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Biomedical subjects

S Fukushima

Publications and source records attributed to S Fukushima.

At least 109 records · Page 6Linked to original sources
PubMed1999

Urinary bladder carcinogenicity of dimethylarsinic acid in male F344 rats.

The present study was conducted to determine the carcinogenicity of dimethylarsinic acid (DMA) administered to male F344 rats in a 2 year bioassay. A total of 144 rats (10 weeks old at the start) were divided into four groups of 36 rats each. Groups 1-4 received DMA (purity 100%) at concentrations of 200, 50, 12.5 and 0 p.p.m. in the drinking water, respectively, for 104 weeks. From weeks 97 to 104, urinary bladder tumors were observed in 12 of 31, eight of 31 and none of 33 in groups 1-3, respectively. No bladder tumors were observed in group 4. The present study demonstrated that long-term p. o. administration of DMA induced urinary bladder carcinomas in male F344 rats. Therefore, the results indicate that DMA is carcinogenic for the rat urinary bladder, which may be related to the human carcinogenicity of arsenicals.

Administration, Oral↗
PubMed1999

Promotion by sodium L-ascorbate in rat two-stage urinary bladder carcinogenesis is dependent on the interval of administration.

In our two-stage model of rat urinary bladder carcinogenesis employing N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) as the initiator, sodium L-ascorbate (Na-AsA) exhibits dose-dependent promotion. In the present study, in order to assess the possible reversibility of the promoting effects, we investigated how different administration periods of Na-AsA influence its promoting activity. In experiment 1, rats were treated with 5% Na-AsA for different administration periods with or without withdrawal and injected with 5-bromo-2'-deoxyuridine (BrdU) to allow determination of the cell proliferation status. Replicative DNA synthesis in the urinary bladder epithelium was shown to return to normal after removal of the promoting stimulus. In experiment 2, rats were initially given BBN for 4 weeks and subsequently received 16 weeks of Na-AsA, alternating with basal diet, at intervals of 4, 8 or 16 weeks, within a total 32-week period. The longer the continuous exposure to Na-AsA, the greater the yield of papillomas and carcinomas in the urinary bladder. In experiment 3, Na-AsA was given for 4 or 8 weeks after BBN initiation and the animals were killed at weeks 8 and 12. Both promotion of lesion development and increase of DNA synthesis in the urinary bladder epithelium were dependent on the length of exposure to Na-AsA and the total period of exposure. The results indicate that the promoting effects of Na-AsA in urinary bladder carcinogenesis are reversible to a certain extent after its withdrawal, and the existence of a cumulative exposure time threshold seems likely.

Animals↗
PubMed1999

Urinary bladder lesions after the Chernobyl accident: immunohistochemical assessment of p53, proliferating cell nuclear antigen, cyclin D1 and p21WAF1/Cip1.

During the 11-year period subsequent to the Chernobyl accident, the incidence of urinary bladder cancer in Ukraine has increased from 26.2 to 36.1 per 100,000 population. Cesium-137 (137Cs) accounts for 80-90% of the incorporated radioactivity in this population, which has been exposed to long-term, low-dose ionizing radiation, and 80% of the more labile pool of cesium is excreted via the urine. The present study was performed to evaluate the histopathological features and the immunohistochemical status of p53, p21WAF1/Cip1, cyclin D1 and PCNA (proliferating cell nuclear antigen) in urinary bladder mucosa of 55 males (49-92 years old) with benign prostatic hyperplasia who underwent surgery in Kiev, Ukraine, in 1995 and 1996. Group I (28 patients) inhabiting radiocontaminated areas of the country, group II (17 patients) from Kiev city with less radiocontamination and a control group III (10 patients) living in so-called "clean" areas of Ukraine were compared. In groups I and II, an increase in multiple areas of moderate or severe dysplasia or carcinoma in situ was seen in 42 (93%) of 45 cases. In addition, two small transitional cell carcinomas were found in one patient in each of groups I and II. Nuclear accumulation of p53, PCNA, cyclin D1, and to a lesser extent p21WAF1/Cip1, was significantly increased in both groups I and II as compared with the control group III, indicating possible transformation events or enhancement of repair activities, that may precede the defect in the regulatory pathway itself, at least in the G1 phase of the cell cycle. Our results suggest that early malignant transformation is taking place in the bladder urothelium of people in the radiocontaminated areas of Ukraine and that this could possibly lead sometime in the future to an increased incidence of urinary bladder cancer.

Aged↗
PubMed1999

Loss of heterozygosity in (LewisxF344)F1 rat urinary bladder tumors induced with N-butyl-N-(4-hydroxybutyl)nitrosamine followed by dimethylarsinic acid or sodium L-ascorbate.

Dimethylarsinic acid (DMA), a main metabolite of arsenicals which are carcinogenic in man, exerts tumor-promoting activity on rat urinary bladder carcinogenesis initiated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). Sodium L-ascorbate (Na-AsA) is also a strong tumor promoter in this animal model. In this study, we used (LewisxF344)F, rats to compare molecular alterations in urinary bladder tumors caused by BBN followed by DMA or Na-AsA. Male, 6-week-old rats were given 0.05% BBN in their drinking water for 4 weeks, and then the rats in group 1 were maintained with no further treatment for 40 weeks. The animals of groups 2 and 3 were administered 0.01% DMA in their drinking water (group 2) or 5% Na-AsA in the powder diet (group 3) after the BBN treatment. Group 4 rats were given 0.05% BBN continuously for 36 weeks. At weeks 12, 20, 36 and 44, subgroups of rats were killed. Histopathological examination revealed promoting activity for DMA and, to a greater extent, Na-AsA on urinary bladder carcinogenesis. Loss of heterozygosity (LOH), detected with the polymerase chain reaction using 36 microsatellite markers, was found to be present in 2 of 9 (22%) urinary bladder tumors after treatment with DMA and 3 of 22 (14%) induced by continuous administration with BBN. No LOH was, however, detected in urinary bladder tumors after treatment with Na-AsA. The results thus suggest that the mechanisms of action of these two promoters, DMA and Na-AsA, may differ in rat urinary bladder carcinogenesis.

Animals↗
PubMed1999

Low-dose-dependent carcinogenic potential of 2-amino-3-methylimidazo[4,5-f]quinoline in the immunodeficient (SCID) mouse colon.

The carcinogenic potential of 2-amino-3-methyl-imidazo[4,5-f]quinoline (IQ), one of the most potent mutagenic heterocyclic aromatic amines in food, for the colon was assessed in mice with severe combined immunodeficiency (SCID). In Experiment I, 60 male animals, 7-8 weeks old, were administered 300, 100, or 0 ppm IQ in the diet for 20 weeks. The incidence of aberrant crypt foci (ACF), preneoplastic lesions, was 100% in the two IQ-administered groups, whereas no ACF were found in the controls. Larger lesions, at least four aberrant crypts per focus, were noted in the colons of both treated groups. Most ACF were located in the proximal colon, and the bromodeoxyuridine-labeling indexes were elevated in a dose-dependent manner, especially in this region. In Experiment II, IQ was administered in the diet at 50, 10, 2, or 0 ppm to 60 female and male 7- to 8-week-old SCID mice for 30 and 23 weeks, respectively. The incidence of ACF was dose dependent in both sexes: 100%, 100%, and 63% in the females administered 50, 10, and 2 ppm, respectively, and 100%, 83%, and 38%, respectively, in the males. Lesions of at least four aberrant crypts per focus were again evident with the 50-ppm dose. The long-term or higher dose administration of IQ in the diet might thus be applied to elucidate colon carcinogenesis in the SCID mouse.

Animals↗
PubMed1999

Enhancement of propylene glycol distribution in the skin by high purity cis-unsaturated fatty acids with different alkyl chain lengths having different double bond position.

Enhancement of skin distribution of propylene glycol (PG) in the skin by high purity cis-unsaturated fatty acids with different alkyl chain lengths was studied in the rat using Fourier transform/attenuated total reflection (FT-IR/ATR) analysis. Two fatty acids with the double bond at the delta9 position, palmitoleic acid (omega7, delta9) and oleic acid (omega9, delta9), enhanced PG flux into the dermis and increased the dermal steady state level of PG. In contrast, myristoleic acid (omega5, delta9) was extremely weak in its action. A positional effect of the omega chain was observed. The rate of skin structural alteration increased in proportion to omega chain length. The application of three fatty acids with the double bond at the omega9 position, oleic acid (omega9, delta9), gondoic acid (omega9, delta11), erucic acid (omega9, delta13) enhanced PG distribution in the skin. While, nervonic acid (omega9, delta15) did not increase PG distribution in the skin. The relationship of the delta/omega ratio to parameters characterizing the action of enhancers (PG(peak area max), T(max alteration), and the slope) suggest that skin distribution increases as the position of the double bond is shifted toward the hydrophilic end. It is therefore likely that the ratio of the delta/omega chain length of the cis-unsaturated fatty acid determines the efficacy of these compounds as skin penetration enhancers. An adequate molecular volume may be required for cis-unsaturated fatty acids to act as enhancers.

Animals↗
PubMed1999

Lack of inhibitory effects of the Ju-myo protein on development of glutathione S-transferase placental form-positive foci in the male F344 rat liver.

The effects of the 77 kDa Ju-myo protein, isolated from Drosophila melanogaster, on the development of glutathione S-transferase placental form (GST-P) positive foci in the male F344 rat liver were evaluated using a medium-term bioassay system. No modifying potential was evident in terms of the numbers or areas of GST-P positive foci. Ju-myo protein did not exert any influence on cell proliferation, as reflected by ornithine decarboxylase (ODC) or spermidine/spermine N1-acetyltransferase (SAT) activity and BrdU labeling. These results demonstrated that Ju-myo protein is unlikely to have inhibitory or promoting effects on rat liver carcinogenesis.

Acetyltransferases↗
PubMed1999

Selective delivery of adriamycin to a solid tumor using a polymeric micelle carrier system.

The anticancer drug, adriamycin (ADR), was incorporated by physical entrapment into polymeric micelles for selective delivery to a murine solid tumor colon adenocarcinoma 26 (C 26). In vivo antitumor activity of ADR was greatly enhanced by this incorporation into polymeric micelles. Using one polymeric micelle delivery system, the tumor completely disappeared at two doses, while free ADR exhibited a fair inhibition effect on tumor growth only at the maximum tolerated dose. Biodistribution analysis revealed that the physically entrapped micellar ADR accumulated at tumor sites in a highly selective manner. These results indicate that these polymeric micelles are a promising system for delivering hydrophobic anticancer drugs selectively to solid tumor sites using a passive targeting mechanism.

Adenocarcinoma↗
PubMed1999

[Mediastinoscopic resection combined with a sternum lift technique in a case of thymic cyst].

We report on a case of thymic cyst which was successfully treated with mediastinoscopic resection combined with a sternum lift technique. A 62-year-old man was admitted to our hospital with a thymic cyst, which was causing chest discomfort and was increasing in size. The tumor was located above the pulmonary artery in the anterior mediastinum. He underwent mediastinoscopic resection while lifting the inferior portion of the sternum with a Laparolift. The cyst was resected sharply and bluntly with the Harmonic Scalpel without rupture. The patient was discharged on the 6th postoperative day in a good condition. Mediastinoscopic resection of a thymic cyst through a xiphoid approach is a useful surgical approach because of the absence of postoperative pain and because it allows early discharge from the hospital.

Endoscopy↗
PubMed1999

An autopsy report of graft-versus-host disease (GVHD) following blood transfusion.

A case of graft-versus-host disease (GVHD) associated with blood transfusion in a 71-year-old man is reported. The patient received transfusions (irradiation red cells M.A.P 14 units, fresh frozen plasma 11 units) and developed features of GVHD including fever, a skin rash, diarrhea, liver dysfunction, hypoplastic bone marrow, and pancytopenia. He died on day 32 posttransfusion. Pathologically, lymphocyte infiltration of skin and liver lesions, degeneration of small bile ducts, crypt cell necrosis in the gastrointestinal tract, and bone marrow hypoplasia were observed. Immunohistochemically, infiltrating lymphocytes were CD8+ T type, the result suggesting that they role a part in posttransfusion GVHD.

Aged↗
PubMed1998

Promotion of NCI-Black-Reiter male rat bladder carcinogenesis by dimethylarsinic acid an organic arsenic compound.

Dimethylarsinic acid (DMAA) is a major metabolite of inorganic arsenicals in mammals. In the present study, we investigated its promoting effects on urinary bladder carcinogenesis in NCI-Black-Reiter (NBR) rats, which lack alpha2u-globulin synthesizing ability. Male 9-14-week-old NBR rats were treated sequentially with 0.05% N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) for 4 weeks and then given 100 ppm DMAA in their drinking water (group 1) for 32 weeks. Induction of preneoplastic lesions (papillary or nodular hyperplasia) in this DMAA-treated group was significantly increased as compared to the carcinogen alone control group (P < 0.01). The development of carcinomas was also enhanced and a significant increase in the 5-bromo-2'-deoxyuridine (BrdU) labeling index of the urinary bladder epithelial cells was observed for the DMAA treatment group. These results indicate that DMAA has promoting effects on urinary bladder carcinogenesis even in NBR rats, so its effects are not dependent on the presence of alpha2u-globulin.

Alpha-Globulins↗
PubMed1998

Infrequent somatic mutation of the adenomatous polyposis coli gene in aberrant crypt foci of human colon tissue.

BACKGROUND: The authors examined somatic mutations of the adenomatous polyposis coli (APC) gene in 84 human aberrant crypt foci (ACF) to determine whether APC gene mutations were involved in the histologic progression of ACF. METHODS: Mutation cluster regions of the APC gene were subjected to polymerase chain reaction single-strand conformation polymorphism analysis and direct sequencing. RESULTS: Four kinds of deletion were detected in the mutation cluster regions of APC gene in five ACF. APC mutation was detected in 1 of 18 ACF with Stage I abnormalities (6%). Four of 10 adenomatous ACF (40%) harbored the mutation. There were no mutations in 56 hyperplastic ACF. CONCLUSIONS: These results suggest that APC mutations may be involved initially in only a limited number of adenomas in ACF.

Adenomatous Polyposis Coli↗
PubMed1998

High susceptibility of p53(+/-) knockout mice in N-butyl-N-(4-hydroxybutyl)nitrosamine urinary bladder carcinogenesis and lack of frequent mutation in residual allele.

The loss of p53 functions is considered to compromise the growth-suppression machinery of the cell and facilitate neoplastic change. In humans, genetic alteration in the p53 gene is one of the most frequently observed molecular changes in tumors, including urinary bladder carcinomas. We have investigated the susceptibility of heterozygote p53 knockout mice to N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in terms of urinary bladder tumor induction. Both p53(+/-) knockout mice and C57BL/6 original parent strain were administered 0, 0.002, 0.004, 0.0075 and 0.025% BBN in the drinking water for 20 weeks. As compared with the C57BL/6 strain, greater lesion yields were observed in knockout mice after 20 weeks of treatment. Transitional cell carcinomas were found in 9 (75%) and 12 (100%) of each 12 mice of the 0.0075 and 0.025% BBN treatment groups, respectively, whereas only 1 (11%) and 6 (67%) of each 9 of the C57BL/6 mice demonstrated tumors. Preneoplastic lesions (dysplasia) were also observed more frequently in the lower dose groups in the knockout mice than C57BL/6 mice. PCR single-strand conformation polymorphism analysis followed by DNA direct sequencing of the p53 gene (exons 5-8) extracted from bladder tumors demonstrated mutations in 3 of 11 (27.3%; exon 7) and 8 of 29 (27.6%; exons 5-8) tumors in C57BL/6 and knockout mice, respectively. There was no significant difference in the mutation rates at the residual p53 gene between the two cases. All mutations observed in knockout mice were restricted to the normal allele, and none were present in the gene-targeted null allele. In a separate experiment, 5-bromo-2'-deoxyuridine labeling indices after treatment with BBN for 2 or 4 weeks were significantly higher in knockout mice than wild-type mice. Measurement of the urinary concentration of N-butyl-N-(3-carboxypropyl)nitrosamine, a proximate carcinogenic metabolite, revealed no significant differences between knockout and original parent strain after administration of 0.0075% BBN in the drinking water for 4 weeks. In conclusion, knockout mice are distinctly more sensitive to urinary bladder carcinogenesis induced by BBN than their original parent strain, as evidenced by elevated DNA synthesis during carcinogen administration and an increased tumor yield. The high susceptibility of p53 knockout mice appeared to be related to the high level of cell proliferation rather than that of N-butyl-N-(3-carboxypropyl)nitrosamine in the urine or that of mutations at the p53 gene.

Alleles↗
PubMed1998

Rational design of antitumor prostaglandins with high biological stability.

microolecular design can overcome the metabolic instability of Delta7-PGA1, while maintaining its antitumor potency. Saturation of the C(13)-C(14) double bond enhances the biological stability but decreases the antiproliferative activity. Configurational inversion of the isomerase-sensitive C(12) stereocenter from the natural S to the unnatural R geometry not only enhances biological stability but also significantly suppresses the growth of the tumor cells. The 12R derivatives markedly increase the induction of p21, a Cdk inhibitor, leading to sharp cell cycle arrest at the G1 phase at a dose level so low that at this dose Delta7-PGA1 methyl ester scarcely exerts an effect. These conspicuous biological properties lead to long-term suppression of tumor cell growth. The structure-stability relationship demonstrates that the stability of prostaglandins (PGs) is crucially controlled by the C(12) configuration and is unaffected by the geometry of the hydroxy-bearing C(15). The successful design of antitumor PGs resistant to enzymatic metabolism provides a new strategy applicable to creating a useful PG for cancer chemotherapy.

Animals↗
PubMed1998

Urinary excretion of arsenic metabolites after long-term oral administration of various arsenic compounds to rats.

The metabolism of arsenic compounds in rats was studied by comparing urinary metabolites of arsenic compounds administered for 1 wk or 7 mo. Male F344/DuCrj rats were given 100 mg As/L as monomethylarsonic acid (MMA), dimethylarsinic acid (DMA), trimethylarsine oxide (TMAO), or arsenobetaine (AsBe), or 10 mg As/L as arsenite [As(III)] via drinking water for 7 mo. Urine was collected by forced urination after 1 wk or 7 mo. Arsenic metabolites in urine were analyzed by ion chromatography with inductively coupled plasma mass spectrometry. In the case of As(III) ingestion, a small portion of all arsenic excreted in urine (about 6%) was excreted in inorganic form, while most arsenic was excreted as methylated arsenic metabolites. Following MMA treatments for 1 wk or 7 mo, the predominant products excreted were unchanged MMA and DMA accompanied by small amounts of TMAO and tetramethylarsonium (TeMA). In the case of DMA treatment the urinary compounds found were mainly the parent DMA and TMAO with minute amounts of TeMA. TMAO was methylated to TeMA to a slight extent after 1 wk and 7 mo of administration, although most TMAO was excreted in the form of unchanged TMAO. AsBe was predominantly eliminated in urine without any transformation. Two unidentified metabolites were detected in urine after 7 mo of arsenic species exposure; the amounts of these metabolites increased in the order DMA > MMA > TMAO with only small quantities of these detected in the As(III)-treated group. These results suggest that these unidentified metabolites are formed during a demethylation process, and not during methylation. Our findings indicate that long-term exposure to As(III), MMA, or DMA decreases the proportion of TMAO elimination in urine and increases that of DMA, M-1, and M-2, and that further methylation to TMAO to TeMA does occur to a slight extent following long-term exposure to arsenical compounds in rats.

Administration, Oral↗
PubMed1998

Structural significance of azaheterocyclic amines related to Parkinson's disease for dopamine transporter.

We have evaluated the neuronal uptake of 12 neutral and quaternary azaheterocyclic amines that are possible candidates for idiopathic Parkinson's disease via dopamine transporter of striatal synaptosomes. The double-reciprocal plots for dopamine transporter obtained from Wistar rat and C57BL/6 mouse synaptosomes with N-methyl-4-phenylpyridinium cation (MPP+) as a substrate were identical to each other. Neutral beta-carbolines and tetrahydroisoquinolines were unfavorable substrates for dopamine transporter. The quarternization of these compounds strikingly increased the affinity for dopamine transporter with 2-10 times greater Km and 10 times smaller Vmax values than MPP+. Although catechol tetrahydroisoquinolines were weak substrates, their quarternization reduced their original properties as substrates for dopamine transporter. These results provide both topographic and electrogenic information of azaheterocyclic amines for the dopamine transporter-mediated influx. The intramolecular distance between the N-atom and the centroid of the benzene ring could be an important factor for the recognition of binding site of dopamine transporter, and an adequate net charge similar to dopamine would be further required for translocation into the cells.

1-Methyl-4-phenylpyridinium↗