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Publications (10)29.51 Total impact

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    ABSTRACT: Molecular markers predicting sensitivity to anticancer drugs are important and useful not only for selecting potential responders but also for developing new combinations. In the present study, we analyzed the difference in the sensitivity of xenograft models to capecitabine (Xeloda®), 5'-deoxy-5-fluorouridine (5'-DFUR, doxifluridine, Furtulon®) and 5-FU by comparing the mRNA levels of 12 pyrimidine nucleoside-metabolizing enzymes. Amounts of mRNA in the tumor tissues of 80 xenograft models were determined by real-time RT-PCR and mutual correlations were examined. A clustering analysis revealed that the 12 enzymes were divided into two groups; one group consisted of 8 enzymes, including orotate phosphoribosyl transferase (OPRT), TMP kinase (TMPK) and UMP kinase (UMPK), and was related to the de novo synthesis pathway for nucleotides, with mRNA expression levels showing significant mutual correlation. In the other group, 4 enzymes, including thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD), were involved in the salvage/degradation pathway of the nucleotides, and the mRNA levels of this group were dispersed more widely than that of the de novo group. Antitumor activity was assessed in 24 xenograft models for each drug. The antitumor activity of capecitabine and 5'-DFUR correlated significantly with the mRNA levels of TP and with the TP/DPD ratio, whereas the activity of 5-FU correlated significantly with OPRT, TMPK, UMPK and CD. In a stepwise regression analysis, TP and DPD were found to be independent predictive factors of sensitivity to capecitabine and 5'-DFUR, and UMPK was predictive of sensitivity to 5-FU. These results indicate that the predictive factors for sensitivity to capecitabine and 5'-DFUR in xenograft models may be different from those for 5-FU, suggesting that these drugs may have different responders in clinical usage.
    Oncology Reports 11/2012; 29(2). DOI:10.3892/or.2012.2149 · 2.19 Impact Factor
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    ABSTRACT: Bevacizumab is a humanized monoclonal antibody to human vascular endothelial cell growth factor (VEGF) and has been used for many types of cancers such as colorectal cancer, non-small cell lung cancer, breast cancer, and glioblastoma. Bevacizumab might be effective against gastric cancer, because VEGF has been reported to be involved in the development of gastric cancer as well as other cancers. On the other hand, there are no established biomarkers to predict the bevacizumab efficacy in spite of clinical needs. Therefore, we tried to identify the predictive markers for efficacy of bevacizumab in gastric cancer patients by using bevacizumab-sensitive and insensitive tumor models. Nine human gastric and two colorectal cancer mouse xenografts were examined for their sensitivity to bevacizumab. We examined expression levels of angiogenic factors by ELISA, bioactivity of VEGF by phosphorylation of VEGFR2 in HUVEC after addition of tumor homogenate, tumor microvessel density by CD31-immunostaining, and polymorphisms of the VEGF gene by HybriProbe™ assay. Of the 9 human gastric cancer xenograft models used, GXF97, MKN-45, MKN-28, 4-1ST, SC-08-JCK, and SC-09-JCK were bevacizumab-sensitive, whereas SCH, SC-10-JCK, and NCI-N87 were insensitive. The sensitivity of the gastric cancer model to bevacizumab was not related to histological type or HER2 status. All tumors with high levels of VEGF were bevacizumab-sensitive except for one, SC-10-JCK, which had high levels of VEGF. The reason for the refractoriness was non-bioactivity on the phosphorylation of VEGFR2 and micro-vessel formation of VEGF, but was not explained by the VEGF allele or VEGF165b. We also examined the expression levels of other angiogenic factors in the 11 gastrointestinal tumor tissues. In the refractory models including SC-10-JCK, tumor levels of another angiogenic factor, bFGF, were relatively high. The VEGF/bFGF ratio correlated more closely with sensitivity to bevacizumab than with the VEGF level. VEGF levels and VEGF/bFGF ratios in tumors were related to bevacizumab sensitivity of the xenografts tested. Further clinical investigation into useful predictive markers for bevacizumab sensitivity is warranted.
    BMC Cancer 01/2012; 12:37. DOI:10.1186/1471-2407-12-37 · 3.32 Impact Factor
    This article is viewable in ResearchGate's enriched format
  • Cancer Research 07/2011; 71(8 Supplement):4256-4256. DOI:10.1158/1538-7445.AM2011-4256 · 9.28 Impact Factor
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    ABSTRACT: Previous preclinical and clinical findings have suggested a potential role of epidermal growth factor receptor (EGFR) in osteoclast differentiation and the pathogenesis of bone metastasis in cancer. In this study, we investigated the effect of erlotinib, an orally active EGFR tyrosine kinase inhibitor (TKI), on the bone invasion of human non-small-cell lung cancer (NSCLC) cell line NCI-H292. First, we established a novel osteolytic bone invasion model of NCI-H292 cells which was made by inoculating cancer cells into the tibia of scid mice. In this model, NCI-H292 cells markedly activated osteoclasts in tibia, which resulted in osteolytic bone destruction. Erlotinib treatment suppressed osteoclast activation to the basal level through suppressing receptor activator of NF-κB ligand (RANKL) expression in osteoblast/stromal cell at the bone metastatic sites, which leads to inhibition of osteolytic bone destruction caused by NCI-H292 cells. Erlotinib inhibited the proliferation of NCI-H292 cells in in vitro. Erlotinib suppressed the production of osteolytic factors, such as parathyroid hormone-related protein (PTHrP), IL-8, IL-11 and vascular endothelial growth factor (VEGF) in NCI-H292 cells. Furthermore, erlotinib also inhibited osteoblast/stromal cell proliferation in vitro and the development of osteoclasts induced by RANKL in vitro. In conclusion, erlotinib inhibits tumor-induced osteolytic invasion in bone metastasis by suppressing osteoclast activation through inhibiting tumor growth at the bone metastatic sites, osteolytic factor production in tumor cells, osteoblast/stromal cell proliferation and osteoclast differentiation from mouse bone marrow cells.
    Clinical and Experimental Metastasis 06/2011; 28(7):649-59. DOI:10.1007/s10585-011-9398-4 · 3.46 Impact Factor
  • EJC Supplements 11/2010; 8(7):62-62. DOI:10.1016/S1359-6349(10)71886-3 · 2.71 Impact Factor
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    ABSTRACT: It has been reported that bevacizumab in combination with paclitaxel significantly prolongs progression-free survival compared with paclitaxel alone in the initial treatment for metastatic breast cancer. To understand how bevacizumab enhances the efficacy of paclitaxel, we investigated the mechanism in a MX-1 human breast cancer xenograft model. The antitumor activity of bevacizumab at 5 mg/kg in combination with paclitaxel at 20 or 30 mg/kg was significantly higher than that of either agent alone. First, we measured the paclitaxel concentration in tumor to see whether bevacizumab enhances the activity by increasing the tumor concentration of paclitaxel. When given in combination with bevacizumab, the levels of paclitaxel in the tumor increased. Paclitaxel at 30 mg/kg with bevacizumab showed a similar tumor concentration as paclitaxel alone at either 60 or 100 mg/kg, with a similar degree of tumor growth inhibition. In contrast, no remarkable differences in paclitaxel concentration in the plasma or liver were observed between the paclitaxel monotherapy group and the paclitaxel plus bevacizumab group. An increase in paclitaxel concentration by bevacizumab was also found in another model, A549. In the same MX-1 model, vascular permeability in the tumor was significantly decreased by treatment with bevacizumab. There was no difference in microvessel density between the bevacizumab alone group and the combination group. Results suggest that the synergistic antitumor activity of paclitaxel and bevacizumab in combination may be a result of the increase in paclitaxel concentration in tumor resulting from the downregulation of vascular permeability when co-administered with bevacizumab.
    Anti-cancer drugs 08/2010; 21(7):687-94. DOI:10.1097/CAD.0b013e32833b7598 · 2.23 Impact Factor
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    ABSTRACT: To understand the mechanisms of the effects of combination treatments, we established animal models showing antitumor activity of bevacizumab as a monotherapy and in combination with capecitabine or capecitabine and oxaliplatin and measured thymidine phosphorylase (TP) and vascular endothelial growth factor (VEGF) levels. Tumor-inoculated nude mice were treated with bevacizumab, capecitabine, and oxaliplatin, alone or in combination, after tumor growth was confirmed and volume and microvessel density (MVD) in tumors were evaluated. Levels of TP and VEGF in the tumor were examined by ELISA. Bevacizumab showed significant antitumor activity as a monotherapy in three xenograft models (COL-16-JCK, COLO 205 and CXF280). The MVD in tumor tissues treated with bevacizumab was lower than that of the control. Antitumor activity of bevacizumab in combination with capecitabine was significantly higher than that of each agent alone (COL-16-JCK, COLO 205). Furthermore, the antitumor activity of bevacizumab in combination with capecitabine + oxaliplatin was significantly superior to that of capecitabine + oxaliplatin (COL-16-JCK). TP and VEGF levels were not increased by bevacizumab or capecitabine, respectively, suggesting there are other potentially efficacious mechanisms involved. In the present study we established human colorectal cancer xenograft models which reflect the efficacy of clinical combination therapies, capecitabine + bevacizumab and capecitabine + oxaliplatin + bevacizumab. We will further investigate the mechanisms of the combination therapies using these models.
    Oncology Reports 09/2009; 22(2):241-7. DOI:10.3892/or_00000430 · 2.19 Impact Factor
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    ABSTRACT: To examine the antitumor activity and tolerability of a combination comprising erlotinib and capecitabine in human colorectal, breast and epidermal cancer xenograft models. Further aims of the study were to examine the effects of single-agent erlotinib therapy on tumor growth, and on thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) levels, (enzymes which activate and deactivate capecitabine, respectively) in tumor tissue. BALB/c nu/nu mice bearing LoVo and HT-29 (colon cancer), A-431 (vulval cancer), and KPL-4 and MAXF401 (breast cancer) human tumors were treated with erlotinib 100 mg/kg/day and/or capecitabine 359 or 90 mg/kg/day, by oral administration once daily for 14 days. The maximum tolerated dose (MTD) of erlotinib, formulated in carboxymethylcelluose/Tween 80, was identified as 125 mg/kg/day. Erlotinib at a dose of 100 mg/kg/day achieved significant tumor-growth inhibition in the, LoVo, KPL-4, and A-431 models. Some inhibition of MAXF401 tumor growth was observed, but was not significant. In the HT-29 model, erlotinib showed less marked but statistically significant antitumor activity. On day 15, mean tumor-growth inhibition in HT-29, LoVo, KPL-4, MAXF401, and A-431 models was 46, 74, 71, 20, and 85%, respectively. Evaluation of erlotinib/capecitabine combination therapy, at sub-optimal doses, in the three erlotinib-sensitive tumor models LoVo, KPL-4 and A-431, demonstrated at least additive activity with the combination compared with the single agents. In the A-431 and LoVo models, the combination of agents had greater antitumor activity than the single agent capecitabine alone at the MTD. Erlotinib in combination with capecitabine was not associated with significantly increased toxicity compared with single-agent therapy. Erlotinib 100 mg/kg/day induced significant upregulation of TP and DPD in the LoVo model, a significant upregulation of TP in the HT-29, MAXF401 and A-431 models, but had no obvious effect on TP and DPD levels in the KPL-4 model. In the A-431 model, selective upregulation of TP by erlotinib 100 mg/kg resulted in an increased TP:DPD ratio. In the LoVo model, immunohistochemistry revealed marked upregulation of TP (but not DPD by erlotinib). Erlotinib inhibits tumor growth in a range of human tumor xenograft models, including breast and colorectal cancer (CRC). Erlotinib and capecitabine demonstrated at least additive activity in LoVo, KPL-4 and A-431 tumor models. The antitumor activity of the combination was greater than that of capecitabine alone at the MTD. Erlotinib treatment did affect the TP in the CRC tumor models as confirmed immunohistochemically. The findings of this study support clinical evaluation of erlotinib, both as a single agent and in combination with capecitabine, for the treatment of CRC and breast cancer.
    Cancer Chemotherapy and Pharmacology 06/2006; 57(5):693-702. DOI:10.1007/s00280-005-0079-3 · 2.57 Impact Factor
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    ABSTRACT: Irinotecan (CPT-11) and doxifluridine (5'-DFUR) are active agents against colorectal cancer. Each drug, however, has the possibility of causing diarrhea. First, we determined the optimal dosing regimen in murine models. CPT-11 (i.v., q2d x 3) and 5'-DFUR (p.o., qd x 14) were administered to mice bearing a human colorectal cancer xenograft model. Diarrhea was stronger in the simultaneously administered schedule but not much stronger in the sequentially administered schedule compared with monotherapies. Both schedules yielded similar antitumor efficacies. Next, we conducted a phase I study combining CPT-11 on days 1 and 15, and 5'-DFUR on days 3-14 and 17-28 every 5 weeks in 19 patients with metastatic colorectal cancer. The doses of CPT-11 ranged from 80 to 150 mg/m2 and those of 5'-DFUR from 800 to 1,200 mg. Diarrhea of grade 3/4 developed in only 1 patient at 100 mg/m2/800-mg doses. Dose-limiting toxicities were hyperbilirubinemia and skipping doses due to fatigue at 150 mg/m2/1,200-mg doses. For the phase II study, the recommended dose was set at CPT-11 150 mg/m2 and 5'-DFUR 800 mg.
    Chemotherapy 04/2005; 51(1):32-9. DOI:10.1159/000084416 · 1.55 Impact Factor
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    ABSTRACT: A combination therapy with CPT-11 and 5-FU/LV has been recently established as a first-line therapy for metastatic colorectal cancer. However, severe adverse effects have also been reported from this combination therapy, and a modality to reduce the adverse effects is desired. 5'-DFUR, a pro-drug of 5-FU, shows less myelotoxicity than 5-FU, and thus it may be a better partner to combine with CPT-11. However, since each drug has the possibility of inducing diarrhea, there is concern about their use in combination therapy. Therefore, in the present study, our aim was to establish an optimal schedule in murine models, which shows no increase in diarrhea but maintains potent antitumor activity. In non-tumor bearing mice, CPT-11 was given i.v. at 100 mg/kg/day q2d x 3, and 5'-DFUR was given p.o. at 172 mg/kg/day daily for 14 days. Each of these doses caused diarrhea in the single treatment. CPT-11 was administered simultaneously or sequentially with 5'-DFUR. With the simultaneously administered schedule, the diarrhea appeared stronger than that found in the CPT-11 single or in the 5'-DFUR single treatment groups. On the other hand, with the sequentially administered schedule the diarrhea was not much stronger than that found in the single agent treatment groups. When CPT-11 and 5'-DFUR administrations were separated by three-day intervals, the diarrhea was not augmented at all. In mice bearing human colorectal cancer COLO 205, the antitumor activity of CPT-11 in the combination with 5'-DFUR was additive in all of the examined schedules. The efficacy in the sequential schedule was the same as in the simultaneous schedule. These results suggest that a sequential administration schedule of CPT-11 and 5'-DFUR would be more tolerable than and equally efficacious to the simultaneous administration schedule. Clinical study of this sequential administration in combination therapy is warranted.
    Gan to kagaku ryoho. Cancer & chemotherapy 03/2003; 30(2):223-30.