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Reduced expression in immortalized cells/Dickkopf-3 (REIC/Dkk-3) was identified as a gene whose expression is reduced in many human cancers. REIC/Dkk-3 expression is also downregulated in malignant glioma and regulates cell growth through caspase-dependent apoptosis. cRGD (EMD121974), an antagonist of integrins, has demonstrated preclinical efficacy against malignant glioma. In this study, we investigated the antiglioma effect of combination therapy using an adenovirus vector carrying REIC/Dkk-3 (Ad-REIC) and cRGD. Quantitative real-time reverse-transcription PCR revealed the reduction of REIC/Dkk-3 mRNA levels in malignant glioma cell lines. The reduction of REIC/Dkk-3 protein expression in malignant glioma cell lines was also confirmed with western blot analysis. After treatment with Ad-REIC and cRGD, the proliferative rate of malignant glioma cells was significantly reduced in a time-dependent manner. In vivo, there was a statistically significant increase in the survival of mice treated with Ad-REIC and cRGD combination therapy compared with Ad-REIC monotherapy. We identified an apoptotic effect following monotherapy with Ad-REIC. Moreover, cRGD augmented the antiglioma efficacy of Ad-REIC. These results may lead to a promising new approach for the treatment of malignant glioma. [ABSTRACT FROM AUTHOR]

OBP-301 (a telomerase-specific, replication-competent adenovirus with hTERT promoter) was constructed in a previous study and it showed a strong anticancer effect by inducing cell lysis in human lung and prostate cancer cells. This study investigated the effectiveness of a combination therapy of OBP-301 and interleukin-2 (IL-2) in a mouse model of renal cell carcinoma (RCC). The cell-killing effect of OBP-301 was confirmed in vitro in the RENCA cancer cells. In in vivo experiment, luciferase-expressing RENCA cells were implanted in the left kidney and lung of BALB/c mice to prepare the RCC metastatic model. The animals were randomly divided into four treatment groups: PBS, IL-2 alone, OBP-301 alone and the combination. The analyses of orthotopic tumor weight, lung metastasis and luciferin-stained tumor images 14 days after each treatment showed significant tumor growth inhibition in the combination group in comparison with that in the OBP-301- or IL-2-treated groups. In addition, the percentage of regulatory T-cells (Tregs) in the combination group was significantly suppressed in comparison with that in the PBS and single-agent treatment groups. The outcomes of this study suggest that tumor-specific oncolytic immunovirotherapy may become an attractive strategy for the treatment of human RCC. [ABSTRACT FROM AUTHOR]

The overexpression of reduced expression in immortalized cells (REIC)/Dickkopf-3 (Dkk-3), a tumor suppressor gene, induced apoptosis in human prostatic and testicular cancer cells. The aim of this study is to examine the potential of REIC/Dkk-3 as a therapeutic target against breast cancer. First, the in vitro apoptotic effect of Ad-REIC treatment was investigated in breast cancer cell lines and the adenovirus-mediated overexpression of REIC/Dkk-3 was thus found to lead to apoptotic cell death in a c-Jun-NH2-kinase (JNK) phosphorylaion-dependent manner. Moreover, an in vivo apoptotic effect and MCF/Wt tumor growth inhibition were observed in the mouse model after intratumoral Ad-REIC injection. As multidrug resistance (MDR) is a major problem in the chemotherapy of progressive breast cancer, the in vitro effects of Ad-REIC treatment were investigated in terms of the sensitivity of multidrug-resistant MCF7/ADR cells to doxorubicin and of the P-glycoprotein expression. Ad-REIC treatment in MCF7/ADR cells also downregulated P-glycoprotein expresssion through JNK activation, and sensitized its drug resistance against doxorubicin. Therefore, not only apoptosis induction but also the reversal of anticancer drug resistance was achieved using Ad-REIC. We suggest that REIC/Dkk-3 is a novel target for breast cancer treatment and that Ad-REIC might be an attractive agent against drug-resistant cancer in combination with conventional antineoplastic agents.Cancer Gene Therapy (2009) 16, 65–72; doi:10.1038/cgt.2008.58; published online 25 July 2008 [ABSTRACT FROM AUTHOR]

We previously constructed OBP-301 (Telomelysin, a telomerase-specific replication-competent adenovirus with human telomerase reverse transcriptase (hTERT) promoter), which showed a strong anticancer effect by inducing cell lysis of human non-small cell lung cancer and colorectal cancer cells. To investigate the utility of OBP-301 for prostate cancer treatment, we herein evaluate the cell killing and antitumor effects. First, in vitro hTERT-specific adenovirus transduction in human prostate cancer cells (LNCaP, PC3, DU145) was confirmed using OBP-401 (Telomelysin-green fluorescent protein (GFP)). There was no detectable GFP transduction in the human prostate normal cells (PrEC, PrSC). Consistently, the cell-killing effect of OBP-301 was observed only in the cancer cells. Second, using an in vivo subcutaneous LNCaP tumor model in nude mice, we demonstrated that three intratumoral OBP-301 injections (107 PFU per tumor × 3 days) were sufficient to eradicate the detectable LNCaP prostate tumor. We also demonstrated that the ispilateral treatment with OBP-301 significantly suppressed contralateral LNCaP tumor growth in both sides of the tumor model. Histological and immunohistochemical analyses revealed diffuse oncolytic degeneration and adenoviral E1A protein expression in both sides of the tumors. Therefore, in situ OBP-301 administration could be a promising therapeutic strategy against prostate cancer and its metastatic lesions.Cancer Gene Therapy (2008) 15, 315–322; doi:10.1038/cgt.2008.3; published online 15 February 2008 [ABSTRACT FROM AUTHOR]

We had previously reported that REIC/Dkk-3, a member of the Dickkopf (Dkk) gene family, works as a tumor suppressor. In this study, we evaluated the therapeutic effects of an intratumoral injection with adenoviral vector encoding REIC/Dkk-3 gene (Ad-REIC) using an orthotopic mouse prostate cancer model of RM-9 cells. We also investigated the in vivo anti-metastatic effect and in vitro anti-invasion effect of Ad-REIC gene delivery. We demonstrated that the Ad-REIC treatment inhibited prostate cancer growth and lymph node metastasis, and prolonged mice survival in the model. These therapeutic responses were consistent with the intratumoral apoptosis induction and in vitro suppression of cell invasion/migration with reduced matrix metalloprotease-2 activity. We thus concluded that in situ Ad-REIC/Dkk-3 gene transfer may be a promising therapeutic intervention modality for the treatment of prostate cancer.Cancer Gene Therapy (2007) 14, 765–772; doi:10.1038/sj.cgt.7701071; published online 29 June 2007 [ABSTRACT FROM AUTHOR]

We developed a preclinical prostate cancer model to study the feasibility of adoptive immunotherapy for residual tumor following neo-adjuvant in situ adenoviral-vector-mediated interleukin 12 (AdIL-12) gene therapy. Splenocytes were obtained from mice with orthotopic 178-2 BMA metastatic mouse prostate cancers treated previously with AdIL-12, or a vector with the IL-12 genes plus the costimulatory gene B7-1 (AdIL-12/B7), or a control gene (Adβgal). The splenocytes were subsequently injected intravenously into syngeneic mice bearing orthotopic 178-2 BMA tumors generated 3 days previously. Significant orthotopic tumor growth suppression was achieved with splenocytes derived from mice whose tumors had been injected with AdIL-12 compared to splenocytes from control Adβgal mice (P=0.0005) and splenocytes from AdIL-12/B7-treated mice significantly suppressed spontaneous lung metastases compared to splenocytes from control mice (P=0.0356). Adoptive transfer of splenocytes from either AdIL-12 (P=0.004) or AdIL-12/B7 (P=0.009)-treated mice significantly prolonged survival relative to controls. Transfer of NK and tumor-specific CTL activities was detected and depletion of CD4+ and CD8+ T cells by in vitro antibody-mediated complement lysis of the splenocytes prior to injection abrogated the effects. Systemic IL-12 administration delivered by intramuscular AdIL-12 injection enhanced the antitumor effects of adoptive splenocyte transfer and boosted the CTL response. Our data provide evidence that this form of adoptive immunotherapy can enhance the effectiveness of neo-adjuvant in situ IL-12 gene therapy in cases of persistent malignancy.Cancer Gene Therapy (2006) 13, 91–98. doi:10.1038/sj.cgt.7700872; published online 29 July 2005 [ABSTRACT FROM AUTHOR]

Testicular germ cell-induced autoimmune orchitis is characterized by inflammatory cell infiltration followed by disturbance of spermatogenesis. Experimental autoimmune orchitis (EAO) is an animal model for human immunological male infertility; delayed-type hypersensitivity (DTH) response plays a key role in its induction. Interleukin-10 (IL-10) is a regulatory cytokine that is critical in preventing organ-specific autoimmune inflammation. To determine the effects on EAO of human IL-10 (hIL-10) gene transfer, C3H/He mice immunized by unilateral testicular injury were administered intramuscular (i.m.) injections of adeno-associated viral (AAV) vector-encoding hIL-10 on the day of immunization. Serum hIL-10 was detected beginning at 1 week postinjection, and peaked at 3 weeks. Histological examinations showed a significantly low incidence of orchitis and disturbance of spermatogenesis in AAV hIL-10-treated mice, and the DTH response to autologous testicular cells was significantly suppressed. Immunohistochemical analysis of IFN-γ and IL-2, T-cell-associated cytokines, in the spleen and testes revealed significantly fewer cytokine-expressing cells after treatment. We conclude that a single i.m. administration of AAV hIL-10 significantly suppresses EAO and hypospermatogenesis by regulating cell-mediated immunity in the testes.Gene Therapy advance online publication, 26 May 2005; doi:10.1038/sj.gt.3302463 [ABSTRACT FROM AUTHOR]

Adenoviral vector delivery of the Herpes simplex virus thymidine kinase (HSV-tk) gene in combination with the prodrug ganciclovir (GCV) has been tested in phase I clinical trials for prostate cancer and found to exhibit a satisfactory toxicity profile. We have developed additional adenoviral vectors with differing promoters to optimize the expression profile and in the present study evaluate the potential systemic toxicity of these vectors. Four recombinant adenoviral vectors that express the HSV-tk gene were generated using three different promoters: CMV (leftward orientation); RSV (both rightward and leftward orientation); and the mouse caveolin-1 (cav-1) promoter (leftward orientation). Efficacy was determined in vitro by cytotoxicity assays in a mouse prostate cancer cell line, RM-9, and in vivo by treating orthotopic tumors. Potential toxicity was evaluated from liver histology and apoptotic cell counts and enzyme levels in the serum following intravenous adenoviral vector injection. Although there were differences in HSV-tk expression at the protein level among the four vectors there were no significant differences in in-vitro cytotoxicity studies with GCV or in vivo in tumor growth suppression of an orthotopic mouse prostate cancer model in GCV treated mice. Intravenous delivery of high doses of all adenoviral vectors lead to abnormalities in liver function as measured by specific serum markers and histological evaluation of liver tissue and increased levels of apoptosis in the liver. These abnormalities were most prevalent with the vector containing the CMV promoter and the rightward oriented RSV promoter. They were least prevalent in the vector regulated by the cav-1 promoter. Upregulation of specific chemokines, MIP-2 and MIP-1? was correlated with apoptotic counts. Our results demonstrate that comprehensive toxicological analysis of adenoviral vectors provides internally consistent information that can differentiate vectors with comparable efficacy... [ABSTRACT FROM AUTHOR]

In recent years, the increasing incidence of urinary tract infection (UTIs) caused by Staphylococcus aureus has been noted at the urology ward, Okayama University Hospital. We investigated the molecular epidemiological characteristics of 139 UTI isolates, including 45 methicillin-sensitive S. aureus (MSSA) and 94 methicillin-resistant S. aureus (MRSA), collected over a 10-year period from 1990 to 1999. The antibiotic resistance genes ( mecA, aph(3′ )-III, aac(6′ )-aph(2″ ), ant(4′ )-I) and the toxin genes ( tst, sea, seb, and sec) were detected by using multiplex polymerase chain reaction (PCR). Since 1996, the prevalence of the ant(4′ )-I, tst and sec genes has increased markedly in coagulase type II S. aureus possessing the mecA gene (MRSA). The presence of toxin genes in MRSA was higher than that in MSSA; 66.0% and 26.7% for tst, 7.4% and 4.4% for sea, 24.5% and 8.9% for seb, and 66.0% and 28.9% for sec, respectively. In the review of medical records, it was found that febrile episodes occurred in 12 of 72 patients with monomicrobial UTI caused by S. aureus. For the febrile patients, S. aureus isolates with both the tst and sec genes were found significantly more often (11 of 12; 91.7%) than those without the tst and sec genes ( P= 0.0484). Molecular typing of MRSA isolates, by using random amplified polymorphic DNA analysis and pulsed-field gel electrophoresis analysis, revealed no apparent clonality of these isolates over the 10 years, suggesting that most of the recent MRSA infections are not due to cross-infection in the urology ward. [ABSTRACT FROM AUTHOR]

Epidermal growth factor (EGF), a mitogenic polypeptide with a molecular weight of 6000, is excreted in human urine in nanomolar quantities. Recently, some reports showed that urothelial neoplasm was related to the concentration of EGF in urine. In this study, EGF concentration in urine was measured by enzyme-linked immunosorbent assay (ELISA) in 207 samples from 112 male patients (30–90 years old, median 66.2) who had previously been treated for bladder cancer. Then, we tried to clarify the significance of urinary EGF as a marker for recurrence of bladder cancer in comparison with urine cytology. The samples were collected on occasional follow up cystoscopy. Urine from nine age-adjusted males without urological disease was also measured to obtain normal control values. In 123 samples from patients without tumors, EGF concentrations in urine decreased with age. In 84 samples obtained from patients with recurrent tumor, EGF concentrations were significantly lower than those in 123 samples from patients without tumors (P < 0.001) Furthermore, EGF concentrations in longitudinal samples collected the same patients during tumor recurrence and at the times when no tumor was detected were measured in 56 patients. EGF concentrations in the samples collected during tumor recurrence was significantly lower than that in specimens collected when there was no tumor (P < 0.01). There were no significant differences between the same samples collected during tumor recurrence with regard to tumor grade, stage shape and number of tumors. However, EGF concentration in urine from patients with carcinoma in situ (CIS) was lower than that in specimens from patients without CIS. These results indicate the usefulness of determining the EGF concentration as a marker for detecting bladder cancer recurrence. Urine cytology was also examined in the same series and findings were compared with those of urinary EGF. On cytology, class IV and V were considered positive, and on urinary EGF, less than l0 ng/mgCr were considered positive. Sensitivity was 25% for cytology and 57% for urinary EGF, while specificity was 98% and 66%, respectively. The predictive positive value was 0.88 and 0.53, respectively. With the combined use of urinary EGF and cytology, the sensitivity, specificity and predictive positive value were 68%, 64% and 0.92, respectively. In conclusion, urinary EGF seems to be a useful marker for detecting bladder cancer recurrence if performed in addition to cytology. [ABSTRACT FROM AUTHOR]

Examines the influence of blood flow resistance from pre-penile arteries on the rat penile vasculature. Perfusion pressures; Maximal dilatation; Maximal vasoconstriction.

Numerical aberrations of chromosomes 7 and 9 of exfoliated cells from the urinary tract were examined using fluorescence in situ hybridization (FISH). To minimize contamination with inflammatory, squamous and normal transitional cells all samples were stained using Giemsa's solution and clusters of transitional cells were selected for FISH analysis. Samples collected from 21 patients who had cystoscopic monitoring for bladder cancer were used in this study. Cystoscopy was positive in seven patients and five biopsy-proven transitional cell carcinomas were identified. Among the patients with cancer recurrence, numerical chromosomal aberrations were detected in four cases (sensitivity: 80%) and positive cytology in two cases. This preliminary pilot study shows FISH can be a useful tool for the detection of recurrence during a follow up of bladder cancer. [ABSTRACT FROM AUTHOR]

Transurethral bladder neck collagen injection therapy was performed in a patient with retrograde ejaculation. The phenomenon of retrograde ejaculation and its correction after the therapy were clearly demonstrated by color Doppler ultrasonography. To our knowledge this is the first report showing successful observation of retrograde ejaculation using color Doppler ultrasonography.International Journal of Impotence Research (2004) 16, 456-458. doi:10.1038/sj.ijir.3901202 [ABSTRACT FROM AUTHOR]

Objectives To assess the validity of the prophylactic use of pirarubicin ([2′R]-4-O-tetrahydropyranyl-doxorubicin) immediately after transurethral resection of bladder tumour (TURBT), using pharmacodynamic studies. Patients and methods The study included 20 consecutive patients with superficial bladder cancer. Pirarubicin (30 mg/50 mL or 30 mg/100 mL, 10 patients each) was instilled immediately after TURBT and retained in the bladder for 1 h. Blood samples were obtained before and at 15, 30, 60 and 120 min after the instillation. After retaining the drug for 1 h all the intravesical fluid was collected and assayed for pirarubicin. Results The plasma pirarubicin concentration in those receiving either dose was below detectable levels at any time after instillation. The mean recovery rate of pirarubicin in the drained fluid was 73%. Conclusion The intravesical instillation of pirarubicin immediately after TURBT caused no detectable plasma concentration and few systemic side-effects. [ABSTRACT FROM AUTHOR]

Examines the therapeutic effect of sitafloxacin on the catheter-associated urinary tract infection model. Materials and methods; Results.

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