Malignant gliomas are characterized by active invasiveness, necrosis, and vascular proliferation. These pathological features have been speculated to be caused by tissue hypoxia. Hypoxia-inducible factor-1 (HIF-1), which is controlled by rapid stabilization of the HIF-1• subunit, is a pivotal transcriptional factor in the cellular response to hypoxia. Although many studies have described the relationship between tumor angiogenesis and hypoxic environment, the roles of HIF-1 in cell invasion have been barely elucidated in malignant gliomas. We investigated the role of HIF-1• in the motile and invasive activities of human glioma cells under hypoxia. Four malignant glioma cell lines, U87MG, U251MG, U373MG, and LN18, were cultured under 21 and 1% oxygen concentration. Expression of HIF-1• under hypoxia was observed to be much higher than that under normoxia in all cell lines. Introducing HIF-1•-targeted small interfering RNA (HIF-1• siRNA) into the glioma cell lines resulted in downregulation of HIF-1• expression, and significantly suppressed glioma cell migration in vitro. Furthermore, invasiveness was significantly reduced in the cells transfected with HIF-1• siRNA compared with those transfected with the control siRNA. Co-culture of glioma spheroids and rat brain slices showed that HIF-1• siRNAtransfected glioma cells failed to invade the surrounding normal brain tissue in an organotypic brain slice model. These effects of HIF-1• siRNA were more conspicuous under hypoxia than under normoxia. In addition, under hypoxic conditions, the level of matrix metalloproteinase (MMP)-2 mRNA was upregulated, and that of tissue inhibitor of metalloproteinase (TIMP)-2 was downregulated in all glioma cell lines. Treatment with HIF-1• siRNA resulted in downregulation of MMP-2 mRNA and upregulation of TIMP-2 mRNA. Furthermore, the enzyme activities of MMP-2 and MMP-9, both of which were activated by hypoxia, decreased with the introduction of HIF-1• siRNA. These findings suggest that overexpression of HIF-1• induced by hypoxic stress is an essential event in the activation of glioma cell motility through alteration of invasion-related molecules. Targeting the HIF-1• molecule may be a novel therapeutic strategy for malignant gliomas.
The laminin family is a structural constituent of the extracellular matrix that plays an essential role in promoting the motility of infiltrative tumor cells. We investigated the role of laminin a4 chain, a subset of laminin-8, -9 and -14, in the motile and invasive activities of human glioma cells. All malignant glioma cell lines examined expressed more mRNA for the laminin a4 and b1 chains than for the b2 chain, indicating that these cells predominantly express the laminin-8 isoform. Introducing an antisense oligonucleotide for laminin a4 chain (AS-Ln-a4) into the glioma cells resulted in downregulation of laminin a4 expression. AS-Ln-a4 also significantly suppressed glioma cell adhesion and migration. Furthermore, invasiveness was significantly reduced in cells transfected with AS-Ln-a4 compared to those transfected with the sense oligonucleotide (S-Ln-a4). Indeed, when glioma spheroids were implanted into rat brain slices, AS-Ln-a4-transfected cells failed to invade surrounding normal brain tissues. In addition, intracerebral injection of glioma cells transfected with AS-Ln-a4 into nude mice resulted in the formation of a noninvasive tumor, whereas injection of cells transfected with S-Ln-a4 resulted in diffuse invasion of brain tissue. These results suggest that mainly laminin-8 is essential for the invasive activity of human glioma cells; thus, a novel therapeutic strategy could target this molecule to treat patients with malignant glioma. ' 2005 Wiley-Liss, Inc.
No significant differences were observed between the drugs for the failure rate. Each treatment had a unique factor for prognosis, such as history of AUR for NAF and complications of OAB for TAM. Therefore, it will be necessary to use the two alpha(1)-blockers properly, considering the patient's background.
Objectives: To investigate the efficacy of tadalafil for patients with benign prostatic hyperplasia and especially with chronic prostatitis/chronic pelvic pain syndrome.Methods: Tadalafil 5 mg was given each morning for 12 weeks to patients diagnosed as having either moderate or severe lower urinary tract symptoms. Voiding symptoms were compared between patients with a high (>4; high group) and low (<4; low group) pain subscore of the National Institutes of Health Chronic Prostatitis Symptom Index before and after tadalafil administration. Correlation between changes in the Chronic Prostatitis Symptom Index and the International Prostate Symptom Score during treatment was also investigated.Results: At the pretreatment baseline, the pain subscore of the Chronic Prostatitis Symptom Index was high (>4) in 24 of 74 (32.4%) patients. The International Prostate Symptom Score in the group with high pain subscore was significantly higher than that in the group with low pain subscore. As an indicator of the efficacy of tadalafil, the International Prostate Symptom Score and National Institutes of Health Chronic Prostatitis Symptom Index total score and pain subscore were significantly improved.The change in the Chronic Prostatitis Symptom Index total score correlated positively with the change in the International Prostate Symptom Score. The decrease in the 4 International Prostate Symptom Score was significantly greater in the group with high versus low pain subscore.
Conclusion:Tadalafil was sufficiently effective in the treatment of patients with benign prostatic hyperplasia and severe chronic prostatitis/chronic pelvic pain syndrome.
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