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T Shirahama

Publications and source records attributed to T Shirahama.

At least 19 recordsLinked to original sources
PubMed2003

Overexpression of cyclooxygenase-2 in high-grade human transitional cell carcinoma of the upper urinary tract.

OBJECTIVE: To examine cyclooxygenase (COX)-2 expression (a key enzyme in the synthesis of prostaglandins, and involved in carcinogenesis of human epithelial tumours) in human transitional cell carcinomas (TCCs) of the renal pelvis and ureter, and to determine whether COX-2 expression correlates with the clinicopathological characteristics of the disease. MATERIALS AND METHODS: Specimens from 144 patients with TCC of the upper urinary tract who had undergone nephroureterectomy were analysed immunohistochemically, and 23 were also analysed by immunoblotting. RESULTS: Immunoblot analysis showed COX-2 immunoreactivity in 17 (74%) of 23 tumours, but not in normal transitional epithelium. COX-2 was localized to the cytoplasm of cancer cells and expressed in 108 (75%) of 144 tumours, as assessed by immunohistochemical analysis. COX-2 expression correlated with tumour grade (P < 0.008), being detected in one of nine grade 1, 77 (79%) of 97 grade 2 and 30 (79%) of 38 grade 3 tumours. Other variables including tumour stage were not associated with COX-2 expression. CONCLUSIONS: We show for the first time that COX-2 is frequently expressed in TCC of the upper urinary tract and is associated with the degree of tumour cell differentiation, indicating that COX-2 may be involved in TCC carcinogenesis at an early and/or late stage, and could be a useful target for chemoprevention of this type of cancer.

Aged↗
PubMed2001

Relation between cyclooxygenase-2 expression and tumor invasiveness and patient survival in transitional cell carcinoma of the urinary bladder.

BACKGROUND: Expression of the inducible form of cyclooxygenase (COX)-2 is known to correlate with development of transitional cell carcinoma (TCC) of the human urinary bladder. However, the clinical significance of COX-2 expression with respect to clinicopathologic findings and patient survival is unknown. METHODS: COX-2 expression was examined immunohistochemically in tumor tissues obtained from 108 patients who underwent radical cystectomy for TCCs, without knowledge of clinicopathologic findings. Correlation between COX-2 expression and clinicopathologic findings and patient survival was determined. RESULTS: COX-2 expression was detected in 34 of 108 (31%) tumors but in none of 10 normal uroepithelial samples. Univariate logistic regression analysis showed a significant correlation between COX-2 expression and local invasion, infiltration pattern, lymphatic invasion, and venous invasion. However, multivariate logistic regression analysis revealed that only local invasion correlated significantly with COX-2 expression (P = 0.047). Cox proportional hazards regression analysis showed that both local invasion (P = 0.008) and lymph node metastasis (P = 0.001) were independent prognostic factors; however, COX-2 expression (P = 0.16) was not. CONCLUSIONS: The authors showed that COX-2 overexpression plays a role in development and invasion of TCCs, but not prognosis of patients with TCC. COX-2 inhibitors may be useful for chemoprevention of TCCs and treatment of invasive disease.

Adult↗
PubMed2001

A case of agranulocytosis associated with severe acute hepatitis B.

A 29-year-old male patient with acute hepatitis B developed agranulocytosis about 2 months after the clinical onset of the hepatitis. Bone marrow examination showed hypercellularity and maturation arrest of myeloid leukogenesis at the stage of metamyelocyte. Anti-neutrophil antibody was negative. Since the patient did not show spontaneous recovery for 2 months, the patient received granulocyte-colony stimulating factor, but the therapy was a very short course because he had an elevation of temperature and nausea. Sixty-eight days after admission, he was started on lithium carbonate at a dose of 600 mg per day. About 3 weeks later, peripheral granulocyte counts had recovered to normal level.

Journal Article↗
PubMed2001

Overexpression of cyclooxygenase-2 in squamous cell carcinoma of the urinary bladder.

Epidemiological studies indicate that the development of squamous cell carcinoma of the urinary bladder is closely associated with chronic inflammation of the urinary tract, but the underlying mechanism is unknown. Cyclooxygenase (COX)-2 is involved in tumorigenesis in many tumors. The purpose of this study was to investigate the role of COX-2 in squamous cell carcinoma of the urinary bladder by immunoblot and immunohistochemical analyses. COX-2 protein was undetectable in normal bladder samples, but was expressed in 29 of 29 (100%) squamous cell carcinomas and in 8 of 8 (100%) squamous metaplasias. The expression of COX-2 showed intense, homogenous cytoplasmic immunostaining in squamous cell carcinomas. In contrast, COX-2 was heterogeneously expressed in 6 of 12 (50%) cases of transitional cell carcinoma of the bladder combined with squamous cell carcinoma, consistent with previous findings. We provide the first evidence that COX-2 is expressed in squamous cell carcinomas of the urinary bladder and in the precursor lesions, indicating its involvement in the development of this type of malignancy.

Aged↗
PubMed2000

Expression of thymidine phosphorylase as an indicator of poor prognosis for patients with transitional cell carcinoma of the bladder.

BACKGROUND: Thymidine phosphorylase (TP), which is identical to platelet-derived endothelial cell growth factor (PD-ECGF), stimulates chemotaxis of endothelial cells and is involved in the angiogenesis of human solid tumors. METHODS: The activity and expression of TP were examined in human transitional cell carcinomas (TCCs) of the bladder, and their association with clinicopathologic findings was determined. The activity of the enzyme in 37 TCCs and 12 adjacent nonneoplastic tissues was measured spectrophotometrically. The expression of TP was also examined by immunoblotting. Immunohistochemical analysis was performed on 108 TCCs. RESULTS: TP activity in the carcinomas was higher than that in adjacent normal tissues (P = 0.002). TP activity in Grade 3 tumors or those classified as pT2-4 was higher than in Grade 1 and 2 tumors (P = 0.017) or those classified as pT1 (P = 0.007). The level of expression of TP detected by immunoblotting correlated well with TP activity. Immunohistochemical analyses showed that 62 of 108 cases (57.4%) were TP positive. There was a significant correlation between TP expression and histologic grade, infiltration pattern, local invasion, and lymph node metastasis. TP expression as a prognostic variable was studied using the Cox proportional hazards model. TP overexpression was an independent prognostic factor, as were lymph node metastasis and local invasion. CONCLUSIONS: These findings suggest that TP activity and its level of expression influence the progression of TCC and the prognoses of patients with this disease.

Adult↗
PubMed2000

Cyclooxygenase-2 expression is up-regulated in transitional cell carcinoma and its preneoplastic lesions in the human urinary bladder.

Cyclooxygenase (COX) is a key enzyme in the synthesis of prostaglandins from arachidonic acid. Much evidence, including that from epidemiological and experimental studies, suggests that the inducible form of COX, COX-2, is increased in colon tumor tissues and is involved in colon cancer tumorigenesis. To determine the significance of COX-2 in tumorigenesis in the urinary bladder, the expression of COX-2 in transitional cell carcinoma and preneoplastic lesions of the bladder was examined. Tumor specificity of COX-2 immunoblotting was 100% in 12 of 35 (34%) tumors, but in 0 of the 10 normal urothelia samples. COX-2 expression was significantly correlated with tumor stage in 9 of 20 (45%) muscle-invasive (pT2-4) tumors and in 3 of 15 (20%) superficially invasive (pT1) tumors (P < 0.05). Immunohistochemical examination revealed that 13 of 14 (93%) samples of carcinoma in situ (CIS), which may be the precursor of muscle-invasive-type tumors, expressed COX-2, whereas 10 of 21 (48%) samples of dysplasia, which may be the precursor of both superficially invasive and muscle-invasive tumors, expressed COX-2. From the expression profile of COX-2 in these various urothelia, it is suggested that COX-2 is involved in the development of transitional cell carcinoma of the urinary bladder, especially that of muscle-invasive tumors via CIS. Furthermore, COX-2 may be a therapeutic target for CIS because of the high expression rate of COX-2 in CIS lesions.

Aged↗
PubMed1999

Expression of vascular endothelial growth factor in patients with testicular germ cell tumors as an indicator of metastatic disease.

BACKGROUND: Angiogenesis is essential for tumor growth and metastasis. Vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP)/platelet-derived endothelial cell growth factor (PD-ECGF) are involved in increased angiogenic activity and disease progression in solid tumors. However, there is no information regarding the association of these angiogenic factors with clinicopathologic findings in testicular germ cell tumors (GCTs). METHODS: The authors examined the expression of VEGF and TP as well as microvessel density in GCTs and their association with clinicopathologic findings. Expression of VEGF and TP and microvessel density were examined immunohistochemically in 80 GCTs, including 33 seminomas (25 tumors with organ-confined disease and 8 with metastasis) and 47 nonseminomatous testicular GCTs (NSGCTs) (20 tumors with organ-confined disease and 27 with metastasis). Expression of VEGF also was examined in four GCTs and one nonneoplastic testis by immunoblotting. RESULTS: VEGF protein was expressed more highly in GCTs compared with nonneoplastic testes. VEGF expression in GCTs was correlated significantly with microvessel count (P < 0.001). Both VEGF expression and microvessel count were correlated with metastasis in seminoma (P = 0.008 and P < 0.001, respectively), but only VEGF expression was identified as statistically significant by multiple regression analysis (P = 0.006). Conversely, four variables (VEGF expression, microvessel count, the presence of venous invasion, and the presence of embryonal carcinoma elements in the primary tumor) were correlated with metastasis in NSGCT (P < 0.001, P < 0.001, P = 0.004, and P = 0.029, respectively). However, multiple regression analysis revealed that only VEGF expression and microvessel count were significant factors for metastasis (P < 0.007 and P < 0.001, respectively). In contrast, high levels of TP were observed in infiltrating cells, but not in the majority of cancer cells. CONCLUSIONS: The findings of the current study suggest that VEGF expression is involved in tumor development, angiogenesis, and metastasis in GCT.

Adolescent↗
PubMed1999

Endorectal ultrasonography for the assessment of rectal wall invasion in intrapelvic tumor: a preliminary report.

BACKGROUND: The purpose of the present study was to determine the usefulness of endorectal ultrasonography (ERUS) in assessing rectal wall involvement in intrapelvic tumors. METHODS: Rectal wall invasion was assessed in 16 patients; 14 with deeply invasive bladder tumors, one with prostatic leiomyosarcoma, and one with prostatic leiomyoma. Computed tomography (CT), magnetic resonance (MR) imaging and ERUS with a flexible-type radial scanner (7.5 MHz) were used and the results were compared with the histopathologic findings in surgical specimens. RESULTS: The normal rectum was shown by ERUS to be a five- or seven-layer structure. Characteristic abnormal ERUS findings included disappearance of the perirectal fat tissue layer with or without disruption of the propria muscle layer. Endorectal ultrasonography accurately assessed rectal wall involvement in all four patients who had two bladder tumors, plus the one patient with prostatic leiomyoma and the one with prostatic leiomyosarcoma. However, ERUS overstaged one of 12 bladder tumors with no rectal wall involvement, which was strongly adhesive to the rectum because of an inflammatory change but had no tumor invasion. There were no cases of understaging by ERUS. In comparison, CT accurately assessed rectal wall involvement in two patients, but overstaged in three and understaged in two. Magnetic resonance imaging, which was performed in 14 patients, accurately assessed rectal wall involvement in two patients, but overstaged in three and understaged in one. CONCLUSION: This preliminary study suggests that ERUS more accurately assesses rectal wall involvement in intrapelvic tumor than CT or MRI.

Adult↗
PubMed1999

Multidisciplinary treatment, including laser hyperthermia, for extensive regional metastasis of a penile tumor.

BACKGROUND: There is no reliable treatment for penile tumor with lymph node metastasis. METHODS: We report on a patient with a penile tumor with extensive regional metastasis that was successfully managed with combined laser hyperthermia, radiation and chemotherapy. RESULTS: The patient has survived more than 7 years without evidence of disease. CONCLUSIONS: Multidisciplinary treatment, including laser hyperthermia, may be useful for the treatment of regional metastasis of penile tumor.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

Selectivity of sphingosine-induced apoptosis. Lack of activity of DL-erythyro-dihydrosphingosine.

Sphingosine (Sph) is emerging as an intracellular regulator of cellular differentiation and apoptosis (Ohta, et al., Cancer Res., 55, 691-697, 1995). We have recently found that both Sph and its methylated derivative N,N-dimethylsphingosine (DMS) inhibit mitogen-activated protein kinase (MAPK) activity, suggesting that Sph-induced apoptosis may be mediated at least partly through inhibition of MAPK (Sakakura, et al., Int J Oncol, 11, 31-39, 1997). We report in this study that three stereoisomers, D-erythro-Sph, L-threo-Sph, and DL-erythro-dihydrosphingosine, were tested in induction of apoptosis and inhibition of MAPK activity in three different kinds of solid tumor cell lines. D-erythro-Sph was strongest in these effects among three compounds. L-threo-Sphingosine was partly active. On the other hand, DL-erythro-dihydrosphingosine was totally inactive. These results demonstrate the specificity of sphingosine action in induction of apoptosis and inhibition of MAPK, suggesting that Sph may play an important role as a physiological intracellular messenger of apoptosis in these cancer cells.

3T3 Cells↗
PubMed1998

A new treatment for penile conservation in penile carcinoma: a preliminary study of combined laser hyperthermia, radiation and chemotherapy.

OBJECTIVE: To investigate the role of laser hyperthermia in penis-conserving therapy for penile carcinoma. PATIENTS, MATERIALS AND METHODS: Penile carcinoma KPK-1 cells were transplanted into nude mice to induce tumour; the effects of laser hyperthermia, the chemotherapeutic agent peplomycin, or their combination on the inhibition of KPK-1 tumour growth were assessed. In a clinical study, two patients with well-differentiated, stage T2 penile tumours with corporeal involvement were treated to conserve the penis using concurrent radiation, laser hyperthermia and peplomycin. They had no pathologically identified regional lymph node metastasis. Radiation was given for 5 days a week for 3 weeks at a total dose of 30 Gy. Nd:YAG laser hyperthermia was administered at 42-43 degrees C for 15 min twice a week for 3 weeks immediately after radiation. Peplomycin (10 mg per day) was administered intravenously over 24 h together with the laser hyperthermia. RESULTS: The combined treatment with laser hyperthermia and peplomycin completely inhibited KPK-1 tumour growth, but the treatment with either laser hyperthermia or peplomycin alone had little effect. The results were also corroborated by the histopathological findings; the necrotic area in mice treated with combined therapy was much larger than that in those treated with laser hyperthermia alone. Both patients given combined laser hyperthermia, radiation and peplomycin were treated successfully, with the penis and sexual function conserved, and both survived for > 7 years with no evidence of any local or regional recurrence. There were no major complications related to the combined treatment. CONCLUSIONS: This preliminary study showed that combined treatment with laser hyperthermia, radiation and peplomycin might be a promising therapy for conserving the penis in some patients with stage T2 penile tumours.

Animals↗
PubMed1997

Sphingosine induces apoptosis in androgen-independent human prostatic carcinoma DU-145 cells by suppression of bcl-X(L) gene expression.

Our recent studies have suggested that sphingosine, an endogenous protein kinase C (PKC) inhibitor, may mediate apoptosis induced by a phorbol ester (PMA) in human promyelocytic leukemia HL-60 cells [Ohta et al. Cancer Res. 1995;55:691-697], and that the apoptotic induction by both PMA and sphingosine is accompanied by down-regulation of bcl-2, a gene which acts to prevent apoptotic cell death [Sakakura et al. FEBS Lett. 1996;397:177-180]. In this study, we examined the sphingosine-induced apoptosis of the androgen-independent human prostatic carcinoma cell line DU-145, which expresses bcl-X(L) and Bax but not bcl-2, and found that treatment of DU-145 cells with sphingosine suppressed bcl-X(L) in both mRNA and protein levels but did not change bax expression at all. In contrast, in apoptotic cells treated with a PKC inhibitor, staurosporine, no effect on bcl-X(L) or bax expression was observed. The initial metabolites of sphingosine in the cells, ceramide and sphingosine 1-phosphate, failed to induce apoptosis. These results indicate that, in DU-145 cells, sphingosine, but not its metabolites, induces apoptosis through down-regulation of bcl-X(L), independently of PKC inhibition. Our present results, together with previous observations, strongly suggest that apoptosis regulatory genes differ according to cell type and apoptosis induction through sphingosine is accompanied by inhibition of either bcl-2 or bcl-X(L) activity in these cells.

Androgens↗
PubMed1997

Metanestin, a glycoprotein with metastasis-associated expression in transitional cell carcinoma of the urinary bladder.

A 60-kDa glycoprotein named metanestin was identified by molecular cloning. The glycoprotein had a twice-repeated motif of Pro-Gly-Pro-Gly and carried metastasis-associated carbohydrate epitopes. The antibody to the protein portion of metanestin strongly reacted with lymph-node metastasis of transitional-cell carcinoma of the urinary bladder, but the reactivity to the primary tumor was generally weaker and the normal urothelium was scarcely reactive. Thus both metanestin and the carbohydrate on it showed metastasis-associated expression. In addition, we identified a 100-kDa glycoprotein with a 4-times-repeated motif of Pro-Ala-Pro-Ala. The antibody to the 100-kDa glycoprotein showed reactivity similar to that to metanestin.

Amino Acid Sequence↗
PubMed1997

Overexpression of bax enhances the radiation sensitivity in human breast cancer cells.

Bax-alpha, a splice variant of bax which promotes apoptosis, is expressed in many kinds of untransformed cell lines and breast tissue, whereas only weak or no expression could be detected in breast cancer cell lines and malignant breast tissue. Human breast cancer MCF-7 cells, which have a weak bax gene expression, were stably transfected with pCX2neo bax, encoding human bax and neomycin-resistant genes, and two unique clones (MCF-7/bax-1 and MCF-7/bax-2) were thus generated which expressed different levels of bax-alpha. Sensitivity to ionizing radiation (IR) was examined and each was more sensitive to IR than the parental MCF-7 cells. The degree of enhancement in radiosensitivity was dependent on the expression level of bax, and IR was found to induce intranucleosomal DNA fragmentation in stable transfectant but not in parent cells, thus suggesting that this sensitization is due to apoptosis. We suggest that exogenous bax-alpha expression might therefore be one of the factors determining cellular radiosensitivity in MCF-7 breast cancer cells and may potentially have a therapeutic application by enhancing radiation sensitivity in breast cancer cells.

Apoptosis↗
PubMed1997

Overexpression of bax sensitizes breast cancer MCF-7 cells to cisplatin and etoposide.

Bax, one of the bcl-2 family genes, is expressed in a number of untransformed cell lines and various breast tissues, whereas only weak or no expression has been detected in breast cancer cell lines and malignant breast tissue. Human breast cancer MCF-7 cells, which have a weak bax gene expression, were stably transfected with pCX2neo bax, encoding human bax; and two unique clones, MCF-7/bax-1 and MCF-7/ bax-2, that expressed different levels of bax were generated. Sensitivity to cisplatin (CDDP) and etoposide (VP-16) was examined and each stable transfectant was more sensitive to these agents than the parental MCF-7 cells. The degree of enhancement in sensitivity to these anticancer agents was dependent on the expression level of bax. The enzyme-linked immunosorbent assay (ELISA), which quantifies DNA damage, demonstrated that this sensitization was due to apoptosis. Thus, we suggest that exogenous bax-alpha overexpression may be one of the factors determining cellular chemosensitivity in MCF-7 breast cancer cells and that it could be applied therapeutically to enhance chemosensitivity in breast cancer cells.

Antineoplastic Agents↗
PubMed1997

In vitro and in vivo induction of apoptosis by sphingosine and N, N-dimethylsphingosine in human epidermoid carcinoma KB-3-1 and its multidrug-resistant cells.

Sphingolipid breakdown products, including ceramide and sphingosine, regulate cell growth, cell differentiation, and apoptosis. We examined the effect of various agents, including sphingolipids, on apoptosis induction in human epidermoid carcinoma KB-3-1 and its multidrug-resistant (MDR) subclone KB-C2 cells which express P-glycoprotein. Adriamycin (ADM) induced apoptosis in KB-3-1 cells but not in KB-C2 MDR cells at the concentration of 50 microg/ml. On the other hand, 15 microM sphingosine or its methylated derivative N, N-dimethylsphingosine (DMS) induced apoptosis in both cell types in vitro. These results suggested that KB-C2 MDR cells were resistant to apoptosis induction by ADM but sensitive to that by sphingosine and DMS. Ceramide and sphingosine-1-phosphate, the initial metabolites of sphingosine, failed to induce apoptosis under the same experimental condition as sphingosine/DMS. The protein kinase C (PKC) inhibitors H7 and staurosporine did not induce apoptosis in either cell line, suggesting that PKC-independent signaling is involved in apoptosis induced by sphingosine and DMS, although both sphingosine and DMS have been shown to down-regulate PKC. Furthermore, DMS significantly inhibited the growth of KB-3-1 as well as KB-C2 MDR tumors in vivo, with evidence of increased apoptosis. The intracellular level of exogenously added [3H]sphingosine or [14C]DMS did not differ between the KB-3-1 parent cell line and its MDR subclone KB-C2, whereas that of [14C]ADM was reduced in KB-C2 MDR cells compared to KB-3-1 cells. These results suggest that P-glycoprotein acts as a transporter for ADM but not for sphingosine or DMS. Furthermore, DMS at the concentrations which induce apoptosis in KB-C2 cells did not affect the level of [14C]ADM. Because sphingosine and DMS induce apoptosis regardless of P-glycoprotein expression, they may provide a new strategy and a promising approach to the treatment of anticancer drug-resistant cancer.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Overexpression of bax sensitizes human breast cancer MCF-7 cells to radiation-induced apoptosis.

Resistance to apoptosis plays an important role in tumors that are refractory to chemotherapy and ionizing radiation (IR). bax, which forms a heterodimer with bcl-2 and accelerates apoptosis, is not, or only weakly, expressed in most human breast cancer cells, and weak bax expression is considered to be related to the resistance of breast cancer cells to apoptosis. bax expression vector was introduced to human breast cancer MCF-7 cells, which exhibit weak expression of bax, to demonstrate its role of modulating radiation-induced apoptosis. bax overexpression in MCF-7 cells by stable transfection does not affect viability by itself, but each stable transfectant was more sensitive to IR than the parental MCF-7 cells. The degree of enhancement in radiosensitivity was dependent on the expression level of bax. IR upregulated p53 and p21WAF1 about 5- to 10-fold and downregulated bcl-2 and bcl-XL by 80-90% at 6 hr in both parent and bax stably transfected MCF-7 cells to the same degree. FACS analysis and DNA electrophoresis revealed that this sensitization was due to apoptosis. We suggest that exogenous bax expression might be one of the factors determining cellular radiosensitivity in MCF-7 breast cancer cells and may have therapeutic applications for enhancing radiation sensitivity in breast cancer cells.

Apoptosis↗