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Dive into the research topics where Toyokazu Miki is active.

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Featured researches published by Toyokazu Miki.


Cancer Science | 2003

Multifunctional interleukin‐1β promotes metastasis of human lung cancer cells in SCID mice via enhanced expression of adhesion‐, invasion‐ and angiogenesis‐related molecules

Seiji Yano; Hiroshi Nokihara; Akihiko Yamamoto; Hisatsugu Goto; Hirohisa Ogawa; Takanori Kanematsu; Toyokazu Miki; Hisanori Uehara; Yasuo Saijo; Toshihiro Nukiwa; Saburo Sone

We examined whether interleukin‐1 (IL‐1), a multifunctional proinflammatory cytokine, progresses or regresses metastasis of lung cancer. Exogenous IL‐lβ enhanced expression of various cytokines (IL‐6, IL‐8, and vascular endothelial growth factor (VEGF)) and intracellular adhesion molecule‐1 (ICAM‐1) by A549, PC14, RERF‐LC‐AI, and SBC‐3 cells expressing IL‐1 receptors. A549 cells transduced with human IL‐1β‐gene with the growth‐hormone signaling‐peptide sequence (A549/IL‐1β) secreted a large amount of IL‐1β protein. Overexpression of IL‐1β resulted in augmentation of expression of the cytokines, ICAM‐1, and matrix metallo‐proteinase‐2 (MMP‐2). A549/IL‐1β cells intravenously inoculated into severe combined immunodeficiency (SCID) mice distributed to the lung more efficiently and developed lung metastasis much more rapidly than did control A549 cells. Treatment of SCID mice with anti‐IL‐1β antibody inhibited formation of lung metastasis by A549/IL‐1β cells. Moreover, A549/IL‐1β cells inoculated in the subcutis grew more rapidly, without necrosis, than did control A549 cells, which produced smaller tumors with central necrosis, suggesting involvement of angiogenesis in addition to enhanced binding in the high metastatic potential of A549/IL‐1β cells. Histological analyses showed that more host‐cell infiltration, fewer apoptotic cells, more vascularization, and higher MMP activity were observed in tumors derived from A549/IL‐1β cells, compared with tumors derived from control A549 cells. These findings suggest that IL‐1β facilitates metastasis of lung cancer via promoting multiple events, including adhesion, invasion and angiogenesis. (Cancer Sci 2003; 94: 244–252)


Oncology Research | 2001

Bone metastasis model with multiorgan dissemination of human small-cell lung cancer (SBC-5) cells in natural killer cell-depleted SCID mice

Toyokazu Miki; Seiji Yano; Saburo Sone

Lung cancer is commonly associated with multiorgan metastasis, and bone is a frequent metastatic site for lung cancer. Nevertheless, no bone metastasis model of lung cancer with multiorgan dissemination is available, which could provide opportunity to study the molecular pathogenesis. We examined the abilities of eight human lung cancer cell lines injected intravenously into natural killer (NK) cell-depleted SCID mice to generate metastatic nodules in bone and multiple organs, and explored the correlation of the parathyroid hormone-related protein (PTHrP) with the bone metastasis. Although all the small-cell carcinoma cell lines (SBC-5, SBC-3, SBC-3/ADM, H69, H69/VP) formed metastatic nodules in multiple organs (liver, kidney, and lymph nodes), only SBC-5 cells reproducibly developed bone metastases. Squamous cell carcinoma (RERF-LC-AI) cells metastasized mainly into the liver and kidneys, whereas adenocarcinoma (PC-14, A549) mainly produced colonies in the lungs. As assessed by X-ray photography, the osteolytic bone metastases produced by SBC-5 cells were detected as early as on day 28, and all recipient mice developed bone metastasis by day 35. The expression of PTHrP in eight cell lines was directly correlated with the formation of bone metastasis. No correlation was observed between the formation of bone metastasis and the expression of other metastasis-related cytokines (IL-1, IL-6, IL-8, IL-10, IL-11, TNF-alpha, VEGF, M-CSF). Consistent with the formation of bone metastasis by SBC-5 cells, the levels of PTHrP and calcium in the mouse serum were increased in a time-dependent manner, suggesting that PTHrP produced by human lung cancer may play a crucial role in the formation of bone metastasis and hypercalcemia. These findings indicate that a bone metastasis model of SBC-5 cells may be useful for clarifying the molecular aspects of the metastatic processes in different organ microenvironments and the development of therapeutic modalities for lung cancer patients with bone metastases.


International Journal of Cancer | 2004

Parathyroid hormone‐related protein (PTHrP) is responsible for production of bone metastasis, but not visceral metastasis, by human small cell lung cancer SBC‐5 cells in natural killer cell‐depleted SCID mice

Toyokazu Miki; Seiji Yano; Takanori Kanematsu; Hiroaki Muguruma; Saburo Sone

We previously established an osteolytic bone metastasis model with multiorgan dissemination in natural killer (NK) cell‐depleted severe combined immunodeficient (SCID) mice using human small cell lung cancer cells (SBC‐5), which highly express the parathyroid hormone‐related protein (PTHrP). In our present study, we evaluated the role of PTHrP on bone metastasis by SBC‐5 cells using anti‐PTHrP neutralizing antibody (Ab). Anti‐PTHrP Ab did not affect the proliferation or cytokine production of SBC‐5 cells in vitro. Repeated intravenous injection with anti‐PTHrP Ab inhibited the formation of bone metastasis in a dose‐dependent manner, while the same treatment had no significant effect on the metastasis to visceral organs (lung, liver, kidney and lymph node). In addition, treatment with anti‐PTHrP Ab improved the elevated serum calcium level, associated with inhibition of osteolytic bone metastasis, suggesting that anti‐PTHrP Ab inhibited bone metastasis via suppression of bone resorption probably by neutralizing PTHrP. These findings suggest that PTHrP is essential for bone metastasis, but not visceral metastasis, by small cell lung cancer SBC‐5 cells.


Cancer Science | 2003

A report of two bronchioloalveolar carcinoma cases which were rapidly improved by treatment with the epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 (“Iressa”1

Seiji Yano; Takanori Kanematsu; Toyokazu Miki; Yoshinori Aono; Masahiko Azuma; Akihiko Yamamoto; Hisanori Uehara; Saburo Sone

Bronchioloalveolar carcinoma (BAC), a form of pulmonary adeno‐carcinoma, presents unique clinical features, such as endobron‐chial spread and bronchorrhea in advanced stages. The prognosis for BAC patients in advanced stages is poor, as is the case for patients with other non‐small‐cell lung cancer (NSCLC) types, because of low susceptibility to conventional chemotherapy. Recently, an orally active, selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR‐TKI), ZD1839 (“Iressa”), has been investigated in phase II clinical studies (IDEAL 1 and IDEAL 2) as monotherapy against chemotherapy‐refractory NSCLC, and provided clinically significant antitumor activity. In this study, we examined the therapeutic efficiency of ZD1839 in chemotherapy‐refractory BAC patients with bronchorrhea. Two female BAC patients with bronchorrhea were treated once daily with ZD1839 (250 mg/day). In both cases, serous sputum production was dramatically reduced within 3 days of starting the treatment, and hypoxia and radiographic signs of bilateral lung consolidation were visibly improved within 7 days. Following more than 8 months of treatment, no evidence of recurrence or severe adverse events has been observed. These results suggest that this selective EGFR‐TKI, ZD1839, may be a powerful agent for treatment of chemotherapy‐refractory BAC patients with bronchorrhea. (Cancer Sci 2003; 94: 453–458)


International Journal of Cancer | 2003

A third‐generation matrix metalloproteinase (MMP) inhibitor (ONO‐4817) combined with docetaxel suppresses progression of lung micrometastasis of MMP‐expressing tumor cells in nude mice

Akihiko Yamamoto; Seiji Yano; Minoru Shiraga; Hirohisa Ogawa; Hisatsugu Goto; Toyokazu Miki; Helong Zhang; Saburo Sone

The lung is the common target organ of hematogenous metastasis that restricts the prognosis of cancer patients. MMPs play a pivotal role in metastasis by promoting tumor invasion and angiogenesis; therefore, a large number of MMPIs have been developed. Our purpose was to determine the therapeutic efficacy of a selective‐spectrum MMPI, ONO‐4817 (inhibits MMP‐2 and MMP‐9 but not MMP‐1), against established lung micrometastasis in combination with a cytotoxic anticancer drug, DOC, in a nude mouse model. Human non‐small cell lung cancer PC14PE6 (adenocarcinoma) or H226 (squamous cell carcinoma) cells, expressing MMP‐2, MMP‐9 and/or MMP‐1, were injected i.v. into nude mice on day 0. Mice received a single injection of DOC on day 7 (after establishment of micrometastasis) and/or ONO‐4817 mixed with food from day 7 to the end of experiments. Monotherapy with ONO‐4817 or DOC inhibited formation of lung metastasis by PC14PE6 and H226 cells. In addition, combined use of ONO‐4817 with DOC significantly suppressed the tumor burden of H226 and PC14PE6 cells in the lung and prolonged the survival of PC14PE6‐bearing mice compared to ONO‐4817 or DOC alone. These therapies did not affect the body weight or food intake of tumor‐bearing mice. FIZ revealed that lung lesions, but not nontumor parenchyma of the lung, expressed gelatinolytic activity and that treatment with ONO‐4817 abrogated the gelatinolytic activity in lung lesions. These results suggest that the combined use of MMPIs with cytotoxic anticancer drugs may be helpful in the control of established lung micrometastasis by tumor cells expressing MMPs.


International Journal of Immunopharmacology | 2000

Augmentation by interleukin-18 of MHC-nonrestricted killer activity of human peripheral blood mononuclear cells in response to interleukin-12

Sukh Mahendra Singh; Hiroaki Yanagawa; Toyokazu Miki; Haruki Okamura; Saburo Sone

Interleukin (IL)-18 is a novel cytokine with pleiotropic functions. In the present study, we examined the induction of the killer activity of peripheral blood mononuclear cells (MNC) against lung cancer cell lines upon treatment with IL-18 in combination with IL-12. Cytotoxic activity was measured by standard (51)Cr release assay. IL-18 (100 ng/ml) was found to significantly augment IL-12-induced killer activity in a MHC-nonrestricted manner against allogeneic NK-resistant Daudi cells and lung cancer cell lines: SBC-3, RERF-LC-AI and A549. IL-18 could augment IL-12-induced killer activity both at the optimal as well as suboptimal doses of the latter. However, IL-18 was found to have little effect on the killer activity of MNC induced by optimal or suboptimal dose of IL-2 or IL-15. Treatment of MNC with IL-18 in combination with IL-12 for a period of more than 4 days was observed to optimally induce the killer activity. As for induction of IFN-gamma production by MNC, IL-18 augmented that induced by IL-2 and IL-15, as well as that induced by IL-12. These results show the potential of IL-18 in combination with IL-12 for clinical application in treatment of cancer.


Cancer Science | 2003

Soluble Fas in malignant pleural effusion and its expression in lung cancer cells

Kayo Mitani; Yasuhiko Nishioka; Kazue Yamabe; Hirohisa Ogawa; Toyokazu Miki; Hiroaki Yanagawa; Saburo Sone

Soluble Fas (sFas) has the ability to block Fas‐mediated apoptosis, suggesting that sFas at tumor sites might inhibit tumor cell‐killing by immune effector cells. We examined the sFas level in pleural effusion associated with lung cancer. The level of sFas in malignant pleural effusion was significantly higher than those in transudate and tuberculous pleural effusion. There was no significant difference in the sFas concentration among various histological types of lung cancer. The cytotoxicity mediated by anti‐Fas agonistic antibody against Jurkat cells was inhibited by the addition of malignant pleural effusion, being inversely correlated with the sFas concentration. When Fas expression was examined using flow cytometry, eight of ten (80%) lung cancer cell lines expressed cell surface Fas. On the other hand, sFas protein and mRNA were detected in six of ten (60%) lung cancer cell lines, but there was no correlation between Fas and sFas expression. Furthermore, although the expressions of Fas and sFas were clearly detected in tumor cells derived from malignant effusion, the sFas expression was down‐regulated in an in vitro culture. These results suggest that sFas in malignant pleural effusion is at least in part produced by lung cancer cells, and might play a role in local immunosuppression by tumor cells. (Cancer Sci 2003; 94: 302–307)


International Journal of Cancer | 2001

Transduction of KAI1/CD82 cDNA promotes hematogenous spread of human lung-cancer cells in natural killer cell–depleted SCID mice

Tsutomu Shinohara; Naoki Nishimura; Hiroshi Nokihara; Toyokazu Miki; Hirofumi Hamada; Saburo Sone

KAI1, which is identical to CD82, was initially identified as a metastasis‐suppressor gene for human prostate cancer, and its expression is reported to be a favorable prognostic factor for operable human lung cancer. In this study, we examined the functional role of KAI1/CD82 in the late phase of metastatic spread of human lung‐cancer cells. For this, KAI1/CD82 cDNA was introduced into KAI1/CD82 low‐expressing human lung‐cancer cell lines, SBC‐3 and PC‐14, and then the metastatic potential of the transformants was analyzed by i.v. inoculation of KAI1/CD82‐transduced cells, SBC‐3/KAI1 and PC‐14/KAI1, into NK cell–depleted SCID mice. Contrary to our expectations, KAI1/CD82 gene transfer promoted multiorgan metastasis of i.v.‐inoculated human lung‐cancer cells, while s.c. tumor growth was unaffected. Cancer cells from metastatic tumors of NK cell–depleted SCID mice injected i.v. with SBC‐3/KAI1 expressed appreciable cell‐surface KAI1/CD82, and cells not expressing KAI1/CD82 (revertants) were not detected in the tumors. Our findings indicate that under conditions where the hosts natural cytotoxicity is suppressed, KAI1/CD82 may enhance the formation of tumors by circulating lung‐cancer cells at metastatic sites.


Journal of Anesthesia | 2006

The use of continuous hemodiafiltration in a patient with diabetic ketoacidosis.

Hitomi Kawata; Daisuke Inui; Jun Ohto; Toyokazu Miki; Atsuhiko Suzue; Yasushi Fukuta; Masaji Nishimura

A variety of fatal complications are associated with diabetes mellitus. Among these, diabetic ketoacidosis (DKA) figures largely in fatalities in young diabetics. Although hyperosmotic diuresis in DKA causes extreme fluid loss, acute renal failure is less common than expected in DKA. We treated a case of severe DKA with associated coma, acute respiratory failure, and acute renal failure in a 24-year-old man who had been diagnosed with type 1 diabetes mellitus at age 19. The comatose patient had been intubated before transfer to our hospital for intensive care. Despite infusion with isotonic saline and insulin, metabolic acidosis was refractory. On day 2, urine output decreased and pulmonary congestion developed, so we started continuous veno-venous hemodiafiltration (CVVHDF), which was effective against the metabolic acidosis; urine output increased gradually. CVVHDF was withdrawn on day 7, and the patients renal function recovered completely. He was discharged from the intensive care unit (ICU) on day 14.


Cancer Letters | 2001

Humanized anti-ganglioside GM2 antibody is effective to induce antibody-dependent cell-mediated cytotoxicity in mononuclear cells from lung cancer patients

Prahlad Parajuli; Hiroaki Yanagawa; Eiji Takeuchi; Toyokazu Miki; Seiji Yano; Saburo Sone

Ganglioside GM2 is one of the major gangliosides expressed on the cell surface of human tumors including lung cancer. We have previously reported that a mouse-human chimeric monoclonal antibody (mAb), KM966, against GM2 promotes the lysis of lung cancer cells by human blood mononuclear cells (MNC) of healthy donors. In this study, we examined antibody-dependent cell-mediated cytotoxicity (ADCC) of MNC, using KM966 mAb and its humanized counterpart, KM8969, in 16 lung cancer patients and 18 control patients. The ADCC activity was assessed by 4-h (51)Cr release from GM2 positive SBC-3 small cell lung cancer cells. MNC from lung cancer patients exhibited similar ADCC activity to those from control patients when KM966 and KM8969 were used as mAb. Moreover, effective ADCC activity was observed even in MNC from advanced lung cancer patients. These observations suggest the potential activity of humanized anti-GM2 mAb (KM8969), as well as chimeric KM966, in biological therapy for lung cancer patients.

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Saburo Sone

University of Tokushima

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Seiji Yano

University of Tokushima

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Daisuke Inui

University of Tokushima

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