Basic analysis for developing a novel cancer treatment utilizing mutant p53 modifier CP-31398

• Project/Area Number: 16590610
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: SAPPORO MEDICAL UNIVERSITY
• Principal Investigator: TAKIMOTO Rishu SAPPORO MEDICAL UNIVERSITY SCHOOL OF MEDICINE, FOURTH DEPARTMENT OF INTERNAL MEDICINE, ASSISTANT PROFESSOR, 医学部, 講師 (10336399)
• Project Period (FY): 2004 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥3,800,000 (Direct Cost: ¥3,800,000); Fiscal Year 2005: ¥500,000 (Direct Cost: ¥500,000); Fiscal Year 2004: ¥3,300,000 (Direct Cost: ¥3,300,000)
• Keywords: P53 / CANCER TREATMENT / CP31398 / 消化器癌

Research Abstract

It has been shown that tumor suppressor gene, p53, is mutated in various gastrointestinal (GI) cancers. Loss of function of p53 exerts tumor development and progression, therefore restoration of p53 function might be useful for cancer treatment. CP31398 has developed for restoration of mutated p53 by modifying DNA-binding domain where frequently observed mutation in various cancers. We utilized CP31398 for a novel strategy for cancer treatment combined with modified (activated) p53. We tested mutant p53 and wild-type p53 expressing GI cancer cell lines with CP31398 with or without modified p53 transduction. As a result, CP31398 could enhance the cytotoxicity of modified p53 in SW480 cells possibly by induction of proapoptotic gene in a p53-dependent manner. This novel strategy will be a promising approach for GI cancer treatment.

Research Products

• [Journal Article] Telomerized human bone marrow-derived cell clones maintain the phenotype of hematopoietic-supporting osteoblastic and myofibroblastic stromal cells after long-term culture. (2005)
  • Author(s): Kobune M., Takimoto R., Kato J., Niitsu Y, et al.
  • Journal Title: Exp Hematol. 33 Pages: 1544-53
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Related Involvement of transforming growth factor-beta and thrombopoietin in the pathogenesis of myelodysplastic syndrome with myelofibrosis. (2005)
  • Author(s): Akiyama T, Takimoto R, Niitsu Y, et al.
  • Journal Title: Leukemia. 19 Pages: 558-66
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A patient with TP53 gemline mulation developed Bowen's disease and myelodysplastic syndrome with myelofibrosis after chemotherapy against ovarian cancer. (2005)
  • Author(s): Kuribayashi K, Takimoto R, Niitsu Y, et al.
  • Journal Title: Cancer Biol Ther. 4 Pages: 421-8
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Augmentation of Antitumor Effects of p53 Gene Therapy by Combination with HDAC Inhibitor (2005)
  • Author(s): Takimoto R, Kato J, Niitsu Y, et al.
  • Journal Title: Cancer Biol Ther. 4 Pages: 490-5
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Human mesenchymal stem cells xenografted directly to rat liver are differentiated into human hepatocytes without fusion. (2005)
  • Author(s): Sato Y, Takimoto R, Niitsu Y, et al.
  • Journal Title: Blood. 106 Pages: 756-63
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Telomerized human bone marrow-derived cell clones maintain the phenotype of hematopoietic-supporting osteoblastic and myofibroblastic stromal cells after long-term culture. (2005)
  • Author(s): Kobune M, Kato J, Chiba H, Kawano Y, Tanaka M, Takimoto R, Hamada H, Niitsu Y.
  • Journal Title: Exp Hematol. 33 Pages: 1544-1553
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Related Involvement of transforming growth factor-beta and thrombopoietin in the pathogenesis of myelodysplastic syndrome with myelofibrosis. (2005)
  • Author(s): Akiyama T, Matsunaga T, Terui T, Miyanishi K, Tanaka I, Sato T, Kuroda H, Takimoto R, Takayama T, Kato J, Yamauchi N, Kogawa K, Sakamaki S, Hirayama Y, Kohda K, Niitsu Y.
  • Journal Title: Leukemia. 19 Pages: 1558-1566
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A patient with TP53 germline mutation developed Bowen's disease and myelodysplastic syndrome with myelofibrosis after chemotherapy against ovarian cancer. (2005)
  • Author(s): Kuribayashi K, Matsunaga T, Sakai T, Wada Y, Tateno K, Murase K, Fujimi A, Takimoto R, Terui T, Kato J, Sasaki A, Satoh M, Niitsu Y.
  • Journal Title: Intern Med. 44 Pages: 490-495
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Augmentation of antitumor effects of p53 gene therapy by combination with HDAC inhibitor. (2005)
  • Author(s): Takimoto R, Kato J, Terui T, Takada K, Kuroiwa G, Wu J, Ohnuma H, Takahari D, Kobune M, Sato Y, Takayama T, Matsunaga T, Niitsu Y.
  • Journal Title: Cancer Biol Ther. 4 Pages: 421-428
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Human mesenchymal stem cells xenografted directly to rat liver are differentiated into human hepatocytes without fusion. (2005)
  • Author(s): Sato Y, Araki H, Kato J, Nakamura K, Kawano Y, Kobune M, Sato T, Miyanishi K, Takayama T, Takahashi M, Takimoto R, Iyama S, Matsunaga T, Ohtani S, Matsuura A, Hamada H, Niitsu Y.
  • Journal Title: Blood. 106 Pages: 756-763
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Augmentation of Antitumor Effects of p53 Gene Therapy by Combination with HDAC Inhibitor. (2005)
  • Author(s): Takimoto R, Kato J, Niitsu Y, et al.
  • Journal Title: Cancer Biol Ther. 4 Pages: 421-428
• [Journal Article] Decrease of Smad4 gene expression in patients with essential thrombocythaemia may cause an escape from suppression of megakaryopciesis by transforming growth factor-beta1. (2004)
  • Author(s): Kuroda H, Takimoto R, Niitsu Y, et al.
  • Journal Title: Br J Haematol. 124 Pages: 211-20
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Indian hedgehog gene transfer augments hematopoietic support of human stromal cells including NOD/SCID-beta2m-/-repopulating cells. (2004)
  • Author(s): Kobune M, Takimoto R, Niitsu Y, Hamada H, et al.
  • Journal Title: Blood 15;104(4) Pages: 1002-9
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Plasma glutathione S-Transferase.P1-1 as a prognostic factor in patients with advanced non-Hodgkin's lymphoma (stages III and IV). (2004)
  • Author(s): Katahira T, Takayama T, Takimoto R, Niitsu Y, et al.
  • Journal Title: Clin Cancer Res 1;10(23) Pages: 7934-40
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Fas-mediated apoptosome formation is dependent on reactive oxygen species derived from mitochondrial permeability transition in Jurkat cells. (2004)
  • Author(s): Takimoto R, Niitsu Y.
  • Journal Title: J Immunol 173 Pages: 285-96
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Decrease of Smad4 gene expression in patients with essential thrombocythaemia may cause an escape from suppression of megakaryopoiesis by transforming growth factor-beta1. (2004)
  • Author(s): Kuroda H, Matsunaga T, Terui T, Tanaka I, Takimoto R, Fujikawa K, Takayama T, Kato J, Hirayama Y, Sakarnaki S, Kohda K, Niitsu Y.
  • Journal Title: Br J Haematol. 124 Pages: 211-220
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Indian hedgehog gene transfer augments hematopoietic support of human stromal cells including NOD/SCID-beta2m-/- repopulating cells. (2004)
  • Author(s): Kobune M, Ito Y, Kawano Y, Sasaki K, Uchida H, Nakamura K, Dehari H, Chiba H, Takimoto R, Matsunaga T, Terui T, Kato J, Niitsu Y, Hamada H.
  • Journal Title: Blood. 104 Pages: 1002-1009
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Plasma glutathione S-Transferase P1-1 as a prognostic factor in patients with advanced non-Hodgkin's lymphoma (stages III and IV). (2004)
  • Author(s): Katahira T, Takayama T, Miyanishi K, Hayashi T, Ikeda T, Takahashi Y, Takimoto R, Matsunaga T, Kato J, Niitsu Y.
  • Journal Title: Clin Cancer Res. 10 Pages: 7934-7940
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Fas-mediated apoptosome formation is dependent on reactive oxygen species derived from mitochondrial permeability transition in Jurkat cells. (2004)
  • Author(s): Sato T, Machida T, Takahashi S, Iyama S, Sato Y, Kuribayashi K, Takada K, Oku T, Kawano Y, Okamoto T, Takimoto R, Matsunaga T, Takayama T, Takahashi M, Kato J, Niitsu Y.
  • Journal Title: J Immunol. 173 Pages: 285-296
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Plasma glutathione S-Transferase P1-1 as a prognostic factor in patients with advanced non-Hodgkin's lymphoma (stages III and IV). (2004)
  • Author(s): Katahira T, Takayama T, Takimot R, Niitu Y, et al.
  • Journal Title: Clin Cancer Res. 1;10(23) Pages: 7934-7940
• [Journal Article] Tumor suppressor gene p53 and molecular targeting Therapy. (2004)
  • Author(s): Takimoto R, Niitsu Y.
  • Journal Title: Gan To Kagaku Ryoho 31(9) Pages: 1309-1313
• [Journal Article] Fas-mediated apoptosome formation is dependent on reactive oxygen species derived from mitochondrial permeability transition in Jurkat cells. (2004)
  • Author(s): Takimoto R, Niitsu Y, et al.
  • Journal Title: J Immunol. 1;173(1) Pages: 285-296
• [Journal Article] Indian hedgehog gene transfer augments hematopoietic support of human stromal cells including NOD/SCID-beta2m-/- repopulating cells. (2004)
  • Author(s): Kobune M, Takimoto R, Niitsu Y, Hamada H, et al.
  • Journal Title: Blood 15;104(4) Pages: 1002-1009
• [Journal Article] Ethanol induces transforming growth factor-alpha expression in hepatocytes, leading to stimulation of collagen synthesis by hepatic stellate cells (2003)
  • Author(s): Kato J, Takimoto R, Niitsu Y, et al.
  • Journal Title: Alcohol Clin Exp Res. 8 Suppl
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Telomerized human multipotent mesenchymal cells can differentiate into hematopoietic and cobblestone area-supporting cells. (2003)
  • Author(s): Kobune M, Kato J, Takimoto R, Niitsu Y, et al.
  • Journal Title: Exp Hematol. 31 Pages: 715-22
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Induction of PIG3 and NOXA through acetylation of p53 at 320 and 373 lysine residues as a mechanism for apoptotic cell death by histone deacelylase inhibitors. (2003)
  • Author(s): Teri T, Takimoto R, Niitsu Y, et al.
  • Journal Title: Cancer Res. 63 Pages: 8948-54
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Increased excreased expression of angiogenin in hepatocellular carcinoma in correlation with tumor vascularity. (2003)
  • Author(s): Hisai H, Kato J, Takimoto R, Niitsu Y, et al.
  • Journal Title: Clin Cancer Res. 9 Pages: 4852-9
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Ethanol induces transforming growth factor-alpha expression in hepatocytes, leading to stimulation of collagen synthesis by hepatic stellate cells. (2003)
  • Author(s): Kato J, Sato Y, Inui N, Nakano Y, Takimoto R, Takada K, Kobune M, Kuroiwa G, Miyake S, Kohgo Y, Niitsu Y.
  • Journal Title: Alcohol Clin Exp Res. 8 Suppl
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Telomerized human multipotent mesenchymal cells can differentiate into hematopoietic and cobblestone area-supporting cells. (2003)
  • Author(s): Kobune M, Kawano Y, Ito Y, Chiba H, Nakamura K, Tsuda H, Sasaki K, Dehari H, Uchida H, Honmou O, Takahashi S, Bizen A, Takimoto R, Matsunaga T, Kato J, Kato K, Houkin K, Niitsu Y, Hamada H.
  • Journal Title: Exp Hematol. 31 Pages: 715-722
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Induction of PIGS and NOXA through acetylation of p53 at 320 and 373 lysine residues as a mechanism for apoptotic cell death by histone deacetylase inhibitors. (2003)
  • Author(s): Terui T, Murakami K, Takimoto R, Takahashi M, Takada K, Murakami T, Minami S, Matsunaga T, Takayama T, Kato J, Niitsu Y.
  • Journal Title: Cancer Res. 63 Pages: 8948-8954
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Increased expression of angiogenin in hepatocellular carcinoma in correlation with tumor vascularity. (2003)
  • Author(s): Hisai H, Kato J, Kobune M, Murakami T, Miyanishi K, Takahashi M, Yoshizaki N, Takimoto R, Terui T, Niitsu Y.
  • Journal Title: Clin Cancer Res. 9 Pages: 4852-4859
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Augmentation of Antitumor Effects of p53 Gene Therapy by Combination with HDAC Inhibitor.
  • Author(s): Takimoto R, Kato J, Niitsu Y, et al.
  • Journal Title: Cancer Biol Ther. 2005 Apr.(in press)