats, which inherit a thymoma susceptibility gene (Tsr-1) from the BUF/Mna strain. At 50 weeks of age, 18% of ABF1 rats had developed medium to large thymomas, 54% had just began to develop multiple, small round nodules in their involuted thymuses, and the remaining 29% had involuted thymus only. The nodules were, microscopically, composed of cortex-like tissues with a starry-sky pattern, showing a quite similar structure to that of the large macroscopic thymomas of predominantly lymphocytic type seen in 104-week-old ABF1 or BUF-Mna rats. Thus, the nodule was actually a small thymoma. In fact, their epithelial cells often had larger atypical nuclei than those in the adjacent involuted thymus cortex. At 104 weeks of age, the incidences of the medium to large thymomas and the small thymoma nodules in ABF1 rats were 64 and 19%, respectively. These results suggest that the thymoma of ABF1 rats occurs initially as multiple small nodules which develop further into medium to large overt thymomas as a result of growth and fusion.

Animals↗

PubMed1988

The effect of thymectomy on the development of nephropathy in spontaneous thymoma rats of the BUF/Mna strain.

A close relationship was assumed between the developments of nephropathy and thymoma in the previous study, in which the effect of introduction of the rat nude gene was studied in high thymoma BUF/Mna rats. In this paper, the effect of neonatal thymectomy on the development of nephropathy was examined to clarify the relationship between these two lesions in BUF/Mna rats. The average amount of urinary protein excreted from sham-operated and thymectomized BUF/Mna rats was 30.8 +/- 17.1 and 40.0 +/- 20.0 mg/day, respectively, and the number of affected glomeruli per 100 glomeruli 4.9 +/- 1.0 and 5.3 +/- 2.0, respectively. There were no significant differences in the urinary protein content, the number of the affected glomeruli, and immunofluorescence findings. In a control group, ACI/NMs rats exhibited 8.9 +/- 2.6 mg/day protein in urine and 0.8 +/- 0.4% affected glomeruli, which were significantly different from that of sham-operated and thymectomized BUF/Mna rats. These results indicate that nephropathy in BUF/Mna rats results neither from thymoma itself nor from the immunological abnormality secondary to it, and suggest that this lesion might be ascribed to a genetic factors.

Animals↗

PubMed1987

Lack of carcinogenicity of tartrazine (FD & C Yellow No. 5) in the F344 rat.

The carcinogenicity of tartrazine (C. I. Food Yellow No. 4, FD & C Yellow No. 5), a food, drug and cosmetics colouring, was examined in F344 rats. Tartrazine was dissolved in distilled water at levels of 0, 1 or 2%, and groups of about 50 male and 50 female rats were given one of these solutions ad lib. as their drinking-water for up to 2 yr. No toxic lesions specifically caused by tartrazine were detected in any treated group of either sex. Many tumours developed in all groups including the control group, and the organ distribution of these tumours and their histological characteristics were similar to those of the spontaneous tumours that are known to occur in this strain of rats. Except for mesothelioma in males and endometrial stromal polyp in females, there were no significant increases in the incidences of any tumours over those in the corresponding control group. In males, mesotheliomas were found only in the group given 1% tartrazine and the incidence of this lesion was statistically significant (Fisher's exact test) in comparison with the other two groups (P less than 0.02). The incidence of endometrial stromal polyp was also significantly higher among females given the 1% dose than in the controls (P less than 0.05). However, no positive trend was noted in the occurrence of these two tumours using an age-adjusted statistical analysis. Mesothelioma and endometrial stromal polyp are frequently observed spontaneous tumours in this strain of rats, and their incidences in our historical controls are 4.1 and 21.9%, respectively. However in the present study mesothelioma occurred in none of the male control rats and the incidence of endometrial stromal polyp was only 10.6% in the female control group. Moreover, there was no significant difference between the control and treated groups in hyperplastic or pre-neoplastic changes in the mesothelium or endometrium. From these findings, we concluded that the significant increases in the incidences of mesothelioma and endometrial stromal polyp that occurred in the groups given 1% tartrazine were not attributable to tartrazine administration. Thus, it is concluded that tartrazine was not carcinogenic in F344 rats when administered continuously at doses of up to 2% in the drinking-water for up to 2 yr.

Animals↗

PubMed1987

Sequences responsible for erythroid and lymphoid leukemia in the long terminal repeats of Friend-mink cell focus-forming and Moloney murine leukemia viruses.

Despite the high degree of homology (91%) between the nucleotide sequences of the Friend-mink cell focus-forming (MCF) and the Moloney murine leukemia virus (MuLV) genomic long terminal repeats (LTRs), the pathogenicities determined by the LTR sequences of the two viruses are quite different. Friend-MCF MuLV is an erythroid leukemia virus, and Moloney MuLV is a lymphoid leukemia virus. To map the LTR sequences responsible for the different disease specificities, we constructed nine viruses with LTRs recombinant between the Friend-MCF and Moloney MuLVs. Analysis of the leukemia induced with the recombinant viruses showed that a 195-base-pair nucleotide sequence, including a 75-base-pair nucleotide Moloney enhancer, is responsible for the tissue-specific leukemogenicity of Moloney MuLV. However, not only the enhancer but also its downstream sequences appear to be necessary. The Moloney virus enhancer and its downstream sequence exerted a dominant effect over that of the Friend-MCF virus, but the enhancer sequence alone did not. The results that three of the nine recombinant viruses induced both erythroid and lymphoid leukemias supported the hypothesis that multiple viral genetic determinants control both the ability to cause leukemia and the type of leukemia induced.

Animals↗

PubMed1987

Experimental induction of ovarian Sertoli cell tumors in rats by N-nitrosoureas.

Spontaneous ovarian tumors are very rare in ACI, Wistar, F344 and Donryu rats; the few neoplasms found are of the granulosa/theca cell type. Ovarian tumors were also rare in these strains of rats when given high doses of N-alkyl-N-nitrosoureas continuously in the drinking water for their life-span; however, relatively high incidences of Sertoli cell tumors or Sertoli cell tumors mixed with granulosa cell tumors were induced in Donryu rats after administration of either a 400 ppm N-ethyl-N-nitrosourea solution in the drinking water for 4 weeks or as a single dose of 200 mg N-propyl-N-nitrosourea per kg body weight by stomach tube. Typical Sertoli cell tumors consisted of solid areas showing tubular formation. The tubules were lined by tall, columnar cells, with abundant, faintly eosinophilic, often vacuolated cytoplasm, and basally oriented, round nuclei, resembling seminiferous tubules in the testes. In some cases, Sertoli cell tumor elements were found mixed with areas of granulosa cells. The induction of ovarian Sertoli cell tumors in Donryu rats by low doses of nitrosoureas may provide a useful model for these tumors in man.

Animals↗

PubMed1987

Existence of N-nitroso-N-propylurea target cells in the thymus of F344 rats in thymic lymphomagenesis.

There are two hypotheses for location of first transformation of cells of T-cell lineage into preneoplastic cells from studies of leukemogenesis in mice; one is the bone marrow and another is the thymus. N-Nitroso-N-propylurea [(NPU) CAS: 816-57-9] induces high incidence of thymic lymphoma in F344 rats. In the present experiments, the location of NPU-target cells was examined in F344 rats. In the first experiment, bone marrow cells from NPU-treated male rats were inoculated into sublethally irradiated female rats. However, neither thymic nor other types of leukemias were induced in these rats. In the following experiment, thymectomized male rats received grafts sc with normal thymuses of age-matched female F344 rats. Continuous administration of NPU to the rats successfully induced 9 thymic lymphomas in the grafted thymuses. In 8 thymic lymphomas analyzed, 6 consisted of donor cells and the other 2 consisted of recipient cells. The present results from these 2 experiments strongly suggested that NPU-induced rat thymic lymphomas originate from intrathymic cells but not from bone marrow cells. In other words, target cells of leukemogenic activity of the chemical carcinogen NPU probably exist in the thymus of F344 rats.

Animals↗

PubMed1987

Long-term studies on carcinogenicity and promoting effect of phenylbutazone in DONRYU rats.

The carcinogenicity and promoting effect of phenylbutazone were investigated in inbred DONRYU rats. In the carcinogenicity study, both sexes were administered the chemical at dietary levels of 0 (control), 0.125, or 0.25% for 2 years. Toxic lesions were associated with phenylbutazone treatment in the kidney and digestive tract, appearing to have an adverse effect on life expectancy. Various tumors were detected in all groups including the controls. With the exception of pheochromocytoma in the female high-dose group, no statistically significant increase in yield of any tumors, including leukemia, was apparent in the treated groups of either sex when the data were analyzed by Fisher's exact probability and/or chi-square tests. Application of an age-adjusted statistical analysis revealed a slight positive effect regarding the occurrence of pheochromocytomas, neoplastic liver nodules, and leukemias in females. However, these tumors are commonly observed to develop spontaneously in this rat strain, and no such effect was apparent in the male groups. In addition, no differences in incidences of relevant preneoplastic lesions were evident between control and treated groups. Thus phenylbutazone showed no carcinogenic activity in DONRYU rats when given continuously in the diet for 2 years. For the investigation of promoting effect, phenylbutazone was given as a dietary supplement for 2 years subsequent to initiation with N-ethyl-N-nitrosourea or N-propyl-N-nitrosourea. No enhancement of nitrosourea-induced leukemogenesis was apparent, although a slight promoting effect was demonstrated for renal and thyroid tumorigenesis.

Adrenal Gland Neoplasms↗

PubMed1986

Lack of carcinogenicity of triethanolamine in F344 rats.

The carcinogenic potential of triethanolamine was examined in F344 rats. Triethanolamine was dissolved in distilled water at levels of 0 (control), 1, and 2%, and groups of 50 males and 50 females were given these doses ad libitum as drinking water for 2 yr. The dose levels in females were reduced by half from wk 69, because of associated nephrotoxicity. A variety of tumors developed in all groups, including the control group, and all tumors observed were histologically similar to spontaneous tumors in this strain of rats. No statistically significant increase of the incidence of any tumor was observed in the treated groups of both sexes by the chi-square test. In this study, however, there was an increase in nephrotoxicity, which appeared to have an adverse effect on the life expectancy of the treated animals, especially of females. Therefore, an age-adjusted statistical analysis on incidences of main tumors or tumor groups of both sexes was also done by methods recommended by Peto et al. (1980). The result showed that a positive trend (p less than 0.05) was noted in the occurrence of hepatic tumors (neoplastic nodule/hepatocellular carcinoma) in males and of uterine endometrial sarcomas and renal-cell adenomas in females. These tumors, however, have been observed spontaneously in this strain of rats, and their incidences in the control group of the present study were lower than those of our historical controls. These results may indicate that a positive trend in the occurrence of these tumors is not attributable to triethanolamine administration. Increased incidence of renal tumors in the female high-dose group may have been connected with renal damage. Histological examination of renal damage observed in the treated groups, especially in the female high-dose group, revealed acceleration of so-called chronic nephropathy. In addition, mineralization of the renal papilla, nodular hyperplasia of the pelvic mucosa, and pyelonephritis with or without papillary necrosis were also observed. Thus, it is concluded that under these experimental conditions triethanolamine is not carcinogenic in F344 rats but is toxic to the kidneys.

Animals↗

PubMed1986

Comparison of the acute toxicity of N-nitrosocimetidine with three structurally related carcinogens in the rat.

The acute toxicity of N-nitrosocimetidine, the nitrosated derivative of the histamine H2-receptor blocking agent cimetidine, was compared with the toxicities of three structurally related nitroso compounds known to be potent carcinogens, namely N-methyl-N'-nitro-N-nitrosoguanidine, N-methyl-N-nitrosourea, and N-methyl-N-nitrosourethane, and also with the parent drug cimetidine. The acute toxicity of each compound was investigated in 6-week-old female Fischer-344 rats by estimating the median lethal doses via three different routes of administration, and by assessing the sequence of histopathological alterations induced. According to median lethalities, all three known carcinogens were substantially more toxic than nitrosocimetidine whether administered by the intravenous, intraperitoneal, or oral routes. The widest margin of difference was represented by orally administered N-methyl-N-nitrosourea, the median lethal dose being 59 times greater than oral N-nitrosocimetidine. By this method, the acute toxicities of N-nitrosocimetidine and the parent drug cimetidine were virtually identical for each of the three routes of administration. Sequential histological assessment indicated that the three known carcinogens induced specific pathological alterations mainly in organs which were also known to be targets for their carcinogenic activity. In contrast, no tissue lesions of a specific nature were associated with N-nitrosocimetidine or cimetidine in this study. The comparable results with N-nitrosocimetidine and the parent drug provide biological support for previously obtained biochemical data which suggested that N-nitrosocimetidine is rapidly denitrosated to cimetidine in the rat.

Administration, Oral↗

PubMed1986

Spontaneous neoplastic and non-neoplastic lesions in aging Donryu rats.

Spontaneous neoplastic and non-neoplastic lesions in 95 male and 96 female Donryu rats which were observed up to 120 weeks of age, were examined. The incidence of spontaneous tumors was 73.7% in males and 88.5% in females. In males, the most frequent tumors were pituitary adenomas, followed by pheochromocytomas and insulinomas. In females, uterine adenocarcinomas, mammary fibroadenomas and pituitary adenomas were the most common. Other tumors with relatively high incidences in both sexes included cortical adenomas of the adrenal gland, histiocytic sarcomas of the hematopoietic organs and granular cell tumors of the brain. Various tumors were also found in many other organs and/or tissues, although their incidences were low. The organ distribution and incidences of spontaneous tumors observed in Donryu rats were different from those in other strains of rats such as the ACI, Wistar, F344 or Sprague-Dawley strains. The main non-neoplastic lesions were observed in the lung, cervical lymph nodes and kidney of both sexes. In addition, lesions were also observed in the urinary bladder, prostate and peripheral nerves (spinal nerve roots and peripheral nerves) and/or femoralis muscle of males. Histologically, the most characteristic lesion was radiculoneuropathy with degeneration of the peripheral nerves.

Aging↗

PubMed1985

Effect of Nocardia rubra cell wall skeleton and/or cyclophosphamide on leukemogenesis induced by N-ethyl-N-nitrosourea in Donryu rats.

The effect of Nocardia rubra cell wall skeleton (N-CWS) and/or cyclophosphamide (CP) on chemical carcinogenesis was examined in female Donryu rats exposed to N-ethyl-N-nitrosourea (ENU) in the drinking water for 6 weeks. Five administrations of N-CWS following ENU treatment caused a slight prolongation of the average survival of rats but did not reduce the incidence of leukemia. CP given on two occasions after ENU treatment caused a moderate prolongation of average survival period and a moderate reduction of the incidence of leukemia, but significant differences from ENU-treated control group values were not observed after statistical analysis. Combined treatment with N-CWS and CP after ENU treatment caused prolongation of the average survival period of rats and a statistically significant reduction in the incidence of leukemia. The present experiment indicates that combined treatment with N-CWS and CP effectively reduces induction of leukemia by ENU in rats, although other types of tumors were not affected.

Animals↗

PubMed1985

Organ-specific carcinogenicity of N-methyl-N-nitrosourea in F344 and ACI/N rats.

Male and female F344 rats were continuously administered N-methyl-N-nitrosourea (MNU) in their drinking water at concentrations of 200 or 100 ppm, and both sexes of ACI/N rats were given MNU at a concentration of 200 ppm. By the 42nd week of the experiment, high incidences of brain/spinal cord tumors were observed in both strains of rats. Histologically, many of them were astrocytomas or anaplastic astrocytomas. In addition, malignant neurinomas were also detected in the spinal nerve roots and trigeminal nerves, although their incidences were rather low. There was no difference in the type and incidence of these neurogenic tumors between the two strains of rats. Tumors of the tongue and esophagus were mainly observed in the high-dose group of F344 rats and those of the glandular stomach were observed in the low-dose group of F344 rats. In ACI/N rats, tumors of the heart and renal pelvis were detected. The organ-specific carcinogenicity of MNU in these two strains of rats was compared with that of MNU in Donryu rats. It was demonstrated that organ specificity of MNU given orally was influenced not only by the strain of rats but also by the dose level.

Animals↗

PubMed1985

Lack of evidence of carcinogenicity of technical-grade piperonyl butoxide in F344 rats: selective induction of ileocaecal ulcers.

The carcinogenicity of technical-grade piperonyl butoxide was studied in F344/DuCrj rats fed a dietary level of 0.5 or 1% for 2 yr. Various tumours were detected in all groups, including the untreated control group, but no significant dose-related increase in the incidence of any tumour was found. Thus, it is concluded that under these experimental conditions piperonyl butoxide was not carcinogenic in F344 rats. Unexpectedly, however, ileocaecal ulcers were found in animals of both sexes in both experimental groups and the incidence was dose related. Further studies are required to establish the mechanism of induction of ileocaecal ulcers by piperonyl butoxide.

Administration, Oral↗

PubMed1985

Sequential observations of thymic lymphoma development induced in 10-week-old F344 rats by N-propyl-N-nitrosourea.

N-Propyl-N-nitrosourea (PNU) is a strong carcinogen which induces thymic lymphoma and other tumors in F344 rats. In the present experiment, sequential changes of the thymus, spleen, bone marrow, and other organs were examined histologically in F344 rats which were continuously given PNU in the drinking water. Hematopoietic organs, such as the bone marrow, spleen, and thymus rapidly became hypoplastic. Atrophy of the thymus was followed by repopulation and hyperplasia. The latter was characterized by lymphoblast-like cells and was followed by development of early stage lymphoma, which arose from the 10th experimental week onwards. At first, thymic lymphoma was observed to involve thymic lobes unilaterally, later spreading to bilateral lobes, and at the 16th experimental week, metastatic foci were evident in the bone marrow of one rat. In contrast, hypoplasia of the bone marrow continued until the end of the experiment, while hypoplasia of the red splenic pulp continued until the 12th experimental week. These results indicate that PNU-induced lymphomas arise from within the thymus, although it is not possible to rule out a role for the bone marrow as including target cells of PNU. This PNU-thymic lymphoma system in F344 rats should serve as a good model for the study of experimentally induced thymic lymphoma.

Animals↗