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| 1.
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Izumi, Kouji ; Mizokami, Atsushi ; Lin, Hsiu-Ping ; Ho, Hui-Min ; Iwamoto, Hiroaki ; Maolake, Aerken ; Natsagdorj, Ariunbold ; Kitagawa, Yasuhide ; Kadono, Yoshifumi ; Miyamoto, Hiroshi ; Huang, Chiung-Kuei ; Namiki, Mikio ; Lin, Wen-Jye
概要:
Prostate-specific antigen (PSA) is regarded as the most sensitive biomarker for prostate cancer. Although androgen/andro
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gen receptor (AR) signaling promotes prostate cancer progression, suppression of AR signaling induces chemokine (CC motif) ligand 2 (CCL2), which enables prostate cancer cells to gain metastatic potential. AR-controlled PSA alone may be an unreliable biomarker for patients receiving androgen deprivation therapy. Therefore, we investigated the validity of CCL2 as a complementary biomarker to PSA for prostate cancer. Our in vitro approach of enriching for prostate cancer cells with higher migration potential showed that CCL2 activated cellular migration. Importantly, we found that CCL2 levels were significantly different between men (n = 379) with and without prostate cancer. Patients with CCL2 ≥ 320 pg/mL had worse overall survival and prostate cancer -specific survival than those with CCL2 < 320 pg/mL. A novel risk classification was developed according to the risk factors CCL2 ≥ 320 pg/mL and PSA ≥ 100 ng/mL, and scores of 2, 1, and 0 were defined as poor, intermediate, and good risk, respectively, and clearly distinguished patient outcomes. CCL2 may serve as a novel biomarker for prostate cancer. The novel risk classification based on combining CCL2 and PSA is more reliable than using either alone.
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| 2.
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Maolake, Aerken ; Izumi, Kouji ; Shigehara, Kazuyoshi ; Natsagdorj, Ariunbold ; Iwamoto, Hiroaki ; Kadomoto, Suguru ; Takezawa, Yuta ; Machioka, Kazuaki ; Narimoto, Kazutaka ; Namiki, Mikio ; Lin, Wen-Jye ; Wufuer, Guzailinuer ; Mizokami, Atsushi
概要:
Previous studies have found that tumor-associated macrophages (TAMs) promote cancer progression. We previously reported that TAMs promote prostate cancer metastasis via activation of the CCL2-CCR2 axis. The CCR4 (receptor of CCL17 and
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CCL22) expression level in breast cancer was reported to be associated with lung metastasis. The aim of this study was to elucidate the role of CCR2 and CCR4 in prostate cancer progression. CCR2 and CCR4 were expressed in human prostate cancer cell lines and prostate cancer tissues. In vitro co-culture of prostate cancer cells and macrophages resulted in increased CCL2 and CCR2 levels in prostate cancer cells. The addition of CCL2 induced CCL22 and CCR4 production in prostate cancer cells. The migration and invasion of prostate cancer cells via enhanced phosphorylation of Akt were promoted by CCL17 and CCL22. CCR4 may be a potential candidate for molecular-targeted therapy.
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| 3.
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Arakawa, Hiroshi ; Nakanishi, Takeo ; Yanagihara, Chihiro ; Nishimoto, Tomohiro ; Wakayama, Tomohiko ; Mizokami, Atsushi ; Kawai, Keiichi ; Tamai, Ikumi
概要:
The biological mechanisms underlying castration resistance of prostate cancer are not fully understood. In the present s
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tudy, we examined the role of organic anion transporting polypeptides (OATPs) as importers of dehydroepiandrosterone sulfate (DHEAS) into cells to support growth under androgen-depleted conditions. Cell growth and mRNA expression of OATP genes were studied in human prostate cancer LNCaP and 22Rv1 cells under androgen-depleted conditions. The stimulatory effect of DHEAS on cell growth was investigated in LNCaP cells in which OATP1A2 had been silenced. Growth of both cell lines was stimulated by DHEAS and the effect was attenuated by STX64, an inhibitor of steroid sulfatase which can covert DHEAS to DHEA. OATP1A2 mRNA expression was increased most prominently among various genes tested in LNCaP cells grown in androgen-depleted medium. Similar results were obtained with 22Rv1 cells. Furthermore, the characteristics of [ 3H]DHEAS uptake by LNCaP cells were consistent with those of OATP-mediated transport. Knockdown of OATP1A2 in LNCaP cells resulted in loss of the DHEAS sensitivity of cell growth. Our results suggest that enhanced OATP1A2 expression is associated with adaptive cell growth of prostate cancer cells under androgen-depleted conditions. Thus, OATP1A2 may be a pharmacological target for prostate cancer treatment. © 2012 Elsevier Inc.
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| 4.
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Nagasawa, Joji ; Mizokami, Atsushi ; Koshida, Kiyoshi ; Yoshida, Sei ; Naito, Kenjiro ; Namiki, Mikio
概要:
金沢大学医学部附属病院泌尿器科<br />Purpose: TAK-165 is a new potent inhibitor of human epidermal growth factor receptor 2 (HER2) tyros
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ine kinase. Several reports suggest HER2 expression in bladder cancer, renal cell carcinoma (RCC) and androgen-independent prostate cancer. We therefore investigated the antitumor effect of TAK-165 on these urological cancer cells. Materials and methods: Western blot analysis was performed to confirm HER2 expression in cell lines. To study in vitro efficacy, cells were treated with TAK-165 at various concentrations for 72 h and then counted using a hemocytometer. Then the IC50 value was calculated. In the xenograft model, after the tumor reached 200-300 mm3 in volume, mice were orally administered TAK-165 10 mg/kg per day or 20 mg/kg per day or saline for 14 consecutive days (n = 6-8). Results: HER2 expression was observed in HT1376, UMUC3, T24 (bladder), ACHN (kidney), DU145, LNCaP, LN-REC4 (prostate), although the expression level in these cells was weak compared with BT474 (a breast cancer cell line which expresses HER2 strongly). IC50 was varied from 0.09 to greater than 25 μmol/L in the bladder cancer cell line. ACHN cells were less sensitive in vitro. The prostate cancer cell lines studied were all sensitive (IC50 0.053-4.62 μmol/L). In the xenograft model, treatment with TAK-165 significantly inhibited growth of UMUC-3, ACHN, and LN-REC4. The antitumor effect (T/C [%] = growth of TAK-165 treated tumor/average growth of control tumor × 100) after 14 days treatment were 22.9%, 26.0%, and 26.5% in UMUC3, ACHN and LN-REC4, respectively. Conclusions: TAK-165 may be a hopeful new agent for bladder, kidney and androgen-independent prostate cancer.
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Asahi, Hideki ; Mizokami, Atsushi ; Miwa, Sotaro ; Keller, Evan T. ; Koshida, Kiyoshi ; Namiki, Mikio
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金沢大学医学部附属病院泌尿器科<br />Aim: Bisphosphonates are well established for the management of cancer-induced skeletal complicatio
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ns. Recent studies suggest that bisphosphonates promote apoptosis of cancer cells as well as osteoclasts in bone metastatic sites. To determine the direct effects of bisphosphonate on prostate cancer, we examined the effects of minodronate on prostatic cancer cell growth and the expression of apoptosis-related proteins and osteoclastogenic factors. Methods: PC-3, DU145 and LNCaP cells were treated with amino-bisphosphonate minodronate. Then proliferation, apoptosis and expression of bcl-2, bax, poly (ADP)-ribose polymerase (PARP), caspase-3, receptor activator of nuclear factor-κB ligand (RANKL), osteoprotegerin (OPG), matrix metalloproteinases-2 (MMP-2), and parathyroid hormone related protein (PTHrP) were assessed. Results: The proliferation of prostatic cancer cells was inhibited by minodronate. DNA fragmentation and TUNEL-positive nuclei were observed in minodronate-treated PC-3 cells. Minodronate decreased bcl-2 expression and induced bax expression, caspase-3 activity and degradation of PARP in DU145 and PC-3 cells. Minodronate decreased expression of RANKL, PTHrP and MMP-2 in PC-3 cells. Conclusions: Our results suggest that bisphosphonate not only promotes apoptosis directly but also decreases pro-osteoclastic gene expression in prostate cancer cells.
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| 6.
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Shigehara, Kazuyoshi ; Mizokami, Atsushi ; Komatsu, Kazuto ; Koshida, Kiyoshi ; Namiki, Mikio
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金沢大学医学部附属病院泌尿器科<br />Background: We evaluated the efficacy and complications of high dose rate (HDR) brachytherapy using
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iridium-192 (192Ir) combined with external beam radiotherapy (EBRT) in patients with prostate cancer. Methods: Ninety-seven patients underwent 192Ir HDR brachytherapy combined with EBRT at our institution between February 1999 and December 2003. Of these, 84 patients were analysed in the present study. 192Ir was delivered three times over a period of 2 days, 6 Gy per time, for a total dose of 18 Gy. Interstitial application was followed by EBRT at a dose of 44 Gy. Progression was defined as three consecutive prostate-specific antigen (PSA) rises after a nadir according to the American Society for Therapeutic Radiology and Oncology criteria. The results were classified into those for all patients and for patients who did not undergo adjuvant hormone therapy. Results: The 4-year overall survival of all patients, the nonadjuvant hormone therapy group (NAHT) and the adjuvant hormone therapy group (AHT) was 87.2%, 100%, and 70.1%, respectively. The PSA progression-free survival rate of all patients, NAHT, and AHT was 82.6%, 92.0%, and 66.6%, respectively. Of all patients, the 4-year PSA progression-free survival rates of PSA < 20 and PSA ≥ 20 groups were 100%, and 46.8%, respectively. According to the T stage classification, PSA progression-free survival rates of T1c, T2, T3, and T4 were 100%, 82.8%, 100%, and 12.1%, respectively. Prostate-specific antigen progression-free survival rates of groups with Gleason scores (GS) < 7 and GS ≥ 7 were 92.8% and 60.1%, respectively. Of NAHT, PSA progression-free survival of PSA < 20 was 100% vs 46.8% for PSA ≥ 20, that of T1c was 100% vs 75% for T2, and that of GS < 7 was 100% vs 75% for GS ≥ 7. No significant intraoperative or postoperative complications requiring urgent treatment occurred except cerebellum infarction. Conclusions: 192Ir HDR brachytherapy combined with EBRT was as effective as radical prostatectomy and had few associated complications。
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| 7.
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論文
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Izumi, Kouji ; Chang, Chawnshang
概要:
Inflammatory cytokines and chemokines released by macrophages in the prostate cancer microenvironment may signal via the
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androgen receptor (AR ) to influence tumor progression. In particular, macrophages appear to promote tumorigenesis by altering the chemokine (C-C motif) ligand 4 (CCL4)/AR signaling axis. This process can be blocked by AS C-J9®, an enhancer of AR degradation. AS C-J9® also inhibits the CCL2-dependent, signal transducer and activator of transcription 3 (STAT3)-mediated pro-metastatic signaling cascade that is generally activated by androgen deprivation therapy. Thus, targeting inflammatory cytokines signaling via the AR , with AS C-J9®, represents a promising therapeutic approach against prostate cancer progression. © 2013 Landes Bioscience.
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| 8.
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論文
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Izumi, Kouji ; Chang, Chawnshang
概要:
Inflammatory cytokines and chemokines released by macrophages in the prostate cancer microenvironment may signal via the
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androgen receptor (AR ) to influence tumor progression. In particular, macrophages appear to promote tumorigenesis by altering the chemokine (C-C motif) ligand 4 (CCL4)/AR signaling axis. This process can be blocked by AS C-J9®, an enhancer of AR degradation. AS C-J9® also inhibits the CCL2-dependent, signal transducer and activator of transcription 3 (STAT3)-mediated pro-metastatic signaling cascade that is generally activated by androgen deprivation therapy. Thus, targeting inflammatory cytokines signaling via the AR , with AS C-J9®, represents a promising therapeutic approach against prostate cancer progression. © 2013 Landes Bioscience.
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| 9.
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Takemura, Akihiro ; Togawa, Kumiko ; Yokoi, Tomohiro ; Ueda, Shinichi ; Noto, Kimiya ; Kojima, Hironori ; Isomura, Naoki ; Kumano, Tomoyasu
概要:
In volumetric modulated arc therapy (VMAT) for prostate cancer, a positional and rotational error correction is performe
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d according to the position and angle of the prostate. The correction often involves body leaning, and there is concern regarding variation in the dose distribution. Our purpose in this study was to evaluate the impact of body pitch rotation on the dose distribution regarding VMAT. Treatment plans were obtained retrospectively from eight patients with prostate cancer. The body in the computed tomography images for the original VMAT plan was shifted to create VMAT plans with virtual pitch angle errors of ±1.5° and ±3°. Dose distributions for the tilted plans were recalculated with use of the same beam arrangement as that used for the original VMAT plan. The mean value of the maximum dose differences in the dose distributions between the original VMAT plan and the tilted plans was 2.98 ± 0.96 %. The value of the homogeneity index for the planning target volume (PTV) had an increasing trend according to the pitch angle error, and the values of the D95 for the PTV and D2ml, V50, V60, and V70 for the rectum had decreasing trends (p < 0.05). However, there was no correlation between differences in these indexes and the maximum dose difference. The pitch angle error caused by body leaning had little effect on the dose distribution; in contrast, the pitch angle correction reduced the effects of organ displacement and improved these indexes. Thus, the pitch angle setup error in VMAT for prostate cancer should be corrected. © 2016 Japanese Society of Radiological Technology and Japan Society of Medical Physics<br />Embargo Perios 12 months
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| 10.
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論文
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Kadono, Yoshifumi ; Nohara, Takahiro ; Ueno, Satoru ; Izumi, Kouji ; Kitagawa, Yasuhide ; Konaka, Hiroyuki ; Mizokami, Atsushi ; Onozawa, Mizuki ; Hinotsu, Shiro ; Akaza, Hideyuki ; Namiki, Mikio
概要:
Purpose: The current tumor–node–metastasis (TNM) classification system has been used for many years. The prognosis of pa
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tients with metastatic prostate cancer (mPC) treated using primary androgen deprivation therapy (PADT) was analyzed according to the TNM classification. Methods: A total of 5618 cases with lymph node metastases only (N1M0), non-regional lymph node metastasis (M1a), bone metastasis (M1b), and distant metastasis (M1c) were selected from the Japanese Study Group of Prostate Cancer database. Overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS) rates were calculated using Kaplan–Meier analysis. The influence of clinical variables on patient prognosis was evaluated using the Cox proportional hazard regression model. Results: The 5-year OS, CSS, and PFS were 76.0, 83.2, and 38.8 % in N1M0, 57.5, 69.0, and 23.0 % in M1a, 54.0, 63.1, and 23.0 % in M1b, and 40.0, 51.5, and 16.6 % in M1c, respectively. OS, CSS, and PFS worsened as the stages progressed. OS, CSS, and PFS were all significantly worse in N1M1b compared with N0M1b. Multivariate analysis revealed that OS and CSS were worse in patients with a Gleason score ≥8 and that combined androgen blockade (CAB) treatment provided better OS than non-CAB treatments at any tumor stage. However, OS and CSS were worse in individuals with a prostate-specific antigen >100 ng/ml only in M1b. Conclusions: Patient prognosis worsened with stage progression; therefore, current TNM classification system of mPC for PADT was shown to be trustworthy. Each PC cell that develops bone or lymphoid metastasis may exhibit different characteristics. © 2015, Springer-Verlag Berlin Heidelberg.
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