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T Masui

Publications and source records attributed to T Masui.

At least 55 records · Page 3Linked to original sources
PubMed1996

Large deletions at the HPRT locus associated with the mutator phenotype in a Bloom's syndrome lymphoblastoid cell line.

Bloom's syndrome (BS) is an autosomal recessive disorder with a high cancer incidence. BS cells exhibit increased chromosomal instability and sister-chromatid exchange. The rate of spontaneous mutation at the locus encoding hypoxanthine phosphoribosyltransferase (HPRT) in a lymphoblastoid cell line derived from a BS patient, GM3403, was 1.39 x 10(-6) mutations/cell/generation, whereas that in TK6, a lymphoblastoid cell line derived from an individual who is not suffering from BS, was 1.75 x 10(-8) mutations/cell/generation. Molecular analysis of the HPRT gene in mutant clones by multiplex polymerase chain reaction revealed that 83.3% of the spontaneous mutants from GM3403 cells contained deletions at the HPRT locus, whereas 30.8% of mutants from TK6 cells had deletions. Approximately half of the BS mutants had lost the entire gene. Some mutant clones of GM3403 had also lost markers near the HPRT locus, although no mutant clones from TK6 cells had lost these markers. These results indicate that the mutator phenotype of BS cells is mainly due to an increase in large DNA alterations, reflecting the remarkable genomic instability that could be responsible for cancer proneness in this disease.

Bloom Syndrome↗
PubMed1996

Immunohistochemically demonstrated variation in expression of cathepsin E between uracil-induced papillomatosis and N-butyl-N-(4-hydroxybutyl)nitrosamine-induced preneoplastic and neoplastic changes in rat urinary bladder.

Expression of rat urinary bladder cathepsin E in benign papillomatosis induced by uracil and various stages of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-induced carcinogenesis was investigated immunohistochemically. Seven-week-old, male F344/DuCrj rats were used. In the normal urothelium of control rats, cathepsin E stained in all layers of cells, although in umbrella cells and some basal cells the reaction was relatively weak. In rats given a diet containing 3% uracil for 5 weeks immunoreactivity of cathepsin E in uracil-induced papillomatosis was consistently homogeneous in all layers, but weaker than in normal urothelium. In rats given 0.05% BBN in drinking water for 12 weeks and subsequently maintained without treatment for 48 weeks cells with little cathepsin E, never observed in normal urothelium, appeared at 5 weeks above the basement membrane in the earliest stage of BBN-induced urinary bladder cancer (simple hyperplasia). Throughout the neoplastic process, groups of cells with a little cathepsin E were randomly distributed, with expression in the urothelium being markedly unstable. Almost all areas of squamous cell proliferation in TCC were negative for cathepsin E. Instability of cathepsin E expression in rat urothelium therefore appears characteristic for carcinogenesis and offers the possibility of using this feature as an early biomarker for urinary bladder carcinogenesis.

Animals↗
PubMed1996

Expression of hepatocyte growth factor and c-met mRNAs during rat chemically induced hepatocarcinogenesis.

The receptor for hepatocyte growth factor (HGF), a potent hepatocyte mitogen, is the product of the protooncogene c-met. In order to cast light on their significance for hepatocarcinogenesis, levels of both HGF and c-met mRNA were evaluated in rat livers during development of 2-acetylaminofluorene (2-AAF)-selected preneoplastic nodules and carcinomas following diethylnitrosamine (DEN) initiation. Rats were given a single i.p. injection of 200 mg/kg body wt DEN and, starting 2 weeks later, were administered 0.015% 2-AAF in the diet for up to 6 weeks. All rats were subjected to partial hepatectomy (PH) at week 3. Additional animals undergoing the DEN, 2-AAF and PH regimen were sacrificed at week 40 to allow evaluation of carcinomas. Oval cell proliferation, glutathione S-transferase placental form (GST-P)-positive preneoplastic lesion development and HGF and c-met mRNA levels were sequentially analyzed after PH. Numerous oval cells were observed 1 week after PH, but were remarkably reduced 2 weeks thereafter. The areas of GST-P-positive foci and nodules rapidly increased with time not only during 2-AAF feeding, but also to the same degree for at least 2 weeks after cessation of carcinogenic insult. Dot blot analysis showed HGF transcripts to be elevated after PH and during the selective growth conditions of 2-AAF feeding, dropping after cessation of carcinogenic insult. In the c-met transcript case transient increases were observed after PH, followed by a decrease. c-met over-expression in nodular livers did not correlate with the presence of 2-AAF or lesion development. In most hepatocellular carcinoma samples expression of both HGF and c-met mRNAs was below levels in non-neoplastic regions. These data suggest that HGF and c-met are directly involved in a paracrine growth pathway controlling proliferation in normal hepatocytes and oval cells, but not in preneoplastic and neoplastic cells.

2-Acetylaminofluorene↗
PubMed1996

Chemically induced lung and forestomach neoplasias in transgenic mice carry mutant forms of the human c-Ha-ras transgene.

Susceptibility to lung carcinogens and genetic changes in neoplastic lesions were investigated in transgenic mice carrying a human hybrid c-Ha-ras gene, encoding a prototype p21 gene product. Nine-week-old male and female transgenic mice and non-transgenic littermates were injected i.p. with 6-nitrochrysene (6NC) three times biweekly or administered urethane in their drinking water for 3 weeks. Control mice were given dimethylsulfoxide (DMSO), the solvent for 6NC, alone. The incidences of lung adenocarcinomas were four out of seven female (57%) transgenic mice treated with 6NC and three out of three males (100%) and three out of three females (100%) receiving urethane. No adenocarcinomas were observed in control animals or non-transgenic mice. Adenomas developed in all treated groups, but the incidence and multiplicity were higher in transgenic animals than in their non-transgenic counterparts. In the 6NC-treated group, forestomach papillomas and squamous cell carcinomas were also observed in both male (25 and 50%) and female (56 and 33%) transgenic mice. PCR-SSCP and DNA sequence analysis of these induced lesions revealed point mutations at codon 61 of transgenic human c-Has-ras, from CAG (Gln) to CTG (Leu) or CAG (Gln) to AAG (Lyn) in lung hyperplasias (two out of three), an adenoma (one out of two), adenocarcinomas (five out of seven) and forestomach squamous cell carcinomas (four out of five). Mutations were not observed in forestomach papillomas. No changes in mouse Ha-ras or Ki-ras were found in any lesions. Furthermore, p21 overexpression was not evident in lung or forestomach tumors on immunohistochemical analysis. These findings indicate a high sensitivity to lung carcinogens in transgenic mice carrying the human c-Ha-ras gene and that this might be effected by mutational activation.

Animals↗
PubMed1996

Monoclonal development of squamous cell carcinomas from polyclonal papillary or nodular hyperplasias in the forestomach of C3H/HeN<-->BALB/c chimeric mice treated with N-methyl-N-nitrosourea or diethylnitrosamine.

The clonality of epithelial proliferative lesions of forestomach carcinogenesis was immunohistochemically investigated in C3H/HeN<-->BALB/c chimeric mice using a specific antibody to C3H strain specific antigen (CSA) and as well as in terms of microsatellite DNA polymorphism patterns. The C3H/HeN<-->BALB/c chimeric mice were produced by an aggregation procedure. Male chimeric, C3H/HeN, and BALB/c animals were given N-methyl-N-nitrosourea (MNU) 0.5 mg/mouse once a week for a total of 10 times by intragastric intubation or 30 p.p.m. diethylnitrosamine (DEN) in their drinking water for 20 weeks. Those treated with MNU were killed at weeks 11, 25 and 45 and with DEN at week 35. Normal chimeric forestomach epithelium was found to demonstrate mixtures of epithelial cell groups composed of either CSA positive or negative cells. The same was the case for all simple hyperplasias. Papillary and nodular (PN) hyperplasias increased with time even after cessation of MNU treatment and many of them consisted of both CSA positive and negative cell groups. In one case, a CSA positive and a negative cancer were observed to have developed independently in the same PN-hyperplasia consisting of both parental cell types. In 28 tumor bearing chimeric mice, all squamous cell carcinomas (SCCs) were composed entirely of either CSA positive or negative tumor cells. However, in two animals with advanced CSA positive cancers and negative cancers, tiny cancer nests composed of both parental type cells were found in association. Microsatellite DNA polymorphism patterns of DNAs sampled from histological sections completely conformed with the outcomes of immunohistochemical staining. The results suggest that PN-hyperplasias are aggregates (polyclonal) of preneoplastic changes from which monoclonal SCCs are derived. Polyclonal cancers may also arise secondarily at low incidence during progression, due to two or more lesions coalescing.

Animals↗
PubMed1996

Dose-dependent induction of mammary carcinomas in female Sprague-Dawley rats with 2-amino-1-methyl-6-phenylimidazol[4,5-b]pyridine.

The dose-dependence of 2-amino-l-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) induction of mammary carcinomas was investigated in female Sprague-Dawley (SD) rats given PhIP in the diet for 48 weeks at concentrations of 0, 25, 100 and 200 ppm in experiment 1, and 0, 12.5, 50 in experiment 2. Yields of ductular lesions, including intraductal papillomas and carcinomas, as well as papillo-tubular and solid-tubular carcinomas, showed dependence on the dose, with the respective total incidences being 0, 4.8, 25, 72.2 and 0, 10 and 35%. There was thus no apparent carcinogen exposure threshold. The present results confirmed the carcinogenicity demonstrated in a previous study using F344 rats and revealed the SD rat strain to be more susceptible.

Adenocarcinoma↗
PubMed1996

Assessment of early radiation effects on the liver. Comparison of SPECT and MR.

PURPOSE: To evaluate the early effects of radiation on the liver using single photon emission CT (SPECT) with 99mTc-phytate combined with a pinhole collimator and MR imaging with superparamagnetic iron oxide (SPIO) and to compare 2 modalities regarding the assessment of the reticuloendothelial cell function. MATERIAL AND METHODS: The right sides of the livers of 12 anesthetized rats were irradiated with X-rays (4000 cGy). On the 3rd and 4th days postirradiation, SPECT and MR imaging pre- and postcontrast were performed. RESULTS: On SPECT, the irradiated areas appeared as areas with reduced 99mTc-phytate uptake in 9 rats. In the remaining 3 rats, irradiated lesions were not evident on SPECT. On the early postcontrast MR images, differential negative enhancement of the irradiated and nonirradiated areas in the same 9 rats as on SPECT was apparent. However, on the later postcontrast images of 3 of these rats, the irradiated areas, which were brighter than the nonirradiated areas, were visually less clear than those on the earlier postcontrast images. In the remaining 3 rats, no radiation damage was evident on MR images. CONCLUSION: SPECT with 99mTc-phytate and early postcontrast MR imaging with SPIO can show early radiation damage of the liver. The serial assessment of the postcontrast MR images provides functional information on the Kupffer cells.

Animals↗
PubMed1995

Progression of hormone-dependent adenocarcinoma cells to hormone-independent spindle carcinoma cells in vitro in a clonal spontaneous rat mammary tumor cell line.

A hormone-dependent, clonal carcinoma cell line, designated RM22-F5, was derived from a malignant mammary mixed tumor spontaneously arising in an outbred old female Wistar rat. These cells expressed keratin and desmosomal protein and formed epithelial monolayers in a growth factor and hormone-supplemented medium (LHC-8) containing 10% fetal bovine serum (E-type cells). Cells subcultured for 6 to 8 passages in RPMI 1640 medium containing 10% fetal bovine serum without supplements appeared to be fibroblastic and expressed vimentin (F-type cells). The shift to a fibroblast-like morphology was associated with a more malignant phenotype which included rapid, hormone-independent growth and invasive sarcoma-like character in nude mice. F-type cells were no longer able to express their original epithelial phenotype in LHC-8 medium. Cytogenetic analysis revealed that both E- and F-type cells had essentially the same karyotype. Analysis of PCR-amplified DNA further demonstrated a point mutation of the H-ras-1 gene at codon 12 and loss of the normal H-ras-1 allele in both cell types. Genetic tagging of E-type cells with the neomycin-resistance gene resulted in the generation of F-type cells with neomycin resistance in RPMI 1640 medium, suggesting that F-type cells are a malignant variant of E-type cells arising during in vitro culture. Somatic cell fusion between E- and F-type cells revealed that with most hybrid clones tested, the fibroblast-like phenotype was greatly suppressed. These results suggest that an irreversible phenotypic transition, representative of tumor progression from hormone-dependent adenocarcinoma to more malignant hormone-independent spindle carcinoma cells, is a recessive event and may involve loss of a suppressor function.

Adenocarcinoma↗
PubMed1995

Ki-ras mutations with frequent normal allele loss versus absence of p53 mutations in rat prostate and seminal vesicle carcinomas induced with 3,2'-dimethyl-4-aminobiphenyl.

We have developed a prostate carcinogenesis model in Fischer 344 rats using 3,2'-dimethyl-4-aminobiphenyl (DMAB) as a carcinogen to examine various potential modifying factors. In this study, mutational changes in the ras and p53 genes were assessed in DMAB-induced rat prostate and seminal vesicle carcinomas by single-strand conformation polymorphism analysis and subsequent direct DNA sequencing. Eight of 22 prostate adenocarcinomas (three of nine (33.3%) from the ventral lobe and five of 13 (38.5%) from the dorsolateral lobe, including three transplantable tumors) and one of 11 seminal vesicle adenocarcinomas (9.1%) demonstrated point mutations in the Ki-ras gene. One prostate malignant fibrohistiocytoma examined was negative. Among the positive cases, five (three ventral prostate carcinomas and two transplantable tumors) also showed loss of the normal allele. In contrast, other than one mutation in the p53 gene in the malignant fibrohistiocytoma, there were no mutations in the Ha-ras or p53 genes. These results indicate that mutational activation of the Ki-ras gene, but not of the Ha-ras or p53 genes may play a mechanistic role in prostate and seminal vesicle carcinogenesis by DMAB and that a loss of the normal allele of the Ki-ras gene may also be involved in the process.

Adenocarcinoma↗
PubMed1995

Establishment of an outgrowth culture system to study growth regulation of normal human epithelium.

To study the growth regulation of epithelial cells as a sheet, I developed an outgrowth culture system for normal human ectocervical epithelial (NHCE) cells, whereby outgrowths from tissue explants increase their radius in a constant rate over time. Cinematographic observation revealed that throughout the outgrowths the cells coordinately migrate and proliferate. To date, all 59 specimens examined have shown similar growth characteristics, with explant size not causing any difference in the growth rate; 10(8) cells/specimen can easily be obtained in 3 wk. Cell densities of outgrowths also remain constant. Moreover, there is no fibroblast contamination, and removal of explants does not affect growth rate. Therefore, pure epithelial outgrowth in uniform growth condition can be prepared for further experiments. The results demonstrate that the outgrowth culture system is an attractive model for analysis of growth control mechanisms in normal human epithelium in vitro.

Blood↗
PubMed1995

Acute hemodynamic effects of intravenous bolus injection of ionic and nonionic magnetic resonance contrast media.

RATIONALE AND OBJECTIVES: With the development of fast magnetic resonance (MR) imaging, bolus injection of contrast media is often required. We evaluated the acute hemodynamic effects of intravenous (i.v.) bolus injection of two MR contrast media: ionic gadopentetate dimeglumine and nonionic gadoteridol. METHODS: Twenty normal rats were anesthetized, and the left ventricular pressure (LVP), right atrial pressure (RAP), peripheral arterial pressure (PAP), positive rate pressure development (dP/dt) of the left ventricle, and heart rate were continuously monitored up to 10 min after bolus injections of 0.1, 0.3, and 0.5 mmol/kg of either media. RESULTS: Bolus injections of gadopentetate dimeglumine induced temporal reduction of the blood pressure (the peak LVP was -25.0% at 0.5 mmol/kg and -13.2% at 0.3 mmol/kg). At the injected doses of 0.5 and 0.3 mmol/kg, the systolic PAP, mean PAP, and dP/dt were reduced. The lowest peak systolic LVP was observed at around 20 sec after injection. Those suppressed values returned to the control values within 120 sec. Injection of high doses of gadoteridol caused a temporal increase in the peak systolic LVP (9.2% at 0.5 mmol/kg and 7.4% at 0.3 mmol/kg), systolic PAP, and dP/dt. Approximately 15 sec after injection, the highest peak systolic LVP was observed, and within 30 sec the value normalized. With both ionic and nonionic contrast media, a dose of 0.1 mmol/kg did not cause significant changes in hemodynamics. CONCLUSION: In normal rats, bolus i.v. injection of high-dose gadopentetate dimeglumine has negative hemodynamic effects; gadoteridol produces mild positive effects.

Analysis of Variance↗
PubMed1995

Frequent mutations of the p53 gene and infrequent H- and K-ras mutations in urinary bladder carcinomas of NON/Shi mice treated with N-butyl-N-(4-hydroxybutyl)nitrosamine.

To elucidate whether common genetic events in human urinary bladder carcinogenesis also occur in rodent models, we investigated the presence of p53, H- and K-ras mutations in 18 urinary bladder carcinomas induced by various concentrations of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in male NON/Shi mice. Histopathologically, all were invasive, 11 being squamous cell carcinomas (SCCs) and the remaining seven being transitional cell carcinomas (TCCs). Using polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) analysis followed by DNA sequencing, p53, H- and K-ras mutations were observed in 14 (78%; exons 5-7), two (11%; one each on exons 1 and 2) and one (5.6%; exon 1) animals respectively. The frequencies of mutations in p53 exons 5, 6 and 7 were 7 (39%), 4 (22%), and 9 (50%) respectively, and no mutation was found in exon 8. All mutations involved one base-pair substitution with or without amino acid changes and the types of base-pair substitution were random. No evident association was observed between mutation sites and the histological phenotypes. In conclusion, p53 mutations are frequent in BBN-induced mouse invasive urinary bladder tumors, at similar levels to those observed for human high-grade invasive carcinomas, and this plus their distribution suggests their possible participation in this model of urinary bladder carcinogenesis.

Amino Acid Sequence↗
PubMed1995

Evaluation of effects of chitosan in preventing hemorrhagic cystitis in rats induced by cyclophosphamide.

Hemorrhagic cystitis is a common problem following cyclophosphamide or radiation therapy. Chitosan has been shown to be an effective hemostatic agent and promoter of wound healing in animal experiments. We evaluated the safety and efficacy of intravesical chitosan in an animal model of cyclophosphamide cystitis. Hemorrhagic cystitis was induced in female F344 rats by intraperitoneal cyclophosphamide, 100 mg/kg. Chitosan solution (0.3 ml) was instilled intravesically on day 1 (Group 1), on days 1, 3, and 5 (Group 2), or 1 hour after the administration of cyclophosphamide (Group 3). The rats in group 4 were treated with chitosan diluent on day 1 after cyclophosphamide, and the rats in group 5 received intravesical chitosan without cyclophosphamide. Sequential examination revealed decreased mortality and lower incidences of severe bladder bleeding, necrosis and inflammation in Group 3. Treatment delayed until after the appearance of the cystitis, especially repeated treatments, appeared to make the cyclophosphamide-induced changes worse. Used within 1 hour of cyclophosphamide administration, before the cystitis develops, chitosan seemed to have the possibility to inhibit the appearance of hemorrhagic cystitis. In addition to the changes in the bladder, severe changes occurred in the kidneys secondary to cyclophosphamide.

Administration, Intravesical↗
PubMed1995

Carcinogenicity of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in rats: dose-response studies.

The carcinogenic potential of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), identified as the most abundant mutagenic heterocyclic amine in cooked meat and fish, was investigated in dose-response studies. Six-week-old F344 rats of both sexes were administered PhIP in the diet at concentrations of 0, 25, 100, or 400 ppm for up to 104 weeks. Animals receiving the highest dose were killed at week 52 due to marked retardation in body weight gain. PhIP was demonstrably carcinogenic for the colon in males and for the mammary glands in females, in a clear dose-dependent manner for both cases. Mammary carcinogenicity of PhIP was also confirmed in female SD rats with a clear dose-response relationship. In rat two-stage carcinogenicity models, PhIP exerted tumor-promoting activity in the small intestine as well as in the large intestine, but no promoting effects were apparent in the liver, although DNA adducts were formed dose dependently. The virtually safe dose (VSD) at the 10(-6) risk level calculated from the long-term carcinogenicity test was 0.023-0.52 ppm in the diet. This range of values is very close to or lower than human intake in daily life. Since PhIP is a most abundant heterocyclic amine and its carcinogenic organotropism overlaps with the types of neoplasias most commonly observed in western countries, the compound is likely to be extremely important with respect to human cancer development.

Adenocarcinoma↗
PubMed1994

Hepatocyte growth factor region specifically stimulates gastro-intestinal epithelial growth in primary culture.

Hepatocyte growth factor (HGF) stimulated the growth of fetal rat gastrointestinal epithelial cells in primary culture with a clear dose-response relationship. The epithelial response to the mitogenic activity of HGF was different among the region of the gastro-intestinal tract; glandular stomach most responsive, followed by intestine and forestomach. The interaction of HGF with other growth factors in inducing the epithelial growth was also different depending on the type of the epithelial cells, indicating a region-specific growth regulation in the gastro-intestinal tract. Analyses using Northern blot and RT-PCR revealed that HGF mRNA was expressed only in mesenchymes but not in epithelia of the gastro-intestinal tract while expression of c-met (HGF receptor) gene was observed in both tissues. These results suggest that gastro-intestinal mesenchymes secrete HGF which stimulates the growth of attaching epithelial cells by a paracrine mechanism, and that the epithelial response to HGF is controlled by a region-specific growth regulatory mechanism.

Animals↗
PubMed1994

neu is not involved in N-[4-(5-nitro-2-furyl)-2-thiazolyl]-formamide-induced bladder carcinoma or 2-amino-4-(5-nitro-2-furyl)thiazole transformation of rat bladder epithelial cells.

Enhanced c-erbB-2/neu expression has been linked with a poor prognosis in human bladder cancer. Previous reports have shown that a point mutation at nucleotide T2012 in the coding region of the transmembrane domain of the rat gene is sufficient to confer transformation potential on this gene. We examined the comparative levels of p185neu as well as the sequence around the hotspot (T2012) of the neu gene of rat bladder cells transformed by 2-amino-4-(5-nitro-2-furyl)thiazole (ANFT) or established in culture from N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT)-induced rat bladder tumors. We concluded that increased p185neu expression did not correlate significantly with tumorigenicity. No alterations in nucleotide sequences of the neu gene were observed in either in vitro model.

Animals↗