Biomedical subjects

K Imaida

Publications and source records attributed to K Imaida.

At least 73 records · Page 4Linked to original sources

PubMed1994

Effects of testosterone, dihydrotestosterone and estrogen on 3,2'-dimethyl-4-aminobiphenyl-induced rat prostate carcinogenesis.

Post-initiation effects of testosterone propionate (TP), alpha-dihydrotestosterone (DHT) and ethinyl estradiol (EE) on 3,2'-dimethyl-4-aminobiphenyl (DMAB)-prostate carcinogenesis in F344 rats have been investigated by administration of each hormone individually or either androgen in combination with EE. DMAB plus TP resulted in induction of invasive adenocarcinomas in the lateral and anterior prostate and seminal vesicles, as shown in a previous study, whereas DHT did not exhibit any positive modulation potential. Administration of EE together with TP produced increased carcinoma incidence in the lateral and anterior prostate, from 17 and 28% to 70% and 80%, respectively. Dorsal prostate tumors, all of the non-invasive in situ type, were also evident in 30% of animals receiving both TP and EE. Rats treated with DHT plus EE, however, did not develop tumors. Our experiment thus provides evidence that estrogen may play an important role in prostate carcinogenesis.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1994

Roles of bladder distension, urinary pH and urinary sodium ion concentration in cell proliferation of urinary bladder epithelium in rats ingesting sodium salts.

The relative importance of bladder distension, urinary pH and sodium ion concentration for cell proliferation in the bladder epithelium of rats fed various sodium salts was investigated. When a diet containing 5% NaHCO3 was fed to male rats, the bladder epithelium showed an increase in replicating cells, together with distension, increased urine pH and high urine sodium ion concentration. Cell proliferation also occurred when bladders were subjected to distension in vivo by mechanical (female) or physiological (male) means. Inclusion of CaCO3 in the diet produced high urinary pH without alteration in the other factors and did not induce cell proliferation. Increased proliferation occurred when CaCO3 was combined with these mechanical or physiological treatments. Thus, high urinary pH was of secondary importance to bladder distension as a causative factor, but acted to enhance cell proliferation when distension occurred. Similar findings were obtained with regard to sodium ion concentration. In conclusion, this study demonstrated that bladder distension is one of the prerequisites for promoter-induced cell proliferation in the bladder epithelium, with high urinary pH and sodium ion concentration.

Animals↗

PubMed1994

Increased gap junctional intercellular communication capacity and connexin 43 and 26 expression in rat bladder carcinogenesis.

Many reports have suggested that gap junctional intercellular communication or gap junction proteins (connexins) could have tumor suppression characteristics. We investigated gap junctional intercellular communication capacity and connexin 26, 32 and 43 mRNA expression in four rat bladder cell lines and the results were compared to their tumorigenicity. We also examined connexin expression in rat bladder carcinomas induced by 3,2'-dimethyl-4-aminobiphenyl or N-ethyl-N-(4-hydroxybutyl)nitrosamine (EHBN) and in normal bladders. There was clear tendency that cell lines with greater communication had stronger tumorigenicity and more expression of connexin 26 or 43. We could not detect connexin 32 in these cell lines. In normal bladder tissue, connexin 43 expression was barely detectable and there was no detectable connexin 26. However, in rat bladder carcinomas, especially the EHBN-induced carcinomas, abundant expression of both connexins was observed. These results indicate that increased gap junctional intercellular communication capacity or increased connexin(s) expression may give a growth advantage in rat bladder carcinogenesis.

Aminobiphenyl Compounds↗

PubMed1994

Immunohistochemical demonstration of intestinal-type alkaline phosphatase in stomach tumors induced by N-methyl-N'-nitro-N-nitrosoguanidine in rats.

A polyclonal antibody against rat intestinal-type alkaline phosphatase (I-ALP) was generated and proven to be applicable immunohistochemically to paraffin-embedded sections. Expression of I-ALP in normal tissues, intestinal metaplasia and stomach tumors induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was then investigated in five different strains of rats. Male SD (Crj:CD), Lewis (LEW/Crj), WKY (WKY/NCrj), Wistar (Crj:Wistar) and F344 (F344/DuCrj) animals were given drinking water containing 100 micrograms/ml of MNNG for 30 weeks and were killed at week 50. Among the 5 strains, stomach adenocarcinomas were found most frequently in the SD case. The susceptibility of rats to induction of stomach carcinoma did not correlate with the development of intestinal metaplasias in each strain. Histochemical staining for mucin demonstrated all stomach tumors (adenomatous hyperplasias and well-differentiated adenocarcinomas) to consist mainly of gastric type cells (pyloric gland cell and surface mucous cell types), with intestinal-type tumor cells (goblet cell and intestinal absorptive cell types) being only occasional findings. Immunohistochemically, I-ALP was strongly positive on the striated cell borders of small intestinal absorptive cells of the villus and on brush borders of epithelial cells of kidney proximal tubules. I-ALP was also detected in the normal stomach, limited to the striated cell borders of absorptive cells of the upper one-fourth of intestinal metaplastic glands. I-ALP may thus be a useful marker for stomach tumor cells of intestinal absorptive cell type, indicative of maturation and differentiation. No stomach tumors consisting mainly of intestinal-type cells were found, and therefore there was no suggestion of any derivation from intestinal metaplasias.

Adenocarcinoma↗

PubMed1994

Inhibiting effects of diethylmaleate or NH4Cl on NaHCO3, but not butylated hydroxyanisole, promotion of urinary bladder carcinogenesis in male F344 rats initiated with N-butyl-N-(4-hydroxybutyl)nitrosamine.

The modifying potential of diethylmaleate (DEM) and NH4Cl on promotion by butylated hydroxyanisole (BHA) or NaHCO3 of urinary bladder carcinogenesis in rats initiated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) was investigated. Six week old animals received 0.05% BBN for 4 weeks and then BHA (2%) + DEM (0.15%), BHA + NH4Cl (1%), NaHCO3 (3%) + DEM, NaHCO3 + NH4Cl, BHA, DEM, NH4Cl or no supplement, administered during experimental weeks 5-36. BHA and NaHCO3 clearly amplify the induction of papillary or nodular (PN) hyperplasias and papillomas in rats initiated with BBN. The promoting activity of BHA was not affected by simultaneous administration of DEM or NH4Cl. The enhancing effects of NaHCO3, in contrast, were clearly diminished by concurrent administration of either of these agents. DEM itself did not influence lesion development whereas NH4Cl reduced the incidence of papillomas. In a second experiment, rats exposed to the same protocol were killed at week 8, and assessed for levels of lipid peroxides in the bladder tissue. No remarkable alterations were observed in any group. Thus, the fact that DEM did exert inhibiting effects on tumor promotion by NaHCO3 without decreasing the urinary sodium ion concentration or pH and influence on lipidperoxide levels, suggests essential differences in the mechanisms of action of different types of bladder promoters.

Ammonium Chloride↗

PubMed1994

Medium-term rat liver bioassay for rapid detection of carcinogens and modifiers of hepatocarcinogenesis.

For rapid detection of carcinogenic agents, a medium-term liver bioassay has been established in our laboratory using preneoplastic glutathione S-transferase placental form (GST-P) positive foci in the rat liver as endpoint marker lesions. A total of 237 compounds have so far been tested in this system and the results compared with reported Salmonella/microsome and long-term carcinogenicity test findings. The positive rate was found to be extremely high, 97% (28 of 29 compounds) for genotoxic hepatocarcinogens; and satisfactory, 86% (23 of 27 chemicals) for nongenotoxic ones. The positive rate for carcinogens targeting organs other than the liver, however, is relatively low (24%). Malathion and vinclozolin proved positive, although both have been reported to be noncarcinogenic in rats and mice. Those chemicals which exerted positive results in this system might be hepatopromoting agents even if hepatocarcinogenicity has not been established. Five of the six false-negative hepatocarcinogens could be categorized as peroxisome proliferators. In addition, a number of inhibitory agents for GST-P-positive foci development have been detected and many are categorized as antioxidants. The validity of this system as a tool for rapid detection of carcinogenic and chemopreventive agents is discussed.

Animals↗

PubMed1993

A nude rat model for in vivo studies of human transitional cell carcinogenesis.

A xenograft system was developed for studying experimental carcinogenesis of human transitional cells in vivo. Segments of human ureters were tied to an injection port, ligated at the opposite end, implanted into gamma-irradiated nude rats and weekly irrigated through the injection port with fresh PBS solution. Such implants maintained the normal histologic appearance of human urothelium for at least 20 weeks in vivo in the nude rats. In situ hybridization with a human repetitive sequence DNA probe showed that the urothelium and the submucosal connective tissue and smooth muscle were of human origin. The urothelial lining was positive with an immunohistochemical reaction for acidic cytokeratins. This model allows for the long-term direct exposure of human urothelium to bladder carcinogens for the purpose of induction of human transitional cell tumors.

Animals↗

PubMed1993

Modifying influence of prior treatment with toxic agents on induction of preneoplastic and neoplastic lesions in a medium-term multi-organ carcinogenesis bioassay.

The modifying potential of prior administration of toxic agents was investigated in our multi-organ carcinogenesis model using male F344/DuCrj rats with the aim of assessing the link between tissue damage and initiation. Animals were administered one of four toxic agents for 8 wk, and then treated with N-diethylnitrosamine (DEN, 100 mg/kg body weight (b.w.), intraperitoneally (i.p.), single injection), N-methylnitrosourea (MNU, 20 mg/kg b.w., i.p., four times during wk 9 and 10), and dihydroxy-di-N-propylnitrosamine (DHPN, 0.1% in drinking water, during wk 11 and 12) for multi-organ carcinogenesis. All surviving rats were killed at the end of wk 36, and the major organs carefully examined for preneoplastic and neoplastic lesion development. Immunohistochemical demonstration of glutathione S-transferase placental form (GST-P) positive foci was also performed to facilitate quantitative assessment of liver lesion development. D-galactosamine (300 mg/kg b.w., i.p., once a week), a hepatotoxin, significantly inhibited the induction of GST-P positive foci, while 4,4'-diaminodiphenylmethane (DDPM, 0.1% in diet), a bile duct proliferator which is itself a hepatocarcinogen, possessed enhancing activity. DDPM, also a goitrogen, clearly inhibited the development of follicular cell tumors in the thyroid. Uracil (3.0% in diet), which is an inducer of papillomatosis in the urinary bladder, did not exert any enhancing potential on bladder carcinogenesis. Bleomycin (2 mg/kg b.w., i.p., twice a week), which is an alveolar epithelium injuring agent, also did not modify the induction of alveolar epithelium proliferative lesions. These results indicate that prior organ injury by toxic agents does not always act to enhance sensitivity to carcinogenesis.

Aniline Compounds↗

PubMed1993

Epithelia hyperplasia in the renal papilla and pelvis but not the urinary bladder of male F344 rats associated with dietary sodium phosphates after uracil exposure.

Effects of the bladder tumor promoter Na3PO4 and the non-bladder-tumor promoter NaH2PO4 on development of hyperplastic lesions of urinary bladder and renal papilla/pelvis were investigated after exposure of male F344 rats to the nongenotoxic carcinogen uracil. Animals were administered with 3.0% uracil in the diet for 4 weeks and thereafter fed 3.0% Na3PO4 or 3.0% NaH2PO4 for 32 weeks. No enhancing effect of either phosphate salt on uracil-induced proliferative lesions of urinary bladder was observed. However, the sequential treatments gave rise to enhanced development of hyperplastic lesions in the renal papilla/pelvis compared to the case with uracil alone. In addition, a small number of renal pelvic papillomas were observed in the group given Na3PO4 after uracil. These phosphate salts also induced nephrocalcinosis in the papilla/pelvis concomitant with development of renal hyperplastic lesions in this location. A sequential study revealed calculus formation and proliferative lesions in both the urinary bladder and renal papilla/pelvis after 4 weeks dietary application of uracil. After cessation, calculi disappeared and the majority of hyperplastic lesions regressed, consistent with a decrease in DNA synthesis levels. Persistence of uracil-induced epithelial hyperplasia in renal papilla/pelvis under the influence of phosphate salts might have been directly due to chronic stimulation by nephrocalcinosis in these sites.

Animals↗

PubMed1993

Relationship between bisacodyl-induced urolithiasis and rat urinary bladder tumorigenesis.

Dietary supplementation with bisacodyl at concentrations ranging from 1 to 0.3% was found to induce both calculi and epithelial proliferative lesions, including a transitional-cell carcinoma, in the urinary bladder of F344/DuCrj rats. In order to clarify the relationship between the bisacodyl-associated urinary bladder calculi and the development of proliferative lesions in the urinary bladder, male and female rats were administered bisacodyl-diets at concentrations of 0.3, 0.1, and 0.03% for 32 wk. Both sexes of animals treated with bisacodyl suffered from diarrhea throughout the experimental period. Epithelial proliferative lesions and calculus formation were observed only in the urinary bladder of male rats given the 0.3% bisacodyl diet. Proliferative lesions and increases of bromouracil deoxyriboside (BUdR) labeling indices were found only in the urinary bladder epithelium of rats with calculi, the severity of the former correlating with the calculus weight and being most marked in the dome areas, which are susceptible to physical stimulation. These findings indicate a close relationship between the development of proliferative lesions and the existence of calculi in the urinary bladder, and suggest that bisacodyl-induced proliferative lesions are not caused directly by bisacodyl per se but are secondary to calculus formation.

Administration, Oral↗

PubMed1993

Dose-dependence of 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine (PhIP) carcinogenicity in rats.

The dose-dependence of 2-amino-1-methyl-6-phenylimidazo-[4,5-b]pyridine (PhIP) carcinogenicity was investigated in F344 rats of both sexes administered the heterocyclic amine in the diet at concentrations of 25 or 100 p.p.m. for up to 104 weeks. Incidences of mammary adenocarcinomas were 7% (2/30) for 25 p.p.m. and 47% (14 of 30 rats) for 100 p.p.m. in females and those of colon adenocarcinomas were 43% (13/30) for males and 13% (4/30) for females of the 100 p.p.m. groups. No mammary adenocarcinomas were induced in males and no colon carcinomas were observed in the 25 p.p.m. groups of either sex. Furthermore, development of lymphocytic leukemia was apparently enhanced by PhIP in males. In a separate experiment, dose-dependent induction of aberrant crypts in the large intestine, considered as preneoplastic lesions, was evident after 8 weeks feeding of PhIP-supplemented diet at doses of 25, 100 or 400 p.p.m. Thus a clear dose-dependency was demonstrated for both colon and mammary carcinogenesis. Since PhIP is a particularly abundant heterocyclic amine and its carcinogenic organotropism overlaps with the types of neoplasias most commonly observed in western countries, the compound may be extremely important with respect to human cancer development.

Adenocarcinoma↗

PubMed1993

Temporal dissociation between cell proliferation and eosinophilic foci development in the exocrine pancreas of rats initiated with 4-hydroxyaminoquinoline 1-oxide and administered soybean trypsin inhibitor.

Male Sprague-Dawley rats received a single i.v. injection of 4-hydroxyaminoquinoline 1-oxide (HAQO) 7 mg/kg body weight or vehicle alone, and starting 7 days thereafter, were then fed basal diet with or without a 5% soybean trypsin inhibitor (SBTI) supplement. Subgroups were sequentially killed after 2, 4, 7, 14, 30, 60 and 100 days on this regimen, in each case 1 h after injection of bromodeoxyuridine (BrdU). In the HAQO/SBTI and SBTI alone groups, 2 days after the SBTI treatment the labeling indices of acinar cells were increased approximately 12- and 11-fold respectively, dropping rapidly thereafter and returning to the control value by day 30. The earliest eosinophilic foci were noted in the HAQO/SBTI group 60 days after HAQO initiation, with the component cells demonstrating markedly increased labeling indices in contrast to the completely normalized levels observed in the surrounding exocrine tissue. On the other hand, eosinophilic foci were scarcely induced in the HAQO or SBTI alone group throughout the experiment. These results thus indicate a clear temporal dissociation between initial proliferation in parenchymal pancreatic tissue caused by SBTI and subsequent development of eosinophilic foci in rats initiated with HAQO.

4-Hydroxyaminoquinoline-1-oxide↗

PubMed1993

Sequential observation of rat prostate lesion development induced by 3,2'-dimethyl-4-aminobiphenyl and testosterone.

3,2'-Dimethyl-4-aminobiphenyl (DMAB), when combined with high doses of testosterone propionate (TP) induces invasive adenocarcinomas with metastatic potential in the rat prostate. The processes underlying this tumor development, including the involvement of atypical hyperplasias, were sequentially investigated in F344 rats. DMAB was given subcutaneously at a dose of 50 mg/kg body weight 10 times at 2-week intervals. TP was administered chronically (in Silastic tubes) from the beginning of the experiment or after the DMAB administration until termination (week 60). Invasive adenocarcinomas were induced in the lateral and anterior prostate as well as the seminal vesicles. Atypical hyperplasias appeared from an early stage, with the later appearance of cancers being closely associated with such foci of morphological alteration. The findings confirm that combined administration of DMAB and pharmacological doses of TP yields invasive adenocarcinomas in the rat prostate and provide further support for the conclusion that atypical hyperplasias are premalignant lesions.

Aminobiphenyl Compounds↗

PubMed1993

Three-dimensional analysis of glutathione S-transferase placental form-positive lesion development in early stages of rat hepatocarcinogenesis.

The development of glutathione S-transferase placental form (GST-P)-positive lesions in the rat liver, from single cells to foci, and their locations within liver lobules were examined by a combined stereological approach for calculation of three-dimensional (3-D) data and by 3-D computer graphics for reconstruction of lesions. Two weeks after initiation with diethylnitrosamine, the rats were divided into two groups. Animals in group 1 were given 2-acetylaminofluorene, and animals in group 2 were given basal diet for 6 weeks. Partial hepatectomy (PH) was performed at week 3. The GST-P-positive single cells increased in number per liver after PH in group 1, but not in group 2, where a plateau level was maintained. The number of GST-P-positive foci per liver in group 2 also reached an almost constant low value after 4 weeks. In contrast, foci in group 1 increased greatly after PH. A 3-D reconstruction, performed with a computer graphics system using up to 180 sections at 10 microns intervals, revealed the single cells to be distributed at random. Those that grew into foci were also not preferentially localized in any particular zone of the hepatic lobule. When foci within the same lobule came into contact, they underwent fusion. The present results thus indicate that only a small proportion of GST-P-positive single cells develops into foci, and that their growth is independent of zonal factors within individual lobules in early stages of rat hepatocarcinogenesis.

Animals↗

PubMed1993

Correlation between medium-term multi-organ carcinogenesis bioassay data and long-term observation results in rats.

The effects of four test chemicals [2-acetylaminofluorene (2-AAF), D,L-ethionine (ethionine), butylated hydroxyanisole (BHA), and catechol] were compared in medium- and long-term in vivo systems. In the medium-term assay, animals were sequentially treated with N-diethylnitrosamine (100 mg/kg body weight, i.p., single injection), N-methylnitrosourea (20 mg/kg body weight, i.p., 4 times during weeks 1 and 2), N-butyl-N-(4-hydroxybutyl)nitrosamine (0.05% in the drinking water during weeks 1 and 2), 1,2-dimethylhydrazine (40 mg/kg body weight, s.c., 4 times during weeks 3 and 4) and dihydroxy-di-N-propylnitrosamine (0.1% in the drinking water during weeks 3 and 4) for multi-organ initiation, and then treated with one of the four test chemicals for 24 weeks, and killed at week 28 (group 1). In the long-term assay, animals were treated in the same manner and then given basal diet and tap water (group 3) or test chemical continuously (group 4) for the remainder of the lifespan. Animals receiving multi-organ initiation and then maintained on basal diet for 24 weeks (group 2) or their lifespan (group 5) served as controls. Detailed histopathological examinations were performed on all rats. Hepatocellular carcinoma incidences in the long-term assay were found to reflect closely the respective medium-term results. Induction of proliferative forestomach or glandular stomach lesions by BHA and/or catechol, and bladder lesions by 2-AAF and BHA in the medium-term assay also correlated with tumor development in the long-term. Furthermore, inhibition of thyroid proliferative lesions by all test chemicals corresponded with low thyroid tumor incidences in the long-term assay. The observed strong correlation between medium- and long-term results confirms the applicability of our medium-term multi-organ carcinogenesis bioassay system for detection of modifying effects of test chemicals in different organs.

2-Acetylaminofluorene↗

PubMed1993

Markers of surface mucous cell type human gastric cancer cells: galactose oxidase-Schiff reactive mucins, monoclonal antibody SH-9 reactive mucins and cathepsin E.

Cellular differentiation of gastric cancer cells allows the classification of cell type into surface mucous cell, pyloric gland cell, intestinal absorptive cell and goblet cell types by mucin histochemistry and pepsinogen (Pg) immunohistochemistry. Surface mucous cell differentiation of gastric cancers of each histologic type has previously been detected by the galactose oxidase-Schiff (GOS) reaction although this is not always positive in all cases. Mucus granules of surface mucous cells of normal gastric mucosa show an intense reactivity for SH-9 (monoclonal antibody against CA125-bearing antigenic molecule fragments). Cathepsin E is also expressed in the cytoplasm of surface mucous cells, weakly in absorptive cells of duodenal villi and occasionally in pyloric gland cells. Expression of SH-9 reactive mucin and of cathepsin E were therefore investigated as possible additional markers to distinguish between the gastric cancer cell type in 203 primary stomach cancers. SH-9 reactive mucin was found selectively in GOS positive cancer cells of surface mucous cell type and/or cancer cells unclassified by mucin histochemistry. These latter cells were therefore classified into the surface mucous cell category. Cathepsin E was found mainly in cancer cells of the GOS positive surface mucous cell type and occasionally, in intestinal absorptive and pyloric gland cell types. Galactose oxidase-Schiff, SH-9 and cathepsin E reactive or positive cancer cells were found in 145 (71.4%), 151 (74.4%) and 144 (70.9%), respectively, of the 203 primary stomach cancers investigated.

Antibodies, Monoclonal↗

PubMed1993

Renal cell adenomas and carcinomas in hemodialysis patients: relationship between hemodialysis period and development of lesions.

Step-sections of 96 whole kidneys from 50 chronic hemodialysis patients were subjected to a histopathological and quantitative investigation with regard to the development of renal neoplastic lesions. The range of hemodialysis duration was from 1 to 222 months. A total of 349 renal cell adenomas were found in 41 cases (82%). They were commonly multiple and present bilaterally. Renal cell carcinomas were evident in four cases (8%), with hemodialysis durations of 54, 57, 112 and 222 months. The incidence of adenomas increased in a hemodialysis duration-dependent manner, indicating a high risk of renal cell tumor development in chronic hemodialysis patients. Furthermore, acquired cystic disease of the kidney (ACDK) was also observed in 12 cases (24.0%), where the mean hemodialysis period was 143.4 +/- 48.0 months. This value was significantly longer than that of non-ACDK cases (P < 0.001). There was, however, no clear relationship between the appearance of ACDK and renal cell tumors. The present results underline the necessity for attention to possible neoplasia of the kidney in patients on long-term hemodialysis.

Adenoma↗

PubMed1992

Change of membrane potential in rat urinary bladder epithelium treated with sodium L-ascorbate.

We previously showed that 5% sodium L-ascorbate (Na-AsA) in the diet promotes rat urinary bladder carcinogenesis, whereas 5% ascorbic acid (AsA) and 1% sodium chloride (NaCl) in the diet do not. In order to cast light on basic properties of these compounds regarding the rat urinary bladder, we examined membrane potential levels in the bladder epithelium of F344 rats treated with 5% Na-AsA, 5% AsA or 1% NaCl in the diet for 2, 4 or 8 weeks. Microelectrode measurement showed Na-AsA to induce hyperpolarization of the membrane potential, which was, however, lacking with AsA and NaCl from week 2 until the end of experiment. Thus a good correlation between the effects on membrane potential and tumor promoting activity could be established.

Animals↗