Hideo Yoshida

The University of Tokushima, Tokusima, Tokushima, Japan

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Publications (68)159.32 Total impact

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    ABSTRACT: p27Kip1 is a cyclin-dependent kinase inhibitor which regulates the progression of cells from the G1-into the S-phase in a cell cycle. Loss of p27Kip1 is associated with disease progression and an unfavorable outcome in several malignancies. The purpose of this study was to determine whether p27Kip1 expression can be a useful prognostic factor in oral squamous cell carcinoma (SCC) patients. p27Kip1 expression was investigated by immunohistochemistry in tissue samples from 81 patients with oral SCC. The associations between p27Kip1 expression and clinicopathological characteristics and patient survival were also analyzed. Significant associations were found between p27Kip1 expression and histological grade (p = 0.010), therapeutic effect (p = 0.004) and patient outcome (p = 0.005). The 5-year survival rates of p27Kip1 high- and low-expression tumours were 80.4% and 56.7%, respectively, this difference being significant (p = 0.009) by log-rank test. Multivariate analysis revealed that reduced term survival was related to low levels of p27Kip1 expression (p = 0.008) and advanced stage (stages III and IV) (p = 0.003). These results suggest that reduction of p27Kip1 plays an important role in the progression of oral SCC and is considered to be a useful prognostic factor in oral SCC patients.
    Anticancer research 09/2013; 22(5):2985-9. · 1.71 Impact Factor
  • Koji Harada, Tarannum Ferdous, Hideo Yoshida
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    ABSTRACT: In the present study, we examined the appropriate schedule of S-1 medication in the combination with radiation by investigating the safety, the clinical efficacy, and antitumor effects on tumors in nude mice. In the patients with oral squamous cell carcinoma (OSCC), S-1 was given orally according to a 4-week application followed by 2-week rest regimen (4-week regimen), or a 2-week application followed by a 1-week rest regimen (2-week regimen). Radiation was given (2 Gy/day; 5 days/week) for a total of 60 Gy. In nude mouse models, human oral cancer cell lines were used as subcutaneous xenografts in nude mice. The mice were treated by S-1 (10 mg/kg) and radiation (1 Gy) with a 4-week regimen or a 2-week regimen. Apoptotic cells were detected by TUNEL method. In the patients with OSCC, the response rate with the 4-week regimen was 100% and the response rate with the 2-week regimen was 92.3%. However, a high frequency of adverse effect was found in the 4-week regimen when compared to the 2-week regimen. Grade 3 toxicity of leukopenia, neutropenia and stomatitis were seen in 3 cases, grade 3 toxicity of anorexia and nausea were seen in 2 cases, and grade 3 toxicity of decrease of hemoglobin level, heartburn/dyspepsia and increase of bilirubin level were seen in a case of the 4-week regimen. On the other hand, grade 3 toxicity of stomatitis, anorexia, nausea, heartburn/dyspepsia and increase of bilirubin level were seen in a case of the 2-week regimen. In nude mouse models, the 2-week regimen was more effective than the 4-week regimen. In addition, significant increase in the percentage of apoptotic cells was observed in the tumors treated with the 4-week regimen when compared with the tumors treated with the 2-week regimen. No loss of body weight was observed in mice treated with the 2-week regimen during the experimental period. These results suggested that the 2-week regimen might reduce adverse effects, and enhance therapeutic effects compared to the 4-week regimen. Briefly, this 2-week regimen may be a useful concurrent chemo-radiotherapy improving the quality of life (QOL) of patients with OSCC.
    Oncology Reports 12/2007; 18(5):1077-83. · 2.30 Impact Factor
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    ABSTRACT: A 76-year-old patient with oral squamous cell carcinoma was treated by chemotherapy with S-1. S-1 (100 mg/body/day) was orally administered for 4 weeks followed by a 2-week rest period as one course. The primary lesion markedly decreased at 7 days after the beginning of S-1 treatment, and disappeared after one course of S-1. After two courses, the primary lesion was assessed to show a complete response (CR),and no tumor cells were identified as a result of biopsy. In addition, the value of tumor marker SCC decreased from 2.13 ng/mL before treatment to 0.68 ng/mL after two courses of S-1. Although the patient is still taking UFT, she is well with no signs of recurrence 50 months from the initial treatment.
    Gan to kagaku ryoho. Cancer & chemotherapy 10/2007; 34(9):1455-8.
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    ABSTRACT: A 68-year-old patient with advanced oral squamous cell carcinoma (T3N2bM0, Stage IVA) was treated by concurrent radiotherapy with S-1.S-1 (120 mg/body/day) was orally administered for 4 weeks followed by a 2-week rest period as one course, and radiation was given (1.8 Gy/day; 5 days/week) for a total of 61.2 Gy. After 61.2 Gy radiation and two courses of S-1, the primary region showed a complete response (CR), and that the tumor cell was not identified as a result of biopsy. In addition, the metastatic lymph nodes in the neck were no longer seen on head and neck computed tomography (CT). Although the patient is still taking UFT, he is well with no signs of recurrence 27 months from the initial treatment.
    Gan to kagaku ryoho. Cancer & chemotherapy 06/2007; 34(5):745-7.
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    ABSTRACT: It has been reported that S-1 can exert antitumor effects on various human cancers including oral squamous cell carcinoma (OSCC). However, little is known about the detailed mechanisms of the antitumor activity of S-1. In the present study, we determined whether S-1 could suppress the angiogenesis and growth of human OSCC cells in vitro and in vivo. The S-1 component (5-FU plus CDHP) significantly suppressed the growth and migration of OSCC cells and BAEC, which inhibited tubule formation in HUVECs in vitro. Also, S-1 inhibited the nuclear factor-kappaB (NF-kappaB) activity in human OSCC cells in vitro. Moreover, S-1 inhibited the expression of survival signal, phosphorylated Akt (p-Akt), and of two major proangiogenic molecules, vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2), in cells implanted into the subcutaneous tissue of nude mice. The decreased expression of p-Akt, VEGF and FGF-2 correlated with decreased tumorigenicity and decreased vascularization of lesions in vivo. These findings suggest that S-1 can suppress the angiogenesis and growth of OSCC cells by inhibiting the expression of p-Akt, VEGF and FGF-2 involved in the blockade of Akt/NF-kappaB pathway.
    International Journal of Oncology 03/2007; 30(2):365-74. · 2.66 Impact Factor
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    ABSTRACT: Epithelial-mesenchymal transition (EMT) refers to critical events occasionally observed during tumor progression, including invasion and metastasis, by which cancer cells acquire a fibroblast-like phenotype. Since the stromal cell-derived factor-1 (SDF-1)/CXCR4 system can facilitate lymph node metastasis in oral squamous cell carcinoma (SCC), we have explored the possibility that this system might be involved in EMT. Oral SCC cells, B88 and HNt, which have functional CXCR4 and lymph node metastatic potential, were found to lose their epithelial cell morphology due to SDF-1. In this context, the downregulation of epithelial markers, cytokeratin, E-cadherin and beta-catenin, and the upregulation of mesenchymal marker, vimentin and snail were detected. Furthermore, upregulation of vimentin by treatment with SDF-1 was impaired by phosphatidylinositol 3 kinase (PI3K) inhibitor Wortmannin, but not by mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor U0126. In the type I collagen embedding culture, SDF-1-treated B88 cells formed protruding extensions, but the effect was impaired by treatment with Wortmannin. These results suggested that EMT induced by the SDF-1/CXCR4 system might be involved in the lymph node metastasis of oral SCCs via activation of PI3K-Akt/PKB pathway.
    International Journal of Oncology 12/2006; 29(5):1133-8. · 2.66 Impact Factor
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    ABSTRACT: The purpose of this research was to evaluate the predictive value of expression of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP), or orotate phosphoribosyltransferase (OPRT) genes for response to S-1. Twenty-five patients with oral squamous cell carcinoma (OSCC) received S-1 80 mg/m2/day. Pretreatment tumor biopsies were analyzed for TS, DPD, TP or OPRT mRNA expression by real-time reverse transcription-PCR. TS protein expression was evaluated by immunohistochemistry using a polyclonal TS antibody. Twenty-five patients were evaluable for response and gene expression. Six of the 25 (24%) achieved complete remission and 4 of the 25 (16%) had a partial response. Median TS/beta-actin was 2.51 (range 0.98-7.07). Median TS/beta-actin was 1.26 in responding patients and 3.43 in non-responders (P=0.0001). Ten of 11 patients with TS/beta-actin <1.80 and 0 of 15 with higher values responded (P<0.0001). Overall survival was 29.7 months in patients with TS/beta-actin <1.80 and 41.7 months in patients with higher values (P=0.0013). No correlations were seen between expression of DPD, TP or OPRT mRNA and response or survival. Weak TS staining was seen in 6 of 25 tumors evaluable for immunohistochemistry, including 5 responders. All 4 of the patients with both weak staining and TS/beta-actin <1.80 responded. High TS mRNA expression predicts non-response to S-1. On the other hand, high levels of DPD or TP mRNA and low levels of OPRT mRNA are not associated with S-1 resistance. TS mRNA expression is considered to be a useful prognostic factor in OSCC patients with S-1 single-agent therapy.
    Oncology Reports 07/2006; 15(6):1417-23. · 2.30 Impact Factor
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    ABSTRACT: The neoplastic cells present in a sialadenoma pappiliferum were found by immunoperoxidase method and immunofluorescent staining technique to co-express 3 different types of intermediate-sized filaments (IPs) defined by monoclonal antibodies to cytokeratin, vimentin and desmin. When other salivary gland tumors such as 18 pleomorphic adenomas, 15 adenolymphomas, 2 oxyphilic adenomas, 7 mucoepidermoid tumors, 5 acinic cell tumors, 8 adenoid cystic carcinomas and 6 adenocarcinomas were examined immunohistochemically for the expression of IPs, no tumors with all 3 types of IPs observed in sialadenoma papilliferum were found.
    Journal of Oral Pathology and Medicine 04/2006; 19(7):313 - 318. · 2.06 Impact Factor
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    ABSTRACT: Vesnarinone is a synthesized positive oral inotropic agent that has multiple biological activities on mammalian cells both in vitro and in vivo. This agent has been reported in relation to its antitumor effect with apoptosis-inducing activity. In the present study, we determined whether vesnarinone could suppress angiogenesis and growth of human oral squamous cell carcinoma cells in vitro and in vivo. Vesnarinone significantly inhibited the in vitro and in vivo expression of two major proangiogenic molecules, vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8), in cultured cells and in cells implanted into the subcutaneous tissue of nude mice. Also, vesnarinone inhibited the nuclear factor-kappa B (NF-kappaB) activity in human oral squamous cell carcinoma cells in vitro. The decreased expression of VEGF and IL-8 correlated with decreased tumorigenicity and decreased vascularization of lesions in vivo. These findings suggest that vesnarinone can suppress the angiogenesis and growth of oral squamous cell carcinoma cells by inhibiting the expression of VEGF and IL-8 involved in blockade of NF-kappaB activity.
    International Journal of Oncology 01/2006; 27(6):1489-97. · 2.66 Impact Factor
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    ABSTRACT: Cyclin-dependent kinase (CDK) inhibitor p27Kip1 is a diagnostic and prognostic marker of various malignancies. Low expression of p27Kip1 reflects poor prognosis, and an inverse correlation between the expression of p27Kip1 and degree of tumor malignancy has been reported. Because p27Kip1 mutation is extremely rare in human tumors, expression of p27Kip1 protein is thought to be controlled by post-transcriptional mechanism involved in inactivator, S-phase kinase associated protein 2 (Skp2) and Jun activation domain-binding protein 1 (Jab1). In this study, we investigated the role of gene therapy targeting p27Kip1 in human head and neck cancer cells. Human head and neck cancer (HNt and HSY) cells expressed p27Kip1, Skp2 and Jab1. To determine the function of p27Kip1, Skp2 and Jab1, we transfected head and neck cancer cells with pcDNA3.1-p27Kip1 wt, pcDNA3.1-p27Kip1 mt or treated with Skp2 antisense oligonucleotide (AS) or Jab1 AS. The transfections or treatments inhibited the growth of HNt and HSY cells. The growth inhibition mediated by pcDNA3.1-p27Kip1 mt or Skp2 AS or Jab1 AS specifically due to a significant induction of apoptosis characterized by an increase in fragmentation of nuclei and activation of caspase-3. The transfection of pcDNA3.1-p27Kip1 mt or treatment with Skp2 AS and Jab1 AS induced a strong growth inhibition of xenograft tumors. These findings suggest that p27Kip1 mt, Skp2 AS and Jab1 AS have the potential to become a novel and powerful gene therapy tool, and that stability of p27Kip1 protein may improve therapeutic benefits to patients with head and neck cancer.
    International Journal of Oncology 10/2005; 27(3):627-35. · 2.66 Impact Factor
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    ABSTRACT: To examine the effect of an oral fluoropyrimidine anti-cancer agent (S-1) on the radiosensitivity of a human oral cancer cell line with focusing on inhibition of survival signal, Akt/PKB. A human oral cell cancer cell line B88 was used. Activation of Akt/PKB in vivo was examined by immunohistochemistry, and apoptotic cells were detected by TUNEL method. Activation of Akt/PKB in vitro was investigated by Western blot and ELISA, and apoptotic cells were detected by Hoechst 33258 staining. S-1 (10 mg/kg/day or 50 microg/ml) greatly enhanced radiosensitivity in B88 cells by suppressing the activation of Akt/PKB. Significant increase in the percentage of apoptotic cells was observed in S-1 treated B88 cells. Survival signals Akt/PKB may be involved in determining radiosensitivity. S-1, an oral fluoropyrimidine anti-cancer agent can exert the enhancing effect on radiation by suppressing the activation of Akt/PKB.
    Cancer Letters 09/2005; 226(2):161-168. · 5.02 Impact Factor
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    ABSTRACT: S-phase kinase associated protein 2 (Skp2) is a member of an F-box family of substrate-recognition subunits of SCF ubiquitin-protein ligase complexes that has been implicated in the ubiquitin-mediated degradation of several key regulators of mammalian G1 progression, including the cyclin-dependent kinase inhibitor p27Kip1, a dosage-dependent tumor suppressor protein. The anti-sense effect was confirmed in two cell lines of oral cancer cells that also exhibited over-expression of the Skp2 protein. In this study, we examined the mechanism responsible for anti-sense-mediated growth inhibition of oral cancer cells in vitro and in vivo. Skp2-anti-sense treatment induced apoptosis characterized by an increase in the early apoptosis, fragmentation of nuclei and activation of caspase-3, -8 and -9. Moreover, the growth of xenograft tumors was markedly suppressed by Skp2-anti-sense treatment. Furthermore, histological specimen revealed apoptotic cell death was increased in Skp2-anti-sense treated tumors. Our results suggest that down-regulation of Skp2 appears to induce apoptosis in oral cancer cells, targeting this molecule could represent a promising new therapeutic approach for this type of cancer.
    Oral Oncology 08/2005; 41(6):623-30. · 2.70 Impact Factor
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    ABSTRACT: In this study, we attempted to use a non-viral gene transfer system, in vivo electroporation, in oral cancer cell B88 xenografts. To evaluate this in vivo gene transfer method, the GFP gene was transfected into xenografts by electroporation. Then, the efficiency of transfection of exogenous p27Kip1 gene by electroporation was confirmed by Western blot analysis. Next, to estimate the reduction of oral cancer xenografts by this method, we measured the size of B88 xenografts in nude mice after electroporation with the wild- or mutant-type p27Kip1 gene. The growth of tumors was markedly suppressed by mutant-type p27Kip1 gene transfection by electroporation compared with transfection of wild-type p27Kip1 gene or empty vector only. Moreover, histological specimens revealed apoptotic cell death was increased in mutant-type p27Kip1-transfected tumors compared to wild-type or empty vector only. These results suggest that it is possible to transfer mutant-type p27Kip1 into oral cancer xenografts using electroporation and to suppress the growth of tumors, furthermore, it is suggested that this system might be used for oral cancer.
    Oncology Reports 03/2005; 13(2):201-6. · 2.30 Impact Factor
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    ABSTRACT: Recently, it has been suggested that chemokine/receptor interactions determine the destination of the invasive tumor cells in several types of cancer. It has also been proposed that the stromal cell-derived factor-1 (SDF-1; CXCL12)/CXCR4 system might be involved lymph node metastasis in oral squamous cell carcinoma (SCC). In order to further clarify the role of the SDF-1/CXCR4 system in oral SCC, we generated CXCR4 stable transfectants (IH-CXCR4) using oral SCC cells, and compared them to IH, which did not express CXCR4 and which did not have lymph node metastatic potentials in vivo. We introduced enhanced green fluorescent protein (GFP) fused-CXCR4 into IH cells, and detected the GFP fluorescence in the cytoplasm and cell membrane in approximately 60% of the G418-resistant cells. This bulk-transfectant expressed a high level of CXCR4 mRNA and protein, and exhibited the characteristic calcium fluxes and chemotactic activity observed in treatment with SDF-1. SDF-1 biphasically activated extracellular signal-regulated kinase (ERK)1/2, but continuously activated Akt/protein kinase B (PKB) in IH-CXCR4 cells. Most importantly, IH-CXCR4 cells frequently metastasized to the cervical lymph node, but not to the distant organs in the orthotopic inoculation of nude mice. Furthermore, these lymph node metastases were inhibited by the treatment of a mitogen-activated protein kinase/ERK kinase inhibitor, U0126, or a phosphatidylinositol 3 kinase inhibitor, wortmannin. These results indicate that SDF-1/CXCR4 signaling mediates the establishment of lymph node metastasis in oral SCC via ERK1/2 or Akt/PKB pathway.
    Laboratory Investigation 01/2005; 84(12):1538-46. · 3.96 Impact Factor
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    ABSTRACT: S-1 is a new oral antineoplastic agent which can inhibit cell growth and induces apoptosis in certain types of cancer cells including gastric carcinomas, colorectal cancers and salivary gland cancers, but its effect on response of tumor cells to radiation has not been clarified yet. We have reported that S-1 can sensitize human oral cancer cells to radiation, and that S-1 in combination with radiation can exert remarkable effects on decreasing clonogenic survival and in vivo tumor growth. Here, we demonstrate the mechanism of apoptosis enhancing activity by the combination treatment of S-1 and radiation in salivary gland cancer cells. S-1 in combination with radiation have a remarkable effect on decreasing in vitro cell growth. In addition, the combined treatment of S-1 and radiation resulted in an increased DNA fragmentation by detecting Hoechst 33258 staining. Moreover, apoptosis of the cells by combined treatment of S-1 and radiation was associated with reactive oxygen/nitrogen species generation and the activation of caspase-8, -9 and -3. These results indicate that S-1 in combination with radiation can markedly enhance apoptosis of salivary gland cancer cells, and the combined therapy of S-1 and radiation are currently leading to the design of clinical studies.
    International Journal of Oncology 11/2004; 25(4):905-11. · 2.66 Impact Factor
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    ABSTRACT: A lipoteichoic acid-related molecule OK-PSA is an active component of OK-432. In the in vitro experiments, OK-PSA enhanced expression of MHC class II, CD80 and CD86, as well as IL-12 production on dendritic cells (DCs) were derived from wild-type mice, but not from TLR4-deficient (TLR4-/-) mice. Next we examined the in vivo anti-cancer effect of intratumoral administration of syngeneic DCs followed by OK-PSA against established tumors in mice. Although OK-PSA augmented anti-tumor effect of DC administration in tumor-bearing wild-type mice, anti-tumor effect of DCs and OK-PSA was not significant in TLR4-/- mice. Interestingly, an administration of wild-type mice-derived DCs followed by OK-PSA exhibited a marked anti-tumor effect even in TLR4-/- mice. These findings suggest that OK-PSA may be a potential adjuvant for local DC therapy, and that DC therapy followed by OK-PSA is able to elicit anti-cancer activity even in TLR4-deficient host when TLR4 is expressed only in DCs injected intratumorally.
    Gan to kagaku ryoho. Cancer & chemotherapy 11/2004; 31(11):1770-2.
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    ABSTRACT: It is well known that loss of the cyclin-dependent kinase inhibitor p27Kip1 protein correlates with the poor prognosis of various cancers including oral squamous cell carcinoma (SCC). Posttranslational degradation of p27Kip1 protein is mediated by phosphorylation of Thr-187 of p27Kip1 protein, which follows ubiquitination. In this study, we constructed an expression vector expressing mutant type p27Kip1 gene (pcDNA3.1-p27Kip1 mt), with mutation of Thr-187/Pro-188 (ACGCCC) to Met-187/Ile-188 (ATGATC), which is not influenced by ubiquitin-mediated degradation. We transfected mutant and wild type p27Kip1 genes into an oral SCC cell line, B88 to up-regulate the expression of mutant or wild p27Kip1 gene in each transfectant. B88-p27Kip1 mt showed significant growth inhibition than B88-p27Kip1 wt or B88-neo in vitro (p < 0.01). Also, both types of B88-p27Kip1 showed G1 arrest and apoptosis, however, B88-p27Kip1 mt showed remarkable G1 arrest. In addition, B88-p27Kip1 mt and B88-p27Kip1 wt showed markedly inhibition of the migration and out-growth of cancer cells than B88-p27Kip1 wt or B88-neo. Moreover, B88-p27Kip1 mt also showed remarkable suppression of tumor growth and cervical lymph metastasis than B88-p27Kip1 wt or B88-neo in vivo (p < 0.01). In short, the mutant type p27Kip1 gene could show more potent antitumor effects than wild type p27Kip1 gene in B88 cells. These findings suggest that mutant type p27Kip1 gene has the potential to become a novel and powerful gene therapy tool for patients with oral cancers.
    Oral Oncology 08/2004; 40(7):679-87. · 2.70 Impact Factor
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    ABSTRACT: We evaluated the orally administered S-1, in combination with ionizing radiation both in vivo and in vitro against human oral cancer cell lines. Human oral cancer cell lines were used as subcutaneous xenografts in nude mice. S-1 (10 mg/kg) was administered orally 1 h before radiation treatments (1.5 Gy), or 1 h after radiation for five consecutive days. Apoptotic cells were detected by TUNEL method. For in vitro analysis, attached cells were treated with S-1 (50 microg/ml) for 1 h and then irradiated (3, 6, 9, 12, 15 Gy), or they were treated with S-1 for 1 h after radiation. Cell survival was determined by clonogenic assay. The combination of S-1 and radiation was more effective than either agent alone. In addition, S-1 administration before radiation was more effective than S-1 administration after radiation. Moreover, the combination of S-1 and radiation could induce apoptosis significantly than either agent alone (P < 0.01). In vitro clonogenic survival experiments demonstrated the dose enhancement ratio of 1.22 (radiation + S-1), 1.45 (S-1 + radiation) in B88 cells, and 1.16 (radiation + S-1), 1.28 (S-1 + radiation) in HSG cells. These data demonstrate that the combination of S-1 and fractionated radiotherapy is more effective against human oral cancer xenografts than either agent alone, and that S-1 administration before radiation is more effective than after radiation, suggesting a potential clinical applicability of combination treatment of S-1 and radiation in oral cancer therapies.
    Oral Oncology 08/2004; 40(7):713-9. · 2.70 Impact Factor
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    ABSTRACT: We have demonstrated the possibility that the stromal cell-derived factor-1 (SDF-1; CXCL12)/CXCR4 system might be involved in the establishment of lymph node metastasis in oral squamous cell carcinoma (SCC). In order to further clarify the role of the SDF-1/CXCR4 system in oral SCC, we examined the expression of CXCR4 and SDF-1 in biopsy specimens from 61 patients with oral SCC by means of immunohistochemistry, and investigated several clinicopathological factors, including age, sex, lymph node metastasis, invasion, recurrence and prognosis. The expression of CXCR4 and SDF-1 was observed in 57.3 and 11.4% of our subjects, respectively. Although we were unable to find a statistically significant association between the expression of SDF-1 and any clinicopathological factors, we did find a significant association between the expression of CXCR4 and lymph node metastasis (P=0.0417). Moreover, the mode of invasion (P=0.0002) and recurrence of the tumors (P=0.0185) were strongly associated with CXCR4 expression, and the CXCR4-positive group showed a significantly poorer prognosis than the CXCR4-negative group (P=0.0401). Recombinant SDF-1alpha stimulated in vitro invasiveness and scattering in CXCR4-expressing oral SCC cells, but the treatment did not affect the expression of matrix metalloproteinases or urokinase-type plasminogen activator. These results indicate that SDF-1/CXCR4 signaling in oral SCC cells might be involved in the diverse action of oral SCC, including invasion or micrometastasis at the primary site and lymph node metastasis.
    International Journal of Oncology 08/2004; 25(1):65-71. · 2.66 Impact Factor
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    ABSTRACT: The inducible nitric oxide synthase (iNOS) is associated with inflammatory processes and cancer formation through production of nitric oxide (NO). However, the clinical importance of the expression of iNOS in oral cancer remains unclear. In the present study, we examined whether up-regulation of the iNOS gene can affect growth and metastasis of an oral cancer cell line (B88t cell) in vitro and in vivo. We constructed an expression vector containing sense-oriented murine iNOS cDNA with pcDNA3.1. We transfected B88t cells with the sense expression vector to up-regulate the expression of the iNOS gene in the sense transfectants. The expression of iNOS protein was up-regulated in the sense transfectants and that up-regulation of the iNOS gene exerted a growth inhibitory effect on B88t cells in vitro and in vivo. Moreover, up-regulation of the iNOS gene markedly inhibited the migration of cancer cells in a Boyden chamber. Furthermore, up-regulation of the iNOS gene dramatically inhibited metastases to the cervical lymph node in vivo. These findings suggest that up-regulation of the iNOS gene may suppress the tumorigenicity and metastasis of oral cancer cells.
    In vivo (Athens, Greece) 01/2004; 18(4):449-55. · 1.15 Impact Factor