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Biomedical subjects

S Kagawa

Publications and source records attributed to S Kagawa.

At least 73 records · Page 4Linked to original sources
PubMed1999

Prevention of the initial testosterone surge induced by a luteinizing hormone-releasing hormone analogue in prostate cancer patients: the endocrinological effects of pretreatment with chlormadinone acetate.

We investigated the endocrinological effects of pretreatment with chlormadinone acetate (CMA) in preventing the initial testosterone surge induced by a luteinizing hormone-releasing hormone (LH-RH) analogue. A total of 25 patients with previously untreated prostate cancer were included in this study. The patients were randomly assigned to 2 treatment groups: Group 1; CMA therapy was begun 4 weeks before the initial LH-RH analogue injection. Group 2; CMA therapy was begun 2 weeks before the initial LH-RH analogue injection. After the initial LH-RH analogue injection, CMA was administered during this study. After LH-RH analogue application, the mean values of serum luteinizing hormone (LH) and testosterone increased in both groups on day 3. However, LH and testosterone levels remained beneath pretreatment values in both groups. The mean relative PSA levels did not significantly increased on day 3 and day 7 in both groups. Our results indicate that pretreatment with CMA for 2 weeks was sufficient to prevent the initial testosterone surge in the maximal androgen blockade which was associated with CMA.

Administration, Oral↗
PubMed1999

[Late phase II clinical study for bropirimine (U-54461S) in situ carcinoma of the bladder: follow-up investigation. Bropirimine Study Group].

A follow-up investigation was conducted on a Late Phase II clinical study of bropirimine for carcinoma in situ (CIS) of the bladder. We previously reported that 48 patients were enrolled and 17 patients achieved complete remission (CR) in the Late Phase II study. Of the 17 CR patients, 5 had recurrence, but 9 were recurrence free for a year and 5 have remained so for more than 2 years (median follow-up: 29.1 +/- 4.2 months). The 1-year and 2-year recurrence-free rates calculated using the Kaplan-Meier method were 70.3% and 61.5% respectively. Of all the 47 bropirimine-treated patients, 11 underwent total cystectomy (median follow-up: 31.8 +/- 5.2 months). The rates of bladder preservation after 1 year, 2 years, and 3 years calculated using the Kaplan-Meier method were 87.2%, 80.7%, and 74.0% respectively. Of the 39 patients who did not respond to bropirimine or suffered from recurrence after bropirimine treatment, 19 received subsequent intravesical bacillus Calmette-Guerin (BCG) therapy and 13 achieved CR (68.4%). This suggests that bropirimine does not decrease the efficacy of BCG therapy. In the present study, the prognosis was confirmed to be favorable after bropirimine therapy. Bropirimine would thus seem to be a useful oral anticancer agent for bladder CIS.

Administration, Intravesical↗
PubMed1999

[Serum alkaline phosphatase flare in prostate cancer accompanied by bone metastases and treated with hormonal therapy. TEKK Study Group].

To clarify the roles of alkaline phosphatase (ALP) flare in prostate cancer accompanied by bone metastases and treated with hormonal therapy, we evaluated the clinicopathological character, treatment efficacy and outcome for patients with and without ALP flare. We evaluated 60 patients with newly diagnosed prostate cancer accompanied by bone metastases and treated with hormonal therapy, whose response in terms of serum prostate specific antigen (PSA) levels showed a partial response (PR) or better response. The patients were classified into two groups, an ALP flare group (13 cases) and a non-ALP flare group (47 cases). The former showed serum ALP elevation of more than double, and the latter less than double that of pretreatment levels following hormonal therapy. Patient characteristics, PSA response and outcome were compared between the two groups. Extent of disease (EOD) as grade of bone metastasis was significantly higher in the ALP flare group than in the non-flare group (p = 0.0352). Pre-treatment serum PSA levels were also significantly higher in the ALP flare group (p = 0.0010). However, there were no significant differences in pretreatment serum ALP levels. Serum PSA levels were normalized in 37 of the 47 patients (78.7%) in the non-ALP flare group compared with 6 of the 13 (46.2%) in the ALP flare group (p = 0.0211). Moreover, the period until biochemical failure was significantly shorter for the ALP flare than the non-flare group (p = 0.0027). These results suggest that prostate cancer patients with bone metastases in whom ALP flare is observed in response to hormonal therapy tend to have more extensive bone metastases, high pretreatment PSA levels, to be resistant to PSA normalization and more likely to experience biochemical failure.

Aged↗
PubMed1999

Induction of differentiation-dependent apoptosis in human esophageal squamous cell carcinoma by adenovirus-mediated p21sdi1 gene transfer.

When keratinocytes withdraw from the cell cycle, they migrate from the basal to the superficial layers of the epidermis and undergo morphological and biochemical changes during the process of terminal differentiation. These differentiation features of keratinocytes are known to be altered or reduced in esophageal cancer cells. Therefore, we examined the effects of transferring the cyclin-dependent kinase inhibitor p21sdi1 gene into human esophageal cancer cell lines as well as normal keratinocytes using an adenovirus vector system. Ectopic expression of p21sdi1 protein resulted in cell cycle arrest at the G1 phase and produced morphological changes, such as enlarged nuclei and a flattened cellular shape, changes specific to the differentiated phenotype. The human involucrin protein is a specific product of keratinocyte differentiation, which is selectively expressed in the suprabasal epidermal layers. Western blot analysis and immunohistochemical staining demonstrated that involucrin expression was 3- to 5-fold enhanced by the forced expression of p21sdi1 in esophageal cancer cells, whereas only a mild up-regulation up to 1.2-fold occurred in normal keratinocytes. We also found that exogenous introduction of the p2sdi1 gene transcriptionally activated the upstream promoter function of the involucrin gene. These stimulatory effects on involucrin expression were not observed when another cyclin-dependent kinase inhibitor gene, p16(INK4a), was transduced. Moreover, p21sdi1 expression in esophageal cancer cells transduced with p21sdi1 led to a rapid apoptotic cell death after a transient dormant phase, although keratinocytes transduced with p21sdi1 survived longer by terminally withdrawing from the cell cycle. These results may have an important implication for understanding the biology of differentiation-dependent apoptosis in human esophageal squamous cell carcinoma.

Adenoviruses, Human↗
PubMed1998

The HIV-1 Vpr displays strong anti-apoptotic activity.

Mutations in the human immunodeficiency virus type 1 (HIV-1) vpr gene only slightly reduce the replication rate of the virus. To study the role of HIV-1 Vpr in biological effects on cells, HEp-2 cells, which express HIV-1 Vpr constitutively but at a low level, were established. While control HEp-2 cells underwent apoptosis when incubated with sorbitol, the morphological and biochemical apoptotic changes were inefficiently induced in the HIV-1 Vpr-expressing cells by the same treatment. These results clearly indicate that HIV-1 Vpr has anti-apoptotic activity, and raise the possibility that Vpr acts as a weak activator of virus replication through anti-apoptosis.

Animals↗
PubMed1998

Prognostic values of matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 expression in bladder cancer.

BACKGROUND: Matrix metalloproteinase-2 (MMP-2), which degrades the extracellular matrix or the basement membrane, has an essential role in tumor invasion and metastasis. To evaluate the roles of MMP-2, its inhibitor (tissue inhibitor of metalloproteinase-2 [TIMP-2]), and its activator (membrane-type matrix metalloproteinase-1 [MT1-MMP]) in tumor invasion or as a prognostic factor in patients with bladder carcinoma, the authors investigated the expression of MMP-2, TIMP-2, and MT1-MMP in patients with bladder carcinoma. METHODS: Tissues obtained from 41 patients with bladder carcinoma were used for analysis. Expression of MMP-2, TIMP-2, MT1-MMP, and glyceraldehyde-3-phosphate dehydrogenase was examined by reverse transcriptase-polymerase chain reaction analysis. Correlations between the levels of MMP-2, TIMP-2, and MT1-MMP expression and histologic findings or patient outcome were evaluated. RESULTS: Expression of MMP-2 and TIMP-2 was significantly higher in muscle invasive pT2< or = bladder tumors than in pT1a tumors (MMP-2: P < 0.0005; TIMP-2: P < 0.005). Moreover, high levels of MMP-2 and TIMP-2, as well as MT1-MMP expression, all were strongly associated with decreased survival (MMP-2: P < 0.0001; TIMP-2: P < 0.0001; and MT1-MMP: P < 0.005). Even within the radically cystectomized muscle invasive pT2< or = tumor group, patients with a high expression of any of these three genes had a worse prognosis than those with low expression (MMP-2: P < 0.05; TIMP-2: P < 0.05; and MT1-MMP: P = 0.0641). CONCLUSIONS: MMP-2 and TIMP-2 are believed to contribute to the invasive properties of bladder carcinoma. The authors report that expression of MMP-2, TIMP-2, and MT1-MMP are useful prognostic indicators in patients with bladder carcinoma and may be helpful in designing treatment protocols.

Aged↗
PubMed1998

Overexpression of Bcl-2 in bladder cancer cells inhibits apoptosis induced by cisplatin and adenoviral-mediated p53 gene transfer.

To investigate the effects of the expression of Bcl-2 protein in bladder cancer on the apoptosis induced by cisplatin or adenoviral-mediated p53 gene (Ad5CMV-p53) transfer, we transfected the bcl-2 gene into KoTCC-1, a human bladder cancer cell line that does not express the Bcl-2 protein. The Bcl-2-transfected KoTCC-1 (KoTCC-1/B) exhibited significantly higher resistance to both cisplatin and Ad5CMV-p53 transfer than did either the parental KoTCC-1 (KoTCC-1/P) or the vector-only transfected cell line (KoTCC-1/C). The flow cytometric analysis of the propidium iodide-stained nuclei and DNA fragmentation analysis after cisplatin or Ad5CMV-p53 treatment revealed DNA degradation in both KoTCC-1/P and KoTCC-1/C, whereas KoTCC1/B showed a marked inhibition of DNA degradation. Following the treatment with cisplatin or Ad5CMV-p53, the accumulation of p53 protein was highly detectable for a long period in KoTCC-1/B compared to that in KoTTC-1/P and KoTCC-1/C. Furthermore, the cisplatin and Ad5CMV-p53 treatments each reduced the volume of the subcutaneous tumors established in nude mice formed by KoTCC-1/P or KoTCC-1/C; in contrast, their reductive effects on the tumors formed by KoTCC-1/B were significantly suppressed. The intraperitoneal tumor cell implantation model revealed that the prognoses of mice injected with KoTCC-1/B were significantly inferior to those of the mice injected with either KoTCC-1/P or KoTCC-1/C after treatment with cisplatin or Ad5CMV-p53. These findings suggest that the expression of Bcl-2 in bladder cancer cells interferes with the therapeutic effects of cisplatin and Ad5CMV-p53 through the inhibition of the apoptotic pathway.

Adenoviruses, Human↗
PubMed1998

Serum levels of soluble interleukin-2 receptor in renal cell carcinoma.

OBJECTIVES: To evaluate increased serum soluble interleukin-2 receptor (sIL-2R) levels in patients with renal cell carcinoma (RCC). METHODS: Serum sIL-2R levels were measured in 52 patients with RCC and 10 control subjects by an enzyme-linked immunosorbent assay (ELISA) technique. The correlation between serum sIL-2R levels and clinical stage, disease prognostic value, and inflammatory marker levels was analyzed. RESULTS: Serum sIL-2R levels in patients with RCC were significantly higher than those in normal control subjects (857.2 +/- 660.0 versus 291.3 +/- 76.4 U/mL, P < 0.0001). High serum sIL-2R levels appeared to be related to advanced clinical stage (596.0 +/- 276.5 U/mL in Stage II, 776.1 +/- 398.8 U/mL in Stage III, and 1310.0 +/- 926.7 U/mL in Stage IV: Stage II vs. Stage III, P = 0.0078; Stage II vs. Stage IV, P < 0.0001). The overall cause-specific survival curves showed that patients with high sIL-2R levels (more than 1000 U/mL) had a significantly lower survival rate than those with low (less than 500 U/mL, P = 0.0003) or intermediate levels (500 to 1000 U/mL, P = 0.0007). C-reactive protein levels apparently increased in patients with high sIL-2R concentrations. CONCLUSIONS: Measurement of serum sIL-2R concentrations in patients with RCC provides useful information for predicting the extent of disease and length of survival.

Adult↗
PubMed1998

Role of the matrix metalloproteinase and tissue inhibitors of metalloproteinase families in noninvasive and invasive tumors transplanted in mice with severe combined immunodeficiency.

OBJECTIVES: To elucidate the role of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in human urothelial cancers, we studied gene expressions of MMPs, TIMPs, and membrane-type 1 matrix metalloproteinase (MT1-MMP) in noninvasive or invasive tumor lines transplanted in mice with severe combined immunodeficiency (SCID). METHODS: The UCT-1 tumor line, derived from bladder cancer, is a noninvasive transplantable tumor with no evidence of metastasis. The UCT-2 tumor line, derived from a renal pelvic tumor, extensively invades without metastasis. We examined gene expressions of MMPs-1, 2, 3, 7, 8, 9, 10, and 11, TIMPs-1, 2, and 3, and MT1-MMP in UCT-1 and 2 by semiquantitative polymerase chain reaction analysis. RESULTS: Significantly higher gene expression of MMP-2 was detected in the invasive UCT-2 tumor line than in the noninvasive UCT-1 tumor line. Although both tumor lines expressed TIMP-1 and MT1-MMP, stronger gene expression of MT1-MMP was observed in the UCT-2 tumor line than in the UCT-1 tumor line. The other MMPs or TIMPs were not detected in either of the lines. CONCLUSIONS: MMP-2 and MT1-MMP may have an important role in the invasion mechanism of urothelial cancers.

Aged↗
PubMed1998

Immunohistochemical analysis of Ki-67 antigen and Bcl-2 protein expression in prostate cancer: effect of neoadjuvant hormonal therapy.

OBJECTIVE: To determine differences in the immunohistochemical (IHC) expression of Bcl-2 protein and Ki-67 antigen in patients with prostatic cancer who underwent radical prostatectomy with or without neoadjuvant hormonal therapy. MATERIALS AND METHODS: Ki-67 antigen and Bcl-2 protein were detected by IHC using MIB-1 and Bcl-2 antibodies in prostatectomy specimens from 28 patients who received hormonal therapy before surgery (group 1) and 51 patients who did not (group 2). RESULTS: In group 2, the mean MIB-1 index increased with increasing grade of tumour, from 11.6% in low-grade to 24.7% in high-grade tumours (P = 0.002). Bcl-2 expression did not correlate with either tumour grade or stage. In group 1, there were no correlations between Bcl-2 expression or MIB-1 index and tumour grade or stage. More tumours in group 1 were Bcl-2-positive (16 of 28, 57%) than were tumours in group 2 (11 of 51, 22%; P = 0.003). The mean (SD) MIB-1 index of tumours in group 2 [15.6 (14.4)%], was significantly greater than that of tumours in group 2 [6.8 (7.5)%; P = 0.004]. CONCLUSIONS: These results indicate that Bcl-2 positivity is increased by androgen ablation therapy and conversely, that the proliferative activity of cancer cells is significantly reduced. The expression of Bcl-2 protein may play a role in the ability of prostate cancer cells to survive in an androgen-deprived environment.

Aged↗
PubMed1998

Semi-quantitative analysis of telomerase activity in exfoliated human urothelial cells and bladder transitional cell carcinoma.

OBJECTIVE: To determine the utility of detecting telomerase activity in transitional cell bladder cancer, using the telomeric repeat amplification protocol (TRAP) assay, and thus provide a test for the detection and monitoring of bladder cancer, especially low-grade tumours. PATIENTS, SUBJECTS AND METHODS: Telomerase activity was assayed in bladder cancer tissues and the exfoliated urothelial cells from 29 patients with bladder cancer, 10 with benign disease, and in 10 healthy subjects using the TRAP assay. The levels were assessed semiquantitatively by calculating the ratio to an internal telomerase assay standard. RESULTS: Telomerase activity was very low in the exfoliated urothelial cells from all healthy subjects and patients with benign disease, with a mean (SD) ratio of 0.25 (0.03) and 0.33 (0.04), respectively. A threshold ratio of 0.4 was calculated as the mean +/- 2 SD of the telomerase activity level of the exfoliated urothelial cells from patients with benign disease. Using this threshold, telomerase activity was negative in exfoliated urothelial cells from all benign cases (100% specificity) and positive in all 26 bladder cancer tissue samples assayed. In tumour tissue, telomerase activity was not associated with tumour grade, size or stage. Telomerase activity in exfoliated urothelial cells from patients with bladder cancer was positive in 25 of 29 samples (86% sensitivity). The sensitivity of telomerase activity in exfoliated cells was seven of nine in G1, 10 of 12 in G2 and all eight G3 tumours; the corresponding sensitivity for voided urine cytology in G1, G2 and G3 tumours was two of nine, six of 12 and six of eight, respectively. CONCLUSION: These results indicate that telomerase activation occurs as an early step in carcinogenesis and the semi-quantitative analysis of telomerase activity in exfoliated urothelial cells could be a minimally invasive and useful method for detecting bladder cancer, even in low-grade tumours.

Aged↗
PubMed1998

Immediate effects of extracorporeal shock waves on the male genital system of rabbit. Preliminary report.

Hemospermia was reported to occur following extracorporeal shock wave lithotripsy of lower ureteric stones. Because no studies showed clearly the possible effect of extracorporeal shock waves (ESW) on the male genital system, we were prompted to study this effect. Eighteen male white New Zealand rabbits were divided into three groups (six in each) and subjected to different doses of ESW (2000, 3000 and 4000) using a Dornier MFL 5000. Shocks were focused on the lower parts of the bladder. Four animals were used as controls. Two hours later, the animals were dissected. Gross examination of the genital systems showed bleeding in the testicles and prostates of only some animals, whereas microscopic examination revealed bloody spots in the genital structures of all animals. The amount of bleeding was ESW dose-independent. In conclusion, ESW showed evident immediate effects on the male genital system. Application of shock waves in treating lower ureteric or vesical stones in doses between 2000 and 4000 may cause bleeding in the structures of this system, which can lead to hemospermia. More studies will be needed to show the long-term sequelae of these changes on the male genital system.

Animals↗
PubMed1998

Activation of the Ca2+-activated K+ channel via protein kinase A-dependent phosphorylation in human prostatic smooth muscle cells.

BACKGROUND: We investigated the functional importance of the Ca2+-activated K+ channel (K(Ca)-channel) of human prostatic smooth muscle cells in cyclic adenosine 3',5'-monophosphate (cAMP)-induced relaxation, to clarify signal transduction pathways and intracellular mechanisms of relaxation in prostatic smooth muscle. METHODS: Using the patch-clamp technique, we characterized the K(Ca)-channel of cultured human prostatic smooth muscle cells. We also investigated the effects on the K(Ca)-channels of forskolin, an activator of adenylate cyclase, amrinone, a phosphodiesterase inhibitor, and protein kinase A (A-kinase)-dependent phosphorylation. RESULTS: Single-channel current recordings from cultured human prostatic smooth muscle cells revealed the presence of K(Ca)-channels (conductance 296.7 +/- 5.67 pS, n = 7). In cell-attached patch configurations, the K(Ca)-channel was activated by forskolin (10(-4) mol/L) and amrinone (10(-4) mol/L). In inside-out patch configurations, it was activated by catalytic subunits of A-kinase (10 U/mL). CONCLUSIONS: We conclude that the K(Ca)-channel of human prostatic smooth muscle cells is regulated by intracellular cAMP levels and that A-kinase mediates the cAMP-induced activation of the K(Ca)-channel. This regulation of the K(Ca)-channel by cAMP may at least partially explain cAMP-induced prostatic smooth muscle relaxation and the effectiveness of certain drugs for treatment of obstruction in benign prostatic hyperplasia.

Adenylyl Cyclases↗
PubMed1998

Biphasic action of phenylephrine on the Ca(2+)-activated K+ channel of human prostatic smooth muscle cells.

The elevation of cytosolic Ca2+ ([Ca2+]i) is known to regulate smooth muscle contractility. A physiological concentration of phenylephrine induced the elevation in [Ca2+]i of human prostatic smooth muscle cells; however, contraction of prostatic tissues in vitro needs a higher concentration of phenylephrine than the physiological level. To investigate this discrepancy, we investigated the functional importance of the Ca(2+)-activated K+ channel (KCa channel) of human prostatic smooth muscle cells in phenylephrine-induced contraction. Using the patch-clamp technique, the KCa channel of human prostatic smooth muscle cells was activated by phenylephrine at a physiological concentration (10(-7)-10(-5) M) but was inhibited at a higher concentration (10(-4)-10(-3) M). Phenylephrine (10(-3) M) also inhibited the KCa channel which was activated by 10 microM A23187, a calcium ionophore. Similar inhibition was obtained with 1 microM phorbol 12-myristate 13-acetate, an activator of protein kinase C (C-kinase). Both inhibitions were reversed by subsequent application of 1 nM staurosporine, a protein kinase inhibitor. These results suggested that C-kinase mediated the phenylephrine-induced inhibition of the KCa channel. In this study, a physiological concentration of phenylephrine induced activation of the KCa channel of human prostatic smooth muscle cells, which brought about membrane hyperpolarization and relaxation of human prostatic smooth muscle cells. The regulation of the KCa channel by phenylephrine may explain the need of a high concentration of phenylephrine for the contraction of prostatic tissue.

Adrenergic alpha-Agonists↗
PubMed1998

Determination of p53 protein and high-risk human papillomavirus DNA in carcinomas of the renal pelvis and ureter.

The presence and distribution of high-risk human papillomavirus (HPV) DNA type-16 and -18 or overexpression of the p53 protein were determined in 31 patients with renal pelvic and ureteral carcinoma in Saga prefecture of Japan, consisting of 28 transitional cell carcinomas (TCCs) and 3 squamous cell carcinomas (SCCs). In situ hybridization with DNA probes for HPV-16 and -18 was performed as well as immunohistochemical techniques using antibody to p53 protein. Fresh tumor tissues from 8 patients were also studied for p53 mutations in exons 5 through 8 by direct sequencing. Of 28 TCC patients at Saga prefecture in Japan, 10 tested were positive for HPV DNA, 5 for HPV type-16, 4 for HPV type-18 and one doubly-positive case. Of the remaining 18 tumors, seven showed positive nuclear staining in cancer cells with p53 antibody. One of the 3 patients with SCCs also revealed the nuclear positivity of the cancer cells with p53 antibody but not with HPV infection. p53 point mutation was detected in 2 cases also showing p53 immunopositivity. Overexpressed p53 protein was statistically more common in invasive and non-papillary (p<0.05) and in high-grade TCCs (p<0.05). These findings suggest that HPV infection, and expression (mutation) of p53 protein may be intimately related to the pathogenesis of urothelial tumor cell growth and progression.

Aged↗
PubMed1998

[Quantitative analysis of telomerase activity in exfoliated urothelial cells for the diagnosis of bladder carcinoma].

Voided urine cytology is the most common non-invasive examination for the detection and monitoring of bladder cancer. However, the result is not satisfactory, especially for low grade tumors. Activity of telomerase can be detected in most tissues of bladder carcinoma using the telomeric repeat amplification protocol (TRAP) assay. We analyzed the quantitative telomerase activity in exfoliated urothelial cells, and evaluated the values for early diagnosis of bladder carcinoma. We performed a quantitative analysis using a hybridization protection assay (HPA) based on TRAP assay. Telomerase activity was significantly higher level in exfoliated urothelial cells from patients with bladder cancer than all of healthy cases and patients with benign disease (p < 0.0001). The cut off value was calculated as mean + 2SD of the telomerase activity level of the exfoliated urothelial cells from healthy cases. Using this cut off value, telomerase activity was positive in 26 of 41 in exfoliated urothelial cells from bladder cancer patients(63.4% sensitivity), and negative in 63 of 69 in exfoliated urothelial cells from healthy cases and patients with benign disease (91.3% specificity). The sensitivity of telomerase activity in exfoliated cells was higher than urinary cytology, especially in low grade tumors. Our results indicate that quantitative analysis of telomerase activity in exfoliated urothelial cells could become minimum invasive and useful method for detection of bladder carcinoma.

Humans↗