PubMed Health⌕ Search

Biomedical subjects

Hiroyuki Tsuda

Publications and source records attributed to Hiroyuki Tsuda.

At least 37 records · Page 2Linked to original sources
PubMed2004

Possible enhancing effects of atrazine and nonylphenol on 7,12-dimethylbenz[a]anthracene-induced mammary tumor development in human c-Ha-ras proto-oncogene transgenic rats.

Our transgenic (Tg) strain carrying copies of the human c-Ha-ras proto-oncogene is highly susceptible to 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary carcinogenesis, possibly due to activation of the transgene, and can be used in medium-term bioassay models to test for modifying effects of estrogenic environmental compounds on tumor development. The present study was conducted to assess the influence of dietary feeding of the endocrine disruptors atrazine and nonylphenol on DMBA-induced carcinogenesis in c-Ha-ras Tg rats. Animals of both sexes were given a single oral dose of DMBA (25 mg/kg body weight) at 50 days of age and thereafter received soybean-free diet containing 5, 50 or 500 ppm atrazine, or 10, 25, 100 or 250 ppm nonylphenol. In female Tg rats, atrazine at a dose of 5 ppm increased the incidences of mammary adenomas and adenocarcinomas (P < 0.01 and P < 0.05), while 50 ppm increased the adenocarcinoma incidence (P < 0.05). In males, skin tumor development, in contrast, was significantly decreased at the highest dose. Nonylphenol at 10 ppm increased adenocarcinoma and total mammary tumor multiplicity in female Tg rats (P < 0.05), but there was no dose dependence, a significant quadratic dose-response trend rather being observed (P < 0.05). In vitro, atrazine did not cause proliferation of MCF-7 cells at any of a range of doses tested. These results suggest that endocrine disruptors may enhance mammary carcinogenesis, but only in a certain limited dose range under the present experimental conditions. The doses applied, moreover, were all extremely high compared to the possible environmental human exposure levels.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2004

Isoliquiritigenin, a flavonoid from licorice, reduces prostaglandin E2 and nitric oxide, causes apoptosis, and suppresses aberrant crypt foci development.

Isoliquiritigenin (ILTG), a flavonoid group compound, exists in some foodstuffs and herbal medicines such as licorice (Glycyrrhiza uralensis Fisher). Previously, we showed that ILTG can suppress azoxymethane (AOM)-induced colon carcinogenesis in ddY mice. In the present report, we present evidence that ILTG markedly decreases both prostaglandin E2 (PGE2) and nitric oxide (NO) production in RAW264.7 mouse macrophage cells. The decrease of PGE2 was dependent on cyclooxygenase-2 (COX-2) expression and the decrease of NO appeared due to a decrease in inducible nitric oxide synthase (iNOS) protein expression. In mouse and human colon carcinoma cells, ILTG treatment suppressed cell growth and caused apoptosis. Furthermore, in vivo administration of ILTG inhibited the induction of preneoplastic aberrant crypt foci (ACF) in the male F344 rat colon. Our results suggest that ILTG is a promising chemopreventive agent against colon carcinogenesis.

Aldehyde Reductase↗
PubMed2004

Chemoprevention of colorectal cancer by grape seed proanthocyanidin is accompanied by a decrease in proliferation and increase in apoptosis.

Effects of proanthocyanidin (PA), procyanidin B-2 (B-2), and epigallocatechin gallate (EGCG) on azoxymethane (AOM)-induced colonic preneoplastic aberrant crypt foci (ACF) formation were investigated using F344 rats. The numbers of total ACF in rats treated with 0.002% PA and 0.05% B-2 were significantly decreased compared with the AOM alone group (control). Cell proliferation in the colon, as shown by proliferating cells nuclear antigen (PCNA), was also reduced in those treatments. The single-stranded DNA (ssDNA) labeling index, a marker for apoptosis, was significantly increased in 0.002% PA and 0.05% B-2 groups compared with control. Moreover, the numbers of CD11b/c+ cells (macrophages) and NKR-P1A+ cells (NK cells) in the all groups were significantly increased compared with control. In an in vitro study using rat colon cancer cell line RCN-9, PA, especially 5-10mer of PA (PA5/10), strong growth inhibition was shown. PA5/10 caused the most remarkable apoptosis as cleared by FACS analysis. These cells showed significantly increased caspase-3 activity. The results would suggest that the PA, especially PA5/10, might strongly enhance caspase-3 activity and cause apoptosis in cancer cells. PA at fairly low doses in the long term might serve as an effective means for preventing colon carcinogenesis.

Animals↗
PubMed2004

Cancer prevention by natural compounds.

Increasing attention is being paid to the possibility of applying cancer chemopreventive agents for individuals at high risk of neoplastic development. For this purpose by natural compounds have practical advantages with regard to availability, suitability for oral application, regulatory approval and mechanisms of action. Candidate substances such as phytochemicals present in foods and their derivatives have been identified by a combination of epidemiological and experimental studies. Plant constituents include vitamin derivatives, phenolic and flavonoid agents, organic sulfur compounds, isothiocyanates, curcumins, fatty acids and d-limonene. Examples of compounds from animals are unsaturated fatty acids and lactoferrin. Recent studies have indicated that mechanisms underlying chemopreventive potential may be combinations of anti-oxidant, anti-inflammatory, immune-enhancing, and anti-hormone effects, with modification of drug-metabolizing enzymes, influence on the cell cycle and cell differentiation, induction of apoptosis and suppression of proliferation and angiogenesis playing roles in the initiation and secondary modification stages of neoplastic development. Accordingly, natural agents are advantageous for application to humans because of their combined mild mechanism. Here we review naturally occurring compounds useful for cancer chemprevention based on in vivo studies with reference to their structures, sources and mechanisms of action.

Animals↗
PubMed2003

Src phosphorylates Cas on tyrosine 253 to promote migration of transformed cells.

Cas is a member of the focal adhesion complex. Phosphorylation of Cas by Src is an important event leading to cell transformation. Using mass spectrometry, we have mapped 11 sites in Cas that are phosphorylated by Src. These sites are all located between residues 132 and 414 of Cas, in a region that is required for binding to a number of other proteins including Crk. We tested synthetic peptides modeled on Cas phosphorylation sites, and found that the sequence containing tyrosine 253 was phosphorylated by Src most efficiently. Using cells derived from Cas-deficient mice, we confirmed that Cas greatly enhanced the ability of Src to transform cells. Phosphorylation of Cas on tyrosine 253 was not required for Src to increase growth rate, suppress contact inhibition, or suppress anchorage dependence. Yet, in contrast to these growth characteristics, phosphorylation of Cas on tyrosine 253 was required for Src to promote cell migration. Thus, a single phosphorylation site on this focal adhesion adaptor protein can effectively separate cell migration from other transformed growth characteristics.

Amino Acid Sequence↗
PubMed2003

Lack of initiation activity in rat liver of low doses of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline.

It has been generally accepted that genotoxic carcinogens have no threshold in exerting their potential for cancer induction. However, the non-threshold theory can be challenged for cancer risk assessment in humans. Here we examined low dose carcinogenicity of a food-derived, genotoxic hepatocarcinogen, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), using an in vivo medium-term bioassay to detect initiating activity for rat hepatocarcinogenesis. With MeIQx initiation at various doses followed by administration of phenobarbital, a well known hepatopromoter, no induction of glutathione S-transferase placental form-positive foci, assessed as preneoplastic lesions, was noted at doses of 0.001-1 ppm. The results imply a no-observed effect level for hepatocarcinogenicity with this genotoxic agent.

Animals↗
PubMed2003

Biological properties and gene expression associated with metastatic potential of human osteosarcoma.

Lung metastasis has a great influence on the prognosis of patients with osteosarcoma. We previously established two high-metastatic sublines, M112 and M132, from the HuO9 human osteosarcoma cell line by in vivo selection. In this study, we newly isolated a high-metastatic subline, H3, and three low-metastatic sublines, L6, L12 and L13, from HuO9 by the dilution plating method. Three high-metastatic sublines produced more than 200 metastatic nodules in the lung, while three low-metastatic sublines produced no or few nodules after injection of 2 x 10(6) cells into the tail vein of nude mice. There were significant differences in the motility and invasiveness between high- and low-metastatic sublines, whereas the growth rates in vitro and the tumorigenicity in vivo showed no correlation with their metastatic abilities. Early adherence to culture plates was significantly lower in two of three low-metastatic sublines, which occupied smaller surface areas on the culture plates than other sublines did. Comparison of the expression of 637 cancer-related genes by cDNA microarray revealed that seven genes were differentially expressed between high- and low-metastatic sublines. Among them, five genes (AXL, TGFA, COLL7A1, WNT5A, and MKK6) were associated with adherence, motility, and/or invasiveness. These results suggest that the differences in motility/invasiveness and adhesive abilities are key determinants of lung metastasis in osteosarcoma.

Animals↗
PubMed2003

Carcinogenesis and its modification by environmental endocrine disruptors: in vivo experimental and epidemiological findings.

Although a great deal of concern has been raised about the hazard potential of endocrine disruptors present in the environment, the in vivo data available from both experimental and epidemiological studies suggest that the majority of those agents do not pose a risk with regard to cancer development. Indeed, naturally occurring examples such as isoflavonoids even appear to exert protective effects. Only for xenobiotics such as 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT), polychlorinated biphenyls (PCBs) and tetrachloro-p-dioxin (TCDD) and special cases of phenols and phthalates is there unequivocal evidence of carcinogenicity and this appears to be directly linked to their toxicity. Thus, careful in vivo assessment is required before drawing any conclusions regarding agents capable of affecting the mammalian endocrine system.

Animals↗
PubMed2003

Lack of effect of human c-Ha-ras proto-oncogene overexpression on prostate carcinogenesis in probasin/SV40 T antigen transgenic rats.

We have previously reported that transgenic (Tg) rats bearing the SV40 T antigen under probasin promoter control (PB/SV40T) develop prostate carcinomas at 100% incidence, showing their prostate carcinoma growth to be completely androgen-dependent. Transgenic rats carrying three copies of the human c-Ha-ras proto-oncogene (Hras128) are also highly susceptible to carcinogen induction of multiple mammary carcinomas, in this case estrogen-independent, since ovariectomy does not affect mammary tumor formation. A relationship between ras/mitogen-activated protein kinase signaling and androgen responsiveness of prostate cancer cells has been reported. Therefore it is of interest to investigate whether expression of human c-Ha-ras affects the androgen-dependence of prostate carcinomas developing in the PB/SV40T Tg rat. For this purpose, we established double transgenic (rasTag) rats bearing both PB/SV40T and Hras128. In prostate tissues of the rasTag rats, expression of both human c-Ha-ras and SV40T was confirmed, but the prostate tumor incidence and growth were not significantly affected. Castration at 15 weeks of age induced complete tumor involution in the rasTag rats. These results indicate that the human c-Ha-ras proto-oncogene product does not influence the androgen-dependence of prostate carcinogenesis due to the probasin-mediated SV40 T antigen, despite the estrogen-independence of mammary carcinogenesis in Hras128 rats.

Adenocarcinoma↗
PubMed2003

A novel geranylated derivative, ethyl 3-(4'-geranyloxy-3'-methoxyphenyl)-2-propenoate, synthesized from ferulic acid suppresses carcinogenesis and inducible nitric oxide synthase in rat tongue.

OBJECTIVES: We have previously observed the inhibitory effect of ferulic acid on rat tongue carcinogenesis. In this study, we investigated the modifying effects of a novel geranylated derivative, ethyl 3-(4'-geranyloxy-3'-methoxyphenyl)-2-propenoate (EGMP), synthesized from ferulic acid on tongue carcinogenesis initiated with 4-nitroquinoline 1-oxide (4-NQO). METHODS: F344 male rats except those treated with EGMP alone and untreated rats were given 20 ppm 4-NQO in drinking water for 9 weeks to induce tongue neoplasms. Starting 1 week after the cessation of exposure to 4-NQO, the experimental groups given 4-NQO and a basal diet were fed the experimental diets containing EGMP (0.2% and 2%) for 20 weeks. The activities of glutathione S-transferase (GST) and quinone reductase (QR), the expression of proliferating cell nuclear antigen, polyamine content and ornithine decarboxylase activity in the tongue were examined for mechanistic analysis of modifying effects of EGMP on carcinogenesis. The expression of inducible nitric acid synthase (iNOS) was also assessed immunohistochemically. RESULTS: At week 30, the incidence and multiplicity of tongue squamous cell carcinoma were significantly reduced by feeding of a 2% EGMP diet. EGMP feeding (2% in diet) elevated tongue GST activity and lowered QR activity in the tongue. Dietary EGMP decreased the expression of cell proliferation biomarker expression. Interestingly, EGMP feeding altered iNOS expression in the invasive parts of carcinoma. CONCLUSIONS: These results suggest that EGMP, when given at the 2% dose level during the promotion phase, exerts a chemopreventive action against tongue tumorigenesis through modification of cell proliferation activity and/or detoxifying enzymatic activity.

4-Nitroquinoline-1-oxide↗
PubMed2002

Silymarin, a naturally occurring polyphenolic antioxidant flavonoid, inhibits azoxymethane-induced colon carcinogenesis in male F344 rats.

The modifying effect of dietary administration of the polyphenolic antioxidant flavonoid silymarin, isolated from milk thistle [Silybum marianum (L.) Gaertneri], on AOM-induced colon carcinogenesis was investigated in male F344 rats. In the short-term study, the effects of silymarin on the development of AOM-induced colonic ACF, being putative precursor lesions for colonic adenocarcinoma, were assayed to predict the modifying effects of dietary silymarin on colon tumorigenesis. Also, the activity of detoxifying enzymes (GST and QR) in liver and colonic mucosa was determined in rats gavaged with silymarin. Subsequently, the possible inhibitory effects of dietary feeding of silymarin on AOM-induced colon carcinogenesis were evaluated using a long-term animal experiment. In the short-term study, dietary administration of silymarin (100, 500 and 1,000 ppm in diet), either during or after carcinogen exposure, for 4 weeks caused significant reduction in the frequency of colonic ACF in a dose-dependent manner. Silymarin given by gavage elevated the activity of detoxifying enzymes in both organs. In the long-term experiment, dietary feeding of silymarin (100 and 500 ppm) during the initiation or postinitiation phase of AOM-induced colon carcinogenesis reduced the incidence and multiplicity of colonic adenocarcinoma. The inhibition by feeding with 500 ppm silymarin was significant (p < 0.05 by initiation feeding and p < 0.01 by postinitiation feeding). Also, silymarin administration in the diet lowered the PCNA labeling index and increased the number of apoptotic cells in adenocarcinoma. beta-Glucuronidase activity, PGE(2) level and polyamine content were decreased in colonic mucosa. These results clearly indicate a chemopreventive ability of dietary silymarin against chemically induced colon tumorigenesis and will provide a scientific basis for progression to clinical trials of the chemoprevention of human colon cancer.

Animals↗
PubMed2002

Neuronal leucine-rich repeat protein-3 amplifies MAPK activation by epidermal growth factor through a carboxyl-terminal region containing endocytosis motifs.

Neuronal leucine-rich repeat protein-3 (NLRR-3) belongs to the LRR superfamily. Expression of rat NLRR-3 gene isolated from c-Ha-ras transgenic rat tumor is regulated mainly through the Ras-MAPK signaling pathway. NLRR-3 was found to enhance phosphorylation of MAPK when COS-7 cells were transfected with NLRR-3 and stimulated with a low concentration (0.01 ng/ml) of epidermal growth factor (EGF), but the amplification of MAPK phosphorylation by NLRR-3 was no longer observed when the carboxyl-terminal 30 amino acid stretch containing clathrin-mediated endocytosis motifs was deleted. A green fluorescent protein-tagged NLRR-3 localized at the plasma membrane was efficiently internalized in COS-7 cells, but internalization of a carboxyl-terminal-deleted version (NLRRDeltaC) was less efficient. The presence of clathrin-adaptor protein complexes containing NLRR-3 in brain lysate was confirmed by immunoprecipitation and glutathione S-transferase pull-down experiments, and affinity column chromatography revealed that the carboxyl-terminal region of NLRR-3 interacts with beta-adaptin. We propose that NLRR-3 potentiates Ras-MAPK signaling by facilitating internalization of EGF in clathrin-coated vesicles.

3T3 Cells↗
PubMed2002

Photonic encoder and decoder for optical code-division multiplexing with time-to-space converters and angle-multiplexed holograms.

A photonic encoder-decoder pair for optical code-division multiplexing (OCDM) that uses time-to-space converters and angle-multiplexed holograms is proposed. The encoder converts the pulse from each input port into a specific code and multiplexes input signals into the output port. The hologram in the decoder generates a correlation waveform between the transmitted code and the recorded code. The performance of the OCDM system with the encoder-decoder pair is estimated. The maximum spectral efficiency for 8-bit length orthogonal codes in the worst case at a bit-error rate of 10(-9) is 0.17 (bits/s)/Hz when the number of channels is 8.

Journal Article↗
PubMed2002

Establishment of human osteosarcoma cell lines with high metastatic potential to lungs and their utilities for therapeutic studies on metastatic osteosarcoma.

Relevant animal models for metastasis of osteosarcoma is needed to understand the biology and to develop the treatment modality of metastasis of human osteosarcoma. Therefore, we screened six human osteosarcoma cell lines for metastatic ability in nude mice. The HuO9 cell line was identified as being metastatic to the lung after intravenous injection. We established two sublines, HuO9-M112 and HuO9-M132, with high metastatic potential to the lung from the parental HuO9 cells by in vivo selection. There were no differences between these two sublines and the parental cells in the growth rate in vitro and the tumorigenicity after subcutaneous injection in nude mice, however, mice injected with the metastatic sublines became moribund earlier than mice injected with the parental HuO9 cells did. Thus, adriamycin (ADR) and recombinant interleukin-12 (IL-12) were administered to mice injected with the HuO9-M112 subline to suppress experimental lung metastases. Production of lung colonies was significantly suppressed and the prognoses of mice were significantly improved by both ADR and IL-12 treatments. These results indicate that both ADR and IL-12 are effective agents against pulmonary metastatic osteosarcoma, and that these sublines are useful for studies on the biological behavior and treatment of pulmonary metastatic osteosarcoma.

Animals↗
PubMed2002

Inhibitory effects of 17beta-estradiol and 4-n-octylphenol on 7,12-dimethylbenz[a]anthracene-induced mammary tumor development in human c-Ha-ras proto-oncogene transgenic rats.

Experiments were conducted to determine whether the natural estrogen and an environmental compound with estrogenic action, 4-n-octylphenol (4nOP), could modify tumor development in human c-Ha-ras proto-oncogene transgenic (Tg) rats which are highly susceptible to mammary and skin carcinogens. Female and male Tg and non-transgenic (non-Tg) rats were given a single oral dose of 7,12-dimethylbenz[a]anthracene (DMBA) (25 mg/kg body weight) at 50 days of age and thereafter subcutaneously implanted with cholesterol pellets containing 0.01, 0.1 or 1.0 mg beta-estradiol 3-benzoate (E2) per rat or received diets containing 1000 or 100 p.p.m. 4nOP for 12 weeks in females or for 20 weeks in males. E2 reduced the mammary tumor incidence and multiplicity in a dose dependent manner, especially in female Tg rats. In contrast, E2 increased mammary tumor incidence and multiplicity at the lowest dose (0.01 mg), however it reduced skin tumor induction in male Tg rats. 4nOP at a dose of 100 p.p.m. decreased mammary tumor multiplicity in female Tg rats (P < 0.001). No effects were observed in males. In separate in vitro studies, E2 at low doses (10(-11)-10(-8) M) enhanced the growth of both MCF-7 and T47D cells and this was similarly the case for 4nOP at high doses (10(-7)-10(-5) M) in T47D cells. The finding that E2 and 4nOP at high doses caused reduction in mammary tumor development in female Tg and possibly non-Tg rats, may indicate that excess estrogen can exert a paradoxical inhibitory influence. E2 also appears to have bipotential effects in males, promoting mammary, but inhibiting skin carcinogenesis. These contrasting observations may be caused by differences in background physiological estrogen levels. In addition, the results suggest that Tg rats can be used in medium-term bioassay models to test for the modifying effects of estrogenic environmental compounds on mammary tumor development.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2002

Mammary carcinomas induced in human c-Ha-ras proto-oncogene transgenic rats are estrogen-independent, but responsive to d-limonene treatment.

We have previously shown that transgenic rats carrying three copies of the human c-Ha-ras proto-oncogene (Hras128) are highly susceptible to N-methyl-N-nitrosourea (MNU) mammary carcinogenesis. All transgenic rats treated with 50 mg / kg MNU, i.v. at 50 days of age, were found to rapidly develop multiple, large mammary carcinomas within as short a period as 8 weeks. In the present study, the effects of ovariectomy and treatment with d-limonene, known to inhibit mammary carcinogenesis in non-transgenic female rats, were investigated in Hras128 animals treated with MNU to clarify the role of the human c-Ha-ras proto-oncogene and to characterize the induced mammary carcinomas. Although ovariectomy completely inhibited development of mammary carcinomas in their wild-type counterparts, it did not affect either the incidence or the multiplicity of the mammary carcinomas in the Hras128 rats. On the other hand, treatment with d-limonene, an inhibitor of ras protein isoprenylation, inhibited the breast tumor development. These results indicate that aberrant c-Ha-ras gene expression is involved in ovarian hormone-independent growth and c-Ha-ras protein isoprenylation plays an important role in mammary carcinogenesis.

Adenocarcinoma↗
PubMed2002

Lack of a dose-response relationship for carcinogenicity in the rat liver with low doses of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline or N-nitrosodiethylamine.

For a long period, it has been generally considered that carcinogens, particularly genotoxic ones, have no threshold in exerting their potential for cancer induction. However, the non-threshold theory can be challenged with regard to assessment of cancer risk to humans. Here we show that a food-derived, genotoxic hepatocarcinogen, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, forms DNA adducts at low doses, but does not induce glutathione S-transferase placental form (GST-P)-positive foci (considered to be preneoplastic lesions) or 8-hydroxy-2'-deoxyguanosine in rat liver. Moreover a N-nitroso compound, N-nitrosodiethylamine, at low doses was also found not to induce GST-P-positive foci in rat liver. These results imply that there is a no-observed effect level for hepatocarcinogenesis by these genotoxic carcinogens.

Animals↗