Biomedical subjects

T Ogiu

Publications and source records attributed to T Ogiu.

At least 19 recordsLinked to original sources

PubMed1996

Comparison of dose-dependent enhancing effects of gamma-ray irradiation on urethan-induced lung tumorigenesis in athymic nude (nu/nu) mice ac (nu/+) littermates.

The role of immunological surveillance in carcinogenesis is still controversial. In our previous experiments, urethan-induced lung tumorigenesis in athymic (nu/nu) mice and euthymic (nu/+) littermates was examined, and it was concluded that immunosurveillance mediated by T cells could not be demonstrated. However, the reported enhancement of development of various tumors following ionizing radiation might be achieved through modulating the host immunological conditions. In the present experiment, nu/nu and littermate nu/+ mice were treated with 1-4 Gy gamma-rays alone at 6 weeks of age or treated with urethan at 0.5 mg/g body weight when aged 14 days followed by 1-4 GY gamma-rays 4 weeks later. Lung tumors were assessed at 6.5 months of age. Ionizing radiation itself caused a very low incidence of these lesions. On the other hand, multiplicities and incidences of lung tumors after urethan treatment at 0.5 mg/g body weight were similar between the two phenotypically different groups of mice (1.66 and 1.84 tumors/mouse, 73% and 80% incidences, for nu/nu and nu/+ cases respectively). This urethan-induced lung tumorigenesis was significantly enhanced by gamma-rays in both nu/nu and nu/+ mice, and the magnitude of tumor enhancement was somewhat higher in nu/+ mice than in nu/nu mice, especially with a 2-Gy dose. In conclusion, it may be said that lung tumorigenicity of gamma-ray irradiation itself and the enhancing effect of radiation on urethan-induced tumorigenesis are scarcely influenced by immunosurveillance mechanisms mediated by T cells.

Animals↗

PubMed1995

Reduced fidelity of DNA synthesis in cell extracts from chemically induced primary thymic lymphomas of mice.

To examine whether the fidelity of DNA synthesis is reduced in tumor cells, M13 mp2-based fidelity assays were carried out using 15 samples of whole-cell extracts from primary mouse thymic lymphomas induced by alkylating agents. We found that DNA synthesis activities of thymic lymphomas, detected as incorporation of [3H]TTP into acid-insoluble materials, were 2- to 10-fold higher compared to those of normal thymus. Furthermore, mutant frequencies in the forward mutation assay of DNA synthesis were increased 2- to 7-fold in cell extracts from thymic lymphomas compared to those from normal thymus. As the DNA polymerase beta (pol beta) activity was extremely high in the thymic lymphomas, we screened mutations in the pol beta gene to examine the possibility of involvement of mutated pol beta in reduction of the fidelity of DNA synthesis. Of 20 lymphomas, one case of point mutation (T to A) was found by reverse transcription-PCR single-strand conformation polymorphism analysis. These results suggest that the mutagenic DNA synthesis is involved in murine thymic lymphoma genesis, although mutation of the pol beta gene is not a major causal event.

Animals↗

PubMed1995

Genetic regulation of development of thymic lymphomas induced by N-propyl-N-nitrosourea in the rat.

To clarify the linkage between Hbb and Tls-1 (thymic lymphoma susceptible-1) loci and to investigate other loci concerned in thymic lymphomagenesis, the BUF/Mna rat, which is highly sensitive to the lymphomagenic activity of N-propyl-N-nitrosourea (PNU), the WKY/NCrj rat, reported to be resistant, and their cross offspring were subjected to genetic analysis. F1 hybrid and backcross generations were raised from the 2 strains, and 6 genetic markers including Hbb were analyzed in individuals of the backcross generation. However, no linkage between Hbb and Tls-1 loci could be demonstrated since WKY rats also developed a high incidence of thymic lymphomas in response to PNU. Nevertheless, thymic lymphomas developed more rapidly and reached a larger size in the BUF rats. F1 rats expressed a rather rapid and large tumor growth phenotype, while the [(WKY X BUF) X WKY] backcross generation consisted of rats with either rapidly growing or slowly growing tumors. It was thus concluded that rapid development of thymic lymphomas is determined by a gene, provisionally designated Tls-3. Analysis of the relationship between 6 genetic markers and development of thymic lymphoma in the backcross generation demonstrated that the Tls-3 locus is loosely linked to the Gc locus, suggesting a possible location on rat chromosome 14. Tls-3 may not be identical with Tls-1 and other genes known to be relevant to thymic tumors, but its relationship with Tls-2 remains obscure.

Animals↗

PubMed1992

DNA strand breaks and death of thymocytes induced by N-methyl-N-nitrosourea.

N-Methyl-N-nitrosourea (MNU) is a potent carcinogen in various sites of experimental animals and induces thymic lymphoma in rats, which has long been hard to induce by any carcinogen. To analyze the action of MNU on thymocytes, DNA strand breaking in thymocytes from the MNU-treated rat and that in MNU-treated cultured thymocytes were assayed. Fluorometric analysis of DNA unwinding (FADU assay), first reported by Birnboim and Jevcak to detect X-ray-induced DNA damage, was modified and applied to detect DNA damage in thymocytes treated with MNU in vitro or in vivo. In the present modified method, cell lysate was admixed with 0.15 M sodium hydroxide, and DNA unwinding was processed at pH 12.0 for up to 2 h at 0 degree C in iced water. Double-stranded DNA remaining after alkaline reaction was detected by binding ethidium bromide and measuring its fluorescence. The severity of DNA damage, both in vivo and in vitro, depended on the MNU concentration. In addition, the sequential survival rate and cell-size distribution of thymocytes treated with MNU in vitro were investigated. A close relationship between the severity of DNA damage and cell death was demonstrated in MNU-treated thymocytes, and DNA damage by a non-cell-killing dose of MNU was detected with this FADU assay. MNU-induced cell death is not programmed as in apoptosis, which is caused in thymocytes physiologically, immunologically and by X-ray irradiation or corticoids.

Animals↗

PubMed1992

Age-dependent induction of thymic lymphomas by N-propyl-N-nitrosourea in the F344/DuCrj rat.

N-Propyl-N-nitrosourea (PNU) is one of the most potent thymic-lymphomagenic agents in rats. Our previous experiments strongly suggested that leukemogenic viruses were not the cause of thymic lymphomas in rats and that target cells of PNU exist in the thymus but not in the bone marrow. On the other hand, the role of retrovirus in lymphomagenesis is undeniable in mice. Therefore, chemically induced rat thymic lymphoma provides a good model to analyse lymphomagenesis without viral implications. In the present experiment 1, we investigated the relationship between the age of animal at commencement of PNU treatment and the incidence of thymic lymphomas. Incidences of thymic lymphomas were 100, 100, 80 and 18, and average latent periods were 15.1, 18.7, 25.4 and 27.3 weeks after the start of PNU-treatment, in 5-, 10-, 20- and 40-week-old groups, respectively. In experiment 2, rats were sacrificed postnatally at 5, 10, 20, 30 and 40 weeks each, and thymus weight, number of thymocytes in the thymus, frequency of mitosis, and percentage of OX-7 (Thy 1.1), OX-8 (CD8), or W3/25 (CD4) positive cells, were examined cytologically. Thymus weight, number of cells in the thymus and mitotic index were maximum at 10 weeks old, and thereafter decreased gradually. No marked changes were observed in the ratio of each cell-surface marker positive cell. These results indicate that induction of thymic lymphomas by PNU is very closely related with the total number of mitotic cells in the thymus. Thus, chemical induction of rat thymic lymphoma reflects an age-dependent function of the thymus.

Age Factors↗

PubMed1990

Investigation into the effect of DHEA on renal carcinogenesis induced in the rat by a single dose of DMN.

Because long-term oral administration of the adrenal steroid dehydroepiandrosterone (DHEA) has previously been shown to inhibit the development of spontaneous breast cancer and chemically induced lung, colon, skin, and liver tumors in various mouse and rat strains, the effect of DHEA on the development of rat kidney tumors by a single dose of 30 mg/kg dimethylnitrosamine (DMN) was tested. DHEA was administered in the diet for a 26-week period commencing 2 weeks after DMN treatment. DHEA administration caused a reduction in body weight gain in accordance with its known antiobesity activity. However, it did not exert any inhibitory effect on either renal mesenchymal or cortical epithelial tumor induction by DMN, nor did it alter the average survival time. There was a statistically significant increase in the incidence of renal adenocarcinomas in the DHEA-treated group but not of renal adenomas. The results were discussed in relation to the mesodermal origin of kidney and the potency of single-dose systems of experimental cancer induction.

Adenocarcinoma↗

PubMed1990

Genetic regulation of the development of glomerular sclerotic lesions in the BUF/Mna rat.

BUF/Mna strain rats spontaneously develop renal glomerular sclerotic lesions (RSL) at a nearly 100% incidence, diagnosed by hyperalbuminuria (greater than 500 mg/dl) and glomerular lesions morphologically resembling one type of human focal glomerular sclerosis (FGS). Genetic segregation of RSL development was studied by crossing the BUF/Mna strain with two other rat strains, WKY/NCrj and ACI/NMs, which were free of RSL. Two autosomal recessive genes in the BUF/Mna rats were found to determine the susceptibility to RSL in both combinations of crosses.

Albuminuria↗

PubMed1989

Teratoma of the pituitary gland in a young male rat.

A pituitary teratoma was found in a 5-week-old (37-day-old) male Donryu rat. The tumour (10 x 11 x 9 mm) was round in shape and white in colour. The cut surface was solid without haemorrhagic or cystic change. Histologically, it was composed of various kinds of tissue components including mature and immature elements derived from the three embryonic germ layers, i.e., nervous tissue, cartilage, bone, squamous epithelial element, glandular element lined by one or more layers of ciliated columnar or cuboidal epithelial cells, striated muscle tissue, adipose tissue and connective tissue. Neuroepithelial rosettes and immature or embryonal epithelium as well as immature cartilage were intermingled with mature somatic tissues.

Animals↗

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↗