Biomedical subjects

R Oyasu

Publications and source records attributed to R Oyasu.

At least 109 records · Page 6Linked to original sources

PubMed1987

Induction of high-grade, high-stage carcinomas in the rat urinary bladder.

The hypothesis that biologic aggressiveness of bladder cancer is determined by carcinogen dose was tested using heterotopically transplanted rat urinary bladders (HTBs). Young male Fischer rats, which were recipients of normal bladders, were divided into three groups; the first group received 0.5 mg of N-methyl-N-nitrosourea (MNU) into HTBs for six doses, a second, 0.05 mg for six doses and the third, 1 mg for three doses. Separately, a group of animals received bladders from rats treated with 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BHBN) in drinking water for 4 weeks; the transplanted bladders then were treated with 0.5 mg of MNU for six doses. Treatment with the larger dose of MNU resulted in a significant increase in tumor incidence and frequency of invasive carcinomas. The combination carcinogen treatment induced more invasive carcinomas than the single treatment. The data suggest that deeply invasive carcinomas may develop in two ways: the first is by emergence of a more anaplastic cell population within a pre-existing noninvasive carcinoma and the second is by the de novo development of an invasive carcinoma directly from a severely dysplastic urothelium, which is acceptable as carcinoma in situ. Squamous differentiation was characteristic of deeply invasive carcinomas. The dose of carcinogen(s) is a determinant of aggressiveness of bladder carcinomas.

Animals↗

PubMed1987

Rat urinary bladder denuded of urothelium. An in vivo model for the epithelial-stromal interactions in carcinogenesis.

To investigate epithelial-stromal interactions in bladder carcinogenesis, the authors developed an experimental model using a heterotopically transplanted rat urinary bladder (HTB). A rat urinary bladder which was completely denuded of epithelial cells ex vivo with hypotonic shock and a nonionic detergent was transplanted into a syngeneic recipient. No reepithelialization occurred during the 8-week posttransplant period. The basal lamina remained intact throughout this period and showed linear immunofluorescence with antibodies against laminin, Type IV collagen, and heparan sulfate-proteoglycan. When 1 X 10(5) to 5 X 10(5) dispersed normal urothelial cells were delivered into the HTB through an attached reservoir 4 days after transplantation, complete resurfacing by inoculated cells occurred within a few days. A transient hyperplasia was followed by a normal 2-3-cell-thick urothelial organization in 4 weeks. Cultured bladder carcinoma cells also resurfaced the denuded bladder basal lamina; the progressive growth of this neoplastic epithelium resulted in carcinoma in situ as well as foci of invasive carcinoma within 4 weeks following inoculation. This in vivo system has an advantage over other in vivo and in vitro models in that complete removal of epithelial cells can be achieved easily and completely; the course after reepithelialization can be modified by subsequent treatment, progression of neoplastic development can be closely observed by a change in the color of the aspirate, its cytology, and biochemical analysis of secretions; and an adequate amount of tissue can be available for subsequent examinations. The model is potentially useful not only for studying epithelial-stromal interactions during carcinogenesis, but also for examining the mechanisms of tumor invasion and metastasis.

Animals↗

PubMed1986

Effects of formalin-induced injuries on urinary bladder carcinogenesis.

In multistage carcinogenesis, promotion is a long-term or repeated growth stimulation of initiated cells. Possible effects of regenerative hyperplasia induced by repeated intravesical instillation of 0.3% formalin solution on urinary bladder carcinogenesis were examined using heterotopically transplanted rat urinary bladders (HTBs) initiated by N-methyl-N-nitrosourea. The HTB system was chosen because in this system, transient generalized hyperplasia lasting less than a week can be induced readily and repeatedly by intravesical instillation of the formalin solution. No statistically significant tumor enhancement was observed after 15 formalin treatments administered in 30 weeks. It appears that regenerative cytotoxic stimuli, even multiple, may have no significant tumor-promoting activity. Discussed is the possibility that mild and, more importantly, persistent non-cytotoxic stimuli may be more effective as tumor promoters.

Animals↗

PubMed1986

Transient and persistent hyperplasia in heterotopically transplanted rat urinary bladders induced by formalin and foreign bodies.

The effects of formalin instillation or teflon bead insertion on heterotopically transplanted rat urinary bladders (HTBs) were investigated. A single instillation of 0.3 per cent formalin dissolved in 0.9 per cent NaCl into HTBs induced multifocal superficial ulcers which were quickly repaired by lateral spreading of regenerating cells migrating from the adjacent mucosa. This was associated with a sharp increase in labeling index (10-30 per cent) on days 1 and 2, followed by focal mild (up to five cell layers) simple hyperplasia (SH) on days 4 and 7. Repeated weekly instillation of formalin for 30 weeks induced only focal mild epithelial hyperplasia. Six weekly instillations of urine one day after formalin administration slightly enhanced the formalin-induced rise in labeling index. Insertion of teflon beads caused extensive diffuse remarkable changes, especially in the presence of urine: multifocal to diffuse SH (four to eight cell layers) and multifocal papillary or nodular hyperplasia was observed by six weeks. The results indicate that responses to formalin instillation are acute and transient, while reactions to bead insertion are persistent. In both cases, presence of urine appeared to enhance hyperplastic changes. These models of bladder injury, by inducing two different types of reactions in the bladder, may be useful in examining the role of trauma in bladder carcinogenesis.

Animals↗

PubMed1986

Cytological atypia in the prostate gland: frequency, distribution and possible relevance to carcinoma.

Frequency and distribution of atypical prostatic hyperplasia were assessed in 51 total prostatectomy specimens for cancer and the data were compared to similar data obtained from analysis of 51 autopsy specimens. Enlargement of columnar cell nuclei in conjunction with preservation of basal cells was chosen as the only criterion for atypia. Depending on the degree of nuclear enlargement, atypia was divided into mild and severe degrees. The evaluation of nuclear atypia was applied to areas of carcinoma as well as to atypical prostatic hyperplasia. There were 3 major findings. 1) Atypical prostatic hyperplasia was found more frequently in prostatectomy specimens (48 of 51 cases) than in autopsy specimens (14 of 37 cases after exclusion of cancer-associated cases) and the difference was significant (p less than 0.001). In addition, atypical prostatic hyperplasia found in prostatectomy specimens was more frequently of severe degree than that in the autopsy specimens (42 of 48 versus 3 of 14 cases, p less than 0.001). 2) The distribution of atypical prostatic hyperplasia and carcinoma in prostatectomy specimens was similar. 3) In a majority of prostatectomy specimens atypical prostatic hyperplasia, when found, was located at sites separate from carcinoma as well as in contiguous areas. Based on these data it is suggested that the presence of a severe degree of nuclear atypia in specimens removed for benign conditions or in prostatic needle biopsies may signify an increased incidence of coexisting carcinoma elsewhere in the prostate or of carcinoma developing in the future. Close followup of these patients may be indicated.

Aged↗

PubMed1986

The heterotopically transplanted rat urinary bladder as a model for detection of tumor-promoting urinary growth factor(s).

The heterotopically transplanted rat urinary bladder (HTB) was developed in our laboratory as a model to study the role of urine in urinary bladder carcinogenesis. With this model, normal urine was found to enhance urinary bladder carcinogenesis initiated by N-methyl-N-nitrosourea or N-butyl-N-(4-hydroxybutyl)nitrosamine. Two crude urinary components (Fractions I and II) were obtained by gel filtration chromatography; they stimulated ornithine decarboxylase (ODC) in a test bladder carcinoma cell line 804G, and promoted carcinogenesis in the HTB system. Fraction I was found to stimulate growth of 804G cells in vitro. Preliminary data indicate that Fraction I contains at least one, and possibly two heat-stable ODC-inducible and mitogenic components. Further characterization of these components is in progress. The HTB system has been demonstrated to be useful for other investigations; for example, alpha-difluoromethylornithine, an enzyme-activated irreversible inhibitor of ODC, when instilled repeatedly to the bladder lumen, inhibited tumorigenesis in HTBs.

Animals↗

PubMed1986

Stimulation of rat bladder epithelial DNA synthesis by intravesical instillation of distilled water.

Two commonly used cystoscopic infusion fluids were examined to determine whether their infusion stimulates DNA synthesis of the bladder epithelium. Following a single intravesical dose of 0.5 ml of distilled water or 1.5% L-glycine solution, rats were killed periodically up to 1 week. A transient but significant increase in epithelial cell [3H]thymidine labeling was observed at 48 hr after distilled water instillation. Glycine solution did not stimulate DNA synthesis.

Animals↗

PubMed1986

Prevention of inhibitory effects of alpha-difluoromethylornithine on rat urinary bladder carcinogenesis by exogenous putrescine.

We previously demonstrated that repeated instillation of alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase (ODC), inhibits (or retards) urinary bladder carcinogenesis in rats. Since ODC catalyzes the first step in polyamine synthesis, the inhibition of polyamine formation may be responsible for tumor inhibition by DFMO. The present experiment was conducted using male Fischer rats with a heterotopically transplanted urinary bladder (HTB) to determine whether the effects of DFMO are prevented by exogeneous Pu. HTBs were treated with 0.25 mg of N-methyl-N-nitrosourea (MNU) once a week for 3 weeks and the animals were then arbitrarily divided into 6 groups. Beginning one week following the last MNU treatment, all rats received twice a week instillation (0.5 ml each) as follows: Group 1 rats, normal rat urine; Group 2, 2% DFMO in urine; Group 3, 250 microM Pu and 2% DFMO in urine; Group 4, 250 microM Pu in urine; Group 5, urine for 10 weeks followed by 2% DFMO in urine; and Group 6, urine for 10 weeks followed by 250 microM Pu and 2% DFMO in urine. At 10 weeks following the last MNU instillation 5 rats from each of Groups 1 through 4 were killed for determination of urothelial polyamine levels. An additional 4 rats of Group 1 were killed at 10 weeks for histological examination. All remaining rats were killed 20 weeks after the last MNU instillation. Polyamine levels showed no significant difference among the 4 groups. The incidence of carcinoma was significantly lower in the group treated with DFMO (p less than 0.001, Group 1 vs Group 2), confirming our previous observation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1985

Gamma glutamyl transpeptidase activity in rat urothelium treated with bladder carcinogens.

Gamma glutamyl transpeptidase (GGT) activity during urothelial carcinogenesis was examined histochemically in rats treated with N-methyl-N-nitrosourea (MNU) or N-butyl-N-(4-hydroxybutyl)nitrosamine (BHBN). GGT-positive cells developed with a high frequency in foci of nodulopapillary hyperplasia and carcinoma. GGT-positive cells, both individually and in nests, were also frequent in foci of simple hyperplasia and interlesion normal urothelium of carcinogen-treated bladders. The results suggest that development of GGT-positive cells in interlesion normal urothelium is specific to carcinogen treatment.

Animals↗

PubMed1985

alpha-Difluoromethylornithine inhibits cell growth stimulated by a tumor-promoting rat urinary fraction.

The growth stimulating activity of a tumor-promoting rat urinary fraction (Fraction I), and its inhibition by alpha-difluoromethylornithine (DFMO) were examined in vitro using a rat bladder carcinoma cell line, 804G cells. Cell growth was markedly stimulated by Fraction I when added to the basic medium containing 0.2% fetal calf serum (FCS). The increased proliferative activity was associated with an increase in ornithine decarboxylase (ODC) activity and intracellular polyamine content. DFMO effectively inhibited the growth of 804G cells stimulated by Fraction I or by 10% FCS, and the inhibition was associated with suppression of ODC activity and partial depletion of intracellular putrescine and spermidine. Growth inhibition was reversed by exogenous putrescine. These results show that (i) urinary Fraction I, both a tumor promoter in bladder carcinogenesis and an ODC inducer in 804G cells, has potent mitogenicity in 804G cells, and (ii) the mitogenicity is inhibited by DMFO, an irreversible inhibitor of ODC.

Animals↗

PubMed1985

Agglutination by concanavalin A of urothelial cells of heterotropically transplanted rat urinary bladders: effect of bladder carcinogens and urine.

N-butyl-N-(3-carboxypropyl)nitrosamine (BCPN) has been considered to be a carcinogenic urinary metabolite of N-butyl-N-(4-hydroxybutyl)nitrosamine. No tumor developed, however, in the heterotropically transplanted rat urinary bladders (HTBs) following repeated instillation of BCPN dissolved in physiological saline. In the present study, the possibility that BCPN dissolved in urine may induce tumors was explored using a short-term screening assay. When tested with the concanavalin A agglutination assay with which a close correlation between increase in cell agglutinability and carcinogenicity of test compounds has been well demonstrated, no significant increase in agglutinability attributable solely to BCPN was observed in HTB cells whether it was dissolved in saline or urine. Based on the current findings together with other available data, it is suggested that urothelial cells have a very limited capability to activate BCPN to the ultimate carcinogen, and require continuous contact with the carcinogen to respond with tumor formation.

Agglutination↗

PubMed1985

Inhibition of carcinogenesis by alpha-difluoromethylornithine in heterotopically transplanted rat urinary bladders.

Inhibitory effects of alpha-difluoromethylornithine (DFMO) on urinary bladder carcinogenesis were examined using the heterotopically transplanted rat urinary bladder (HTB) model. Male Fischer rats with an HTB were arbitrarily divided into four groups. Group 1 rats received into the HTBs 0.25 mg of N-methyl-N-nitrosourea (MNU) once a week for 3 weeks, followed by instillation twice a week of 0.5 ml of 2% DFMO dissolved in normal rat urine. Group 2 rats received the same amount of MNU, followed by instillation of urine without DFMO. Group 3 rats received a single dose of 0.25 mg of MNU, followed by instillation twice a week of urine containing 2% DFMO. Group 4 rats were treated as those in Group 3 but without DFMO. At 8, 14, and 20 weeks after the last MNU administration, urothelial polyamine levels and [3H] thymidine incorporation by the urothelium of HTBs were determined in nine rats of Groups 1 and 2. The remaining animals of Groups 1 and 2 were killed 25 weeks after the beginning of MNU injection, while those of Groups 3 and 4, 30 weeks after the MNU treatment. The contents of 3 polyamines (putrescine, spermidine, and spermine) in urothelial cells were significantly lower in Group 1 as compared with Group 2. The incidences of carcinoma were significantly lower in the groups treated with DFMO (p less than 0.001, Group 1 versus Group 2; p less than 0.005, Group 3 versus Group 4). These observations indicate that administration of DFMO inhibits (or retards) bladder carcinogenesis in HTBs. A possible mechanism for this effect is suppression of polyamine biosynthesis and proliferation of bladder epithelial cells.

Animals↗

PubMed1984

Correlation of ABH antigenicity and urine cytology results in transitional cell carcinoma of bladder.

Loss of ABH antigens from the cell surface of transitional cell carcinoma of the bladder has been proposed as an indicator of increased cellular dedifferentiation and the tendency toward invasive recurrence. An attempt was made to correlate the urinary cytology and the ABH antigen status of 57 patients with histologically confirmed bladder tumors and 28 with only dysplasia on biopsy. A review of the results of surface antigenicity studies and the preoperative urine cytologies showed no significant difference in the diagnostic sensitivity of cytology between comparable antigen negative and positive groups.

ABO Blood-Group System↗

PubMed1984

Diffuse papillomatosis of rat urinary bladder occurring in association with vesical calculi.

Repeated intravesical administrations of 0.9 per cent NaCl solution with or without bladder carcinogen N-butyl-N-(3-carboxypropyl)nitrosamine resulted in a high incidence of calculus formation in the urinary bladder. In all such cases, diffuse papillomatosis of the bladder urothelium was observed. "Invasion" of the tunica muscularis and the tunica adventitia by tumor was demonstrated as early as week 9 of the experiment. Morphologically, the lesions could not be distinguished from the bladder tumors induced by an orally administered carcinogen. Evidence was presented to conclude that they represent neoplasms of low malignant potential. The results indicate that bladder tumors may develop in the absence of known exposure to carcinogen provided the urothelium is chronically stimulated. Tumors solely attributable to N-butyl-N-(3-carboxypropyl)nitrosamine treatment did not occur.

Animals↗

PubMed1984

The accuracy of diagnostic biopsy specimens in predicting tumor grades by Gleason's classification of radical prostatectomy specimens.

We reviewed the tissue histology of 115 patients with clinically localized carcinoma to determine the correlation between tumor grades in the biopsy and the prostatectomy specimen. Gleason's primary and secondary pattern score systems were used, and each specimen was graded on a scale of 2 to 10 by a referee pathologist in a blind fashion. If the difference in the summed primary and secondary grades in the 2 specimens was no more than 1 grade, the discrepancy was regarded as insignificant. In all but 32 cases initial diagnostic biopsy specimens predicted accurately the final prostatectomy specimen score. The discrepancy was 3 grades in 7 cases and 2 grades in 25 cases. As a result, the lesions in 19 cases were changed from a well differentiated (2 to 4), a moderately differentiated (5 to 7) or a poorly differentiated (8 to 10) lesion to another of these categories. The lesions were upgraded from a well differentiated to a moderately differentiated category in 9 cases and from a moderately to a poorly differentiated category in 4 cases. The lesions were downgraded from a moderately differentiated to a well differentiated category in 6 cases. In 13 other cases the discrepancy was 2 but the lesion remained within the moderately differentiated group. Although in 19 cases the cancerous tissue occupied less than 10 per cent of the biopsy specimen, accurate prediction could be made in 16. The results indicate that diagnostic biopsy specimens will predict the grade of the primary tumor in a majority (72 per cent) but not all of the cases.

Aged↗

PubMed1984

Primary choriocarcinoma of the urinary bladder in association with undifferentiated carcinoma.

A carcinoma of the urinary bladder with a distinct choriocarcinomatous component that developed in a postmenopausal woman was associated with high titers of circulating chorionic gonadotropin. The diagnosis was supported by histochemical demonstration of human chorionic gonadotropin in syncytial tumor giant cells and electron microscopic features consistent with syncytiotrophoblastic cell differentiation.

Carcinoma↗

PubMed1984

Irreversibility of low-grade superficial rat bladder carcinomas.

The present investigation was conducted to determine: (a) whether the superficial papillary tumors developing in heterotopically transplanted bladders (HTBs) of rats after N-methyl-N-nitrosourea (MNU) initiation and subsequent weekly urine treatment would regress when placed in a urine-free environment; (b) whether tumors would develop in HTBs if MNU initiation is not followed by further manipulation, such as instillation of urine or 2.1% NaCl solution; and (c) whether tumors would develop in HTBs if urine instillation is delayed for as many as 25 weeks after MNU initiation. The results indicate: (a) that low-grade superficial tumors, once developed, do not appear to regress in a urine-free environment; (b) that tumors develop in MNU-initiated bladders even if they receive no further treatment; and (c) that late institution of urine instillation to HTBs still effectively enhances MNU-initiated tumorigenesis. If the current observation is extrapolated to the human situation, our data suggest that low-grade superficial tumors are indeed neoplastic, and spontaneous regression cannot be expected by urinary diversion. It, however, might be effective in controlling progression of at least some of the early neoplastic lesions to overt cancer.

Animals↗

PubMed1984

Effects of 12-O-tetradecanoylphorbol-13-acetate on carcinogenesis in the heterotopically transplanted rat urinary bladder.

12-O-Tetradecanoylphorbol-13-acetate (TPA), a potent promoter of mouse skin carcinogenesis, was tested for possible tumor-enhancing effects on urinary bladder carcinogenesis using the heterotopically transplanted bladder (HTB) model. Weekly administration of TPA at 1.0 microgram/week to N-methyl-N-nitrosourea-initiated HTBs did not increase tumor incidence, but instead, resulted in a significantly high incidence of nodulopapillary hyperplasia, an early neoplastic lesion, suggesting possible tumor enhancement by TPA. In addition, administration of a high dose of TPA with or without a carcinogen treatment led to the development of numerous finger-like epithelial projections on the luminal surface of the HTBs. Evidence indicates that epithelial projections are formed as a result of proliferation of intermediate cells. Whether these structures evolve into true neoplastic lesions is at present unknown.

Animals↗