Kotaro Miyake

The University of Tokushima, Tokushima-shi, Tokushima-ken, Japan

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Publications (10)22.14 Total impact

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    ABSTRACT: Tumor hypoxia has been considered to be a potential therapeutic target, because hypoxia is a common feature of solid tumors and is associated with their malignant phenotype. In the present study, we investigated the antitumor effect of a novel hypoxic cytotoxin, 3-[2-hydroxyethyl(methyl)amino]-2-quinoxalinecarbonitrile 1,4-dioxide (TX-2098) in inhibiting the expression of hypoxia inducible factor-1α (HIF-1α), and consequently vascular endothelial cell growth factor (VEGF) expression in pancreatic cancer. The antitumor effects of TX-2098 under hypoxia were tested against various human pancreatic cancer cell lines using WST-8 assay. VEGF protein induced pancreatic cancer was determined on cell-free supernatant by ELISA. Moreover, nude mice bearing subcutaneously (s.c.) or orthotopically implanted human SUIT-2 were treated with TX-2098. Tumor volume, survival and expression of HIF-1 and associated molecules were evaluated in treatment versus control groups. In vitro, TX-2098 inhibited the proliferation of various pancreatic cancer cell lines. In s.c model, tumors from nude mice injected with pancreatic cancer cells and treated with TX-2098 showed significant reductions in volume (P<0.01 versus control). Quantitative real-time reverse transcription-PCR analysis revealed that TX-2098 significantly inhibited mRNA expression of the HIF-1 associated molecules, VEGF, glucose transporter 1 and Aldolase A (P<0.01 versus control). These treatments also prolong the survival in orthotopic models. These results suggest that the effect of TX-2098 in pancreatic cancer might be correlated with the expression of VEGF and HIF-1 targeted molecules.
    Experimental Cell Research 03/2012; 318(13):1554-63. · 3.56 Impact Factor
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    ABSTRACT: Serum soluble interferon-alpha/beta receptor (sIFN-alpha/betaR) and high-sensitivity C-reactive protein (hs-CRP) levels were evaluated in the patients with gastrointestinal and hepatobiliary-pancreatic cancer. We compared the sensitivity and specificity of serum sIFN-alpha/betaR with that of serum hs-CRP and evaluated the two diagnostic parameters in combination. Serum sIFN-alpha/betaR levels were measured in 92 patients and 25 healthy individuals by enzyme-linked immunosorbent assay. The diagnoses were 37 cases of hepatocellular carcinoma, 17 cases of pancreatic cancer, 15 cases of colon cancer, 13 cases of biliary tract cancer, and 10 cases of gastric cancer. Serum levels of sIFN-alpha/betaR and hs-CRP were significantly higher in the patients than in healthy individuals (p<0.05). The optimal cut-off values of sIFN-alpha/betaR and hs-CRP were 3600pg/ml and 0.5microg/ml, respectively. The sensitivity and specificity for these thresholds were 94.6% and 88.0%, whereas positive predictive and negative predictive values were 96.7% and 81.5%. These results suggest that a combination of serum sIFN-alpha/betaR and hs-CRP thresholds may be more reliable diagnostic parameter for gastrointestinal and hepatobiliary-pancreatic cancer.
    Cytokine 10/2009; 49(3):251-5. · 2.52 Impact Factor
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    ABSTRACT: It is well known that hypoxic milieu is the primary cancer environment. Therefore, tumor hypoxia is considered to be a potential therapeutic target. In the present study, we investigated the antitumor and antimetastatic effect of hypoxic cell radiosensitizer, TX-1877 on xenograft model of rectal cancer. Nude mice bearing subcutaneously or orthotopically implanted human colon cancer cell lines HCT-116 and HT-29 were treated with TX-1877, irradiation or TX-1877 with irradiation. Tumor volume, survival, expression of matrix metalloproteinase (MMP)-2, MMP-7, MMP-9 and urokinase-type plasminogen activator (uPA) and incidence of lymph node metastasis were evaluated in treatment versus control group. In subcutaneous model, tumor treated with TX-1877 and irradiation showed significant reductions in volume (P < 0.05 vs. control, TX-1877 or irradiation group). Quantitative real-time reverse transcription-PCR and immunohistochemical analysis revealed that TX-1877 significantly inhibited expression of the MMP-9 and uPA. These treatments also inhibited the para-aortic lymph node metastasis, however, did not prolong the survival in orthotopic model. These data show that the treatment of TX-1877 with irradiation decreased growth of human rectal cancer and, furthermore, suppressed lymph node metastasis.
    Cancer Chemotherapy and Pharmacology 02/2009; 64(5):885-92. · 2.80 Impact Factor
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    ABSTRACT: Tumor hypoxia has been considered to be a potential therapeutic target, because hypoxia is a common feature of solid tumors and is associated with their malignant phenotype. In the present study, we investigated the antitumor effect of hypoxic cell radiosensitizer, TX-1877 in inhibiting angiogenesis and liver metastasis on pancreatic cancer xenograft model. The antitumor effects of TX-1877 were tested against various human tumor cell lines using cell proliferation assay. Nude mice bearing s.c. or orthotopically implanted human SUIT-2 were treated with TX-1877 alone, irradiation alone or TX-1877 and irradiation. Tumor volume, survival, expression of angiogenic molecules and liver metastasis were evaluated in treatment versus control groups. In vitro, TX-1877 inhibited the proliferation and potentiated the radiosensitivity of various pancreatic cancer cell lines. In an orthotopic model, tumors from nude mice injected with pancreatic cancer cells and treated with TX-1877 and irradiation showed significant reductions in volume (p<0.05 versus control, TX-1877 alone or irradiation alone). Quantitative real-time reverse transcription-PCR and immunohistochemical analysis revealed that treatment with TX-1877 alone or with TX-1877 and irradiation inhibited expression of the angiogenic molecules, vascular endothelial growth factor; basic fibroblast growth factor, interleukin-8 and matrix metalloproteinase 9 more than control or did treatment with irradiation alone. These treatments also induced apoptosis in cancer cells. These data show that treatment of TX-1877 and irradiation decreased growth of human pancreatic cancer, suppressed angiogenesis and inhibited liver metastasis, leading to prolonged survival.
    Cancer letters 08/2008; 272(2):325-35. · 5.02 Impact Factor
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    ABSTRACT: Hypoxia-inducible factor 1alpha (HIF-1alpha) is a transcription factor that plays an important role in tumor growth and metastasis. Inhibition of histone deacetylase shows a marked inhibition of HIF-1alpha expression; however, the association between HIF-1alpha and histone deacetylase 1 (HDAC1), metastasis-associated protein 1 (MTA1) is not fully understood. Hypoxia-inducible factor 1alpha, HDAC1, and MTA1 expressions were detected by immunohistochemistry in 39 pancreatic carcinoma patients. The correlations between the expression of HIF-1alpha, HDAC1, or MTA1 and clinical features and the prognosis were analyzed. Hypoxia-inducible factor 1alpha, HDAC1, and MTA1 positive stainings were found in 41%, 56%, and 31%, respectively. There was no correlation between HIF-1alpha, HDAC1, or MTA1 expression levels and any clinical parameters. The survival rate for patients with HIF-1alpha and HDAC1-positive stainings were significantly lower than for patients with HIF-1alpha and HDAC1-negative stainings. The MTA1 overexpression group did not have a significantly lower prognosis than the MTA1 underexpression group. The survival rate for the HDAC1(+)/MTA1(2-3) group was significantly lower than for the other groups. These results suggest that HIF-1alpha expression may be regulated through HDAC1/MTA1, which is associated with a poor prognosis for pancreatic carcinoma and indicates that HIF-1alpha and HDAC1/MTA1 are a promising therapeutic target in pancreatic carcinoma treatment.
    Pancreas 05/2008; 36(3):e1-9. · 2.95 Impact Factor
  • Suizo 01/2008; 23(5):641-643.
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    ABSTRACT: Left lobe graft is an ideal option to minimize potential risk for the donor in adult living-donor liver transplantation (LDLT). However, its use is restricted due to size limitations. The purpose of this study was to determine the impact of a new technique for the acquisition of additional liver volume for left lobe graft. Three donors underwent left hepatic lobectomy by exploiting a new technique as follows: a demarcation line was marked by clamping the right first Glisson's pedicle. A parenchymal transection plane was located 1 cm right side from the demarcation line and just on the left side of the right anterior Glisson's pedicle. A part of the anterior segment added to the left lobe graft by this procedure belonged to right anterior segment by preoperative CT. The preoperative volumetry of the liver was performed using the 3D-CT software, which was able to calculate total liver volume and the volume of each vessel's territories. Additional liver volume was calculated by preoperative CT scan and defined as part of the perfusion area by the right anterior portal branch. Blood perfusion of the additional liver area was postoperatively assessed by dynamic CT, and graft outcome was also evaluated. An additional gain ranged from 40 mL to 51 mL (mean 41.8 mL). GV/SLV was 35.7, 60.0, and 41.0%. The rate of additional volume in GV/SLV ranged from 7.2-8.4% (mean 7.6%). All grafts functioned well. The CT scan performed on early postoperative period confirmed excellent blood perfusion the additional segment. No complication attributable to small-for-size graft was noted. This new technique for left lobe graft harvesting proved a promising approach to gain additional volume, thereby avoiding small-for-size graft in adult LDLT.
    Hepato-gastroenterology 01/2008; 55(85):1206-10. · 0.77 Impact Factor
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    ABSTRACT: Thymidine phosphorylase (TP), orotate phosphoribosyltransferase (OPRT), and dihydropyrimidine dehydrogenase (DPD) are important enzymes related to the metabolism of 5-fluorouracil and its derivatives. In this study, we analyzed the expression of these enzymes and evaluated the association between the expression of these enzymes and clinicopathological features and prognosis in patients with pancreatic cancer. TP, OPRT, and DPD mRNA expressions were detected using a real-time reverse transcriptional-polymerase chain reaction method or by immunohistochemistry, using surgical specimens obtained from 25 patients with pancreatic cancer. TP mRNA expression was lower in cases with an alpha infiltration growth pattern than in cases with other infiltration growth patterns (P < 0.05). OPRT mRNA expression was higher in poorly differentiated-type cases than in differentiated type cases (P < 0.05). TP-, OPRT-, and DPD-positive stainings were found in 15 of 24 cases (63%), 10 of 19 cases (53%), and 14 of 21 cases (67%), respectively. There were significant correlations or trends between the mRNA and protein expressions of TP, OPRT, and DPD. Patients with a low TP/DPD ratio survived significantly longer than those with a high ratio (P < 0.05). Multivariate analysis demonstrated a significantly poorer outcome in patients with a high TP/DPD ratio compared with in patients with a low ratio (P < 0.05). The TP/DPD ratio might be useful as a prognostic factor in patients with pancreatic cancer.
    International Journal of Clinical Oncology 05/2007; 12(2):111-9. · 1.73 Impact Factor
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    ABSTRACT: We evaluated the antitumor and antiangiogenic activities of human natural interferon-alpha (IFN-alpha) alone or in combination with S-1 against human pancreatic cancer cells. Three days after the subcutaneous (s.c.) implantation of tumor cells, mice (n = 12) were received s.c. injection with IFN-alpha alone (10,000 U six times a week), oral administration with S-1 alone (8 mg/kg six times a week), or both with IFN-alpha and S-1 (8, 10, 12 mg/kg six times a week). Administration of IFN-alpha in combination with S-1 significantly decreased progressive growth and angiogenesis of human pancreatic cancer cells. The combination therapy produced more significant inhibition in expression of the representative proangiogenic molecules, vascular endothelial growth factor and basic fibroblast growth factor than individual treatment either IFN-alpha or S-1 alone did. These treatments also decreased the staining of proliferating cell nuclear antigen, induced apoptosis and decreased microvessel density. In order to better understand the precise molecular mechanisms by which IFN-alpha and S-1 exert its effects, we have utilized cDNA microarray including 124 known genes to determine the gene expression profile altered by IFN-alpha and S-1 treatment. We found a total of seven genes which showed a twofold change after IFN-alpha and S-1 treatment in addition to VEGF, bFGF, CD31, MMP-2, MMP-7 and MMP-9. Among these genes, we found down-regulation of six genes and up-regulation of one gene, which are related to angiogenesis, tumor cell invasion and metastasis. These data suggest that administration of IFN-alpha in combination with S-1 may provide a novel and effective approach to the treatment of human pancreatic cancer.
    Cancer Chemotherapy and Pharmacology 02/2007; 59(1):113-26. · 2.80 Impact Factor
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    ABSTRACT: The solitary necrotic nodule of the liver is an uncommon nonmalignant lesion with an uncertain etiology. The lesion was defined as a nodule with a completely necrotic core and fibrous capsule etc. and without a consistency of viable cells. The characteristic features of this benign lesion on the imaging modalities are similar to the metastatic tumor. In this paper we discuss the case of a rapid-growing solitary necrotic nodule of the liver occurring in a patient with chronic renal failure on hemodialysis. The lesion located on the left median lobe of the liver had rapidly enlarged in diameter in the last seven months. Despite some examinations by imaging modalities to confirm the preoperative diagnosis, we were unable to visually confirm. Several histological examinations using a needle biopsy specimen were performed, but the diagnosis was all necrotic tissue. However, we recommended an extended left hepatic lobectomy for this rapid-growing lesion since cholangiocarcinoma with necrosis could be hardly differentiated. Permanent histology revealed that the lesion was solitary necrotic nodule. We consider that permanent histology of the entire lesion is possibly the only accurate method of diagnosis. Since the solitary necrotic nodule does not indicate malignancy, hepatic resection should be performed.
    The Journal of Medical Investigation 09/2006; 53(3-4):325-9.