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• 2012年

  　

  　

  札幌医科大学   医学部   講師

  講師

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• ライフサイエンス   消化器内科学   肝臓病学

• ライフサイエンス   消化器内科学   腫瘍内科

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• 札幌医科大学   医学部 医学科 腫瘍・血液内科学講座   講師  

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• 肝癌

• 遺伝子修復酵素

• 鉄

• 慢性肝炎

• 酸化的DNA損傷

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• Human mesenchymal stem cells xenografted directly to rat liver differentiated into human hepatocytes without fusion.

  Blood   7   0-0  2005年

• Prolonged survival of mice with multiple liver metastases of human colon cancer by intravenous administration of replicable E1B-55K-deleted adenovirus with E1A expressed by CEA promoter

  T Sagawa, M Takahashi, T Sato, Y Sato, Y Lu, T Sumiyoshi, Y Yamada, S Iyama, J Fukaura, K Sasaki, H Hamada, K Miyanishi, T Takayama, J Kato, Y Niitsu

  MOLECULAR THERAPY ( ACADEMIC PRESS INC ELSEVIER SCIENCE )  10 ( 6 ) 1043 - 1050  2004年12月

  　概要を見る

  Liver is the most preferential site for metastasis of colon cancer. We, in the present study, constructed a self-replicable adenovirus in which EIIA is driven by a CEA promoter and E1B-55K is deleted from the E1B region (AdCEAp/Rep) and examined its effects on multiple metastases of a human colon cancer cell in a mouse xenograft model. We first showed effective replication of the virus in various CEA-producing human colon cancer cells (M7609, HT-29) and subsequent lysis of the infected cells in vitro. We then demonstrated that a single intratumoral injection of the virus (1 x 10(8) PFU/100 mul) induced a complete regression of subcutaneous tumors (M7609) inoculated into nude mice. Further, we demonstrated that systemic administration of the virus (1 x 10(8) PFU/100 mul) through the tail vein to nude mice, which 1 week prior had been inoculated with tumor cells (colon carcinoma cell line HT-29) via the spleen and showed apparent multiple metastases in the liver, effectively suppressed the metastasis formation. The mean survival time of the treated mice was significantly longer than that of the controls. Thus, the systemic administration of AdCEAp/Rep was considered to be effective on multiple liver metastases of CEA-positive colon cancer in a xenograft model.

  DOI

• Chemoprevention of colorectal cancer

  Y Niitsu, T Takayama, K Miyanishi, A Nobuoka, T Hayashi, T Kukitsu, K Takanashi, H Ishiwatari, T Abe, T Kogawa, M Takahashi, T Matsunaga, J Kato

  CANCER CHEMOTHERAPY AND PHARMACOLOGY ( SPRINGER )  54   S40 - S43  2004年09月

  　概要を見る

  Colorectal cancer is a disease with a high mortality rate and it has been increasing in prevalence worldwide. Chemoprevention, as well as primary and secondary prevention, for colorectal cancer have attracted much attention. Many chemopreventive trials have been performed, and several agents, including nonsteroidal antiinflammatory drugs, such as aspirin and sulindac, cyclooxygenase-2 selective inhibitors, such as celecoxib, vitamin D, folate, and calcium, have been shown to have some effect. In these chemopreventive trials, the targeted lesions used for evaluation were mainly polyps. However, the chemopreventive effects of some agents on polyps may require several years to evaluate. Further, larger polyps may not be susceptible to chemopreventive agents. Aberrant crypt foci (ACF) are tiny lesions at the earliest stage of colorectal carcinogenesis, which consist of large, thick crypts identified by dense, methylene blue staining. We succeeded in identifying human ACF in situ using magnifying endoscopy and found that the number of ACF, particularly dysplastic ACF, increased significantly from normal subjects to adenoma patients and then to cancer patients. We also found that the number, size, and dysplastic features of ACF are significantly correlated with the number of adenomas in adenoma patients. Thus, it was surmised that ACF are precursor lesions of the adenoma-carcinoma sequence in humans and that ACF may be the most appropriate lesions as targets for chemoprevention. We have shown that the number of ACF was significantly reduced in patients treated with sulindac. We are currently proceeding with a randomized, double-blind, chemopreventive trial targeting ACF.

  DOI

• Glutathione-S-transferase P1-1 protects aberrant crypt foci from apoptosis induced by deoxycholic acid

  A Nobuoka, T Takayama, K Miyanishi, T Sato, K Takanashi, T Hayashi, T Kukitsu, Y Sato, M Takahashi, T Okamoto, T Matsunaga, J Kato, M Oda, T Azuma, Y Niitsu

  GASTROENTEROLOGY ( W B SAUNDERS CO )  127 ( 2 ) 428 - 443  2004年08月

  　概要を見る

  Background & Aims: Aberrant crypt foci, precursors of colonic adenoma, are frequently positive for glutathione-S-transferase P1-1. Because deoxycholic acid is an apoptosis-inducing xenobiotic in the colon, we examined the possibility that aberrant crypt foci, through the cyto-protecting function of glutathione-S-transferase P1-1, resist deoxycholic acid-induced apoptosis, thereby surviving to become adenomas and subsequently cancer. Methods: Glutathione-S-transferase P1-1 or cyclooxygenase-2 expression and the percentage of apoptotic cells in aberrant crypt foci were examined by immunohistochemistry and by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling, respectively. Glutathione-S-transferase P1-1 was transfected into colon cancer cells (M7609) and human lung fibroblasts, and deoxycholic acid-induced apoptosis was evaluated by a dye-uptake assay and flow cytometry. Binding of deoxycholic acid to glutathione-S-transferase P1-1 was analyzed by circular dichroism and immunoprecipitation. Caspase activities were determined by colorimetric protease assay, and sulindac binding to glutathione-S-transferase P1-1 was determined by inhibition assay of glutathione-S-transferase P1-1 activity. Results: Aberrant crypt foci showed positive immunostaining for glutathione-S-transferase P1-1 but negative staining for cyclooxygenase-2. The percentage of apoptotic cells in aberrant crypt foci was significantly lower than in healthy epithelium, and the difference became more apparent with deoxycholic acid treatment. The impaired sensitivity of aberrant crypt foci to deoxycholic acid was restored by the glutathione-S-transferase P1-1-specific inhibitor gamma-glutamyl-S-(benzyl)cysteinyl-R-phenylglycine diethylester. By transfection of glutathion e-S-transferase P1-1, M7609 cells became more resistant to deoxycholic acid-induced apoptosis than mock transfectants. Direct binding of glutathione-S-transferase P1-1 to deoxycholic acid was proven by circular dichroism and by immunoprecipitation. The aberrant crypt foci in adenoma patients treated with sulindac, which was shown to bind to glutathione-S-transferase P1-1, underwent apoptosis in 4 days and mostly regressed in 2-3 months. Conclusions: Glutathione-S-transferase P1-1 protects aberrant crypt foci from deoxycholic acid-induced apoptosis and may play a pivotal role in early colon carcinogenesis.

  DOI

• Plasma glutathione S-Transferase P1-1 as a prognostic factor in patients with advanced non-Hodgkin's lymphoma (stages III and IV).

  Clin Cancer Res   10   7934 - 40  2004年

  DOI

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