Basic Research for the development of a novel strategy for the treatment of chronic myeloid leukemia with STI571

2002 Fiscal Year Final Research Report Summary

• Project/Area Number: 13671079
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Jichi Medical School
• Principal Investigator: FURUKAWA Yusuke Jichi Medical School, Division of Stem Cell Regulation, Associate Professor, 医学部, 助教授 (00199431)
• Project Period (FY): 2001 – 2002
• Keywords: STI571 / BCR / ABL / CML / phosphorylation / molecular target / cell cycle / p18 / combination therapy

Research Abstract

STI571 is a specific inhibitor for BCR/ABL kinase, and has been used in a molecular target therapy for chronic myeloid leukemia (CML). In this study, we aimed to contribute to the establishment of the novel strategy for the treatment of CML by elucidating the molecular basis of the anti-leukemic action of STI571.
1)Molecular mechanisms of the anti-leukemic action of STI571: ARG is a tyrosine kinase closely related to ABL, which is oncogenic when fused to the transcriptional repressor ETV6. We found that leukemogenesis by an aberrant ARG kinase involves the suppression of p18/LNK4c, which is ubiquitously expressed and considered the major CKI in hematopoietic stem cells. STI571 can be an effective drug for the treatment of leukemias with deregulated ARG kinase activity.
2)Combination of STI571 with commonly-used anti-leukemic agents : We investigated the cytotoxic effects of STI571 on CML cells when combined with other anti-leukemic drugs. STI571 produced synergisity with IFN-α, and additive effects with hydroxyurea, cytarabine, homoharringtonine, doxorubicin, and etoposide. This result provides useful information to establish effective protocols for the treatment of CML.

Research Products

• [Publications] Fujita, N., Furukawa, Y., et al.: "Differences in E2F Subunit Expression in Quiescent and Proliferating Vascular Smooth Muscle Cells"Am.J.Physiol.. 283. H204-H212 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Fujita, N., Furukawa, Y., et al.: "Hyperglycemia Enhances Proliferation of Vascular Smooth Muscle Cells through the Induction of Nuclear Factor-κB (NF-κB) Activation by Angiotensin II and the Augmentation of E2F-1 Up-regulation by Growth Factors"Mol.Cell.Endocrinol.. 192. 75-84 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Kano, Y. et al.: "In Vitro Cytotoxic Effects of a Tyrosine Kinase Iinhibitor STI571 in Combination with Commonly used Antileukemic Agents"Blood. 97. 1999-2007 (2001)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Ito, C., et al.: "Modulation of the Erythropoietin-induced Proliferative Pathway by cAMP in Vascular Smooth Muscle Cells"Am.J.Physiol.. 283. C1715-C1721 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Furukawa, Y. et al.: "Apaf-1 is a Mediator of E2F-1-induced Apoptosis."J.Biol.Chem.. 277. 39760-39768 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Nishimura, N., et al.: "Suppression of ARG Kinase Activity by STI571 Induces Cell Cycle Arrest through Up-Regulation of CDK Inhibitor p18/INK4c"Oncogene. 22. 4074-4082 (2003)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Gupta, S., Radha, V., Furukawa, Y., Swarup, G.: "Direct Transcriptional Activation of Human Caspase-1 by Tumor Suppressor p53"J.Biol.Chem.. 276. 10585-10588 (2001)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Kano, Y., Akutsu, M., Mano, H., Sato, Y., Tsunoda, S., Homma, Y., Furukawa, Y.: "In Vitro Cytotoxic Effects of a Tyrosine Kinase Inhibitor STI571 in Combination with Commonly Used Antileukemic Agents"Blood. 97. 1999-2007 (2001)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Mori, M., Terui, Y., Tanaka, M., Tomizuka, H., Mishima, Y., Ikeda, M., Kasahara, T., Uwai, M., Ueda, M., Inoue, R., Ito, T., Yamada, M., Hayasawa, H., Furukawa, Y., Ishizaka, Y., Ozawa, K., Hatake, K.: "Antitumor Effect of β2-Microglobulin in Leukemic Cell-bearing Mice via Apoptosis-inducing Activity : Activation of Caspase-3 and Nuclear Factor-κB"Cancer Res.. 61. 4414-4417 (2001)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Otsuki, T., Furukawa._Y., Ikeda, K., Endo, H., Yamashita, T., Shinohara, A., Iwamatsu, A., Ozawa, K., Liu, J.M.: "Fanconi Anemia Protein, FANCA, Associates with BRG1, a Component of the Human SWI/SNF Complex"Hum.Mol.Genet.. 10. 2651-2660 (2001)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Furukawa, Y., Nishimura, N., Furukawa, Y., Satoh, M., Endo, H., Iwase, S., Yamada, H., Matsuda, M., Kano, Y., Nakamura, M.: "Apaf-1 is a Mediator of E2F-1-induced Apoptosis"J.Biol.Chem.. 277. 39760-39768 (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Inaba, N., Hiruma, T., Togayachi, A., Iwasaki, H., Wang, X.-H., Furukawa, Y., Sumi, R., Kudo, T., Fujimura, K., Iwai, T., Gotoh, M., Nakamura, M., Nanimatsu, H.: "A Novel I-Branching β-1, 6-N-acetylglucosaminyltransferase Involved in the Human Blood Group I Antigen Expression"Blood. 101. 2870-2876 (2003)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Nishimura, N., Furukawa, Y., Nakamura, M., Kishi, K., Okuda, K., Sato, Y., Kano, Y.: "Suppression of ARG Kinase Activity by STI571 Induces Cell Cycle Arrest through Up-Regulation of CDK Inhibitor p18/INK4c"Oncogene. 22. 4074-4082 (2003)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Ishii, H., Vecchione, A., Furukawa, Y., Sutheesophon, K., Han, S.-Y., Druck, T., Kuroki, T., Trapasso, F., Nishimura, M., Saito, Y., Ozawa, K., Croce, C.M., Huebner, K., Furukawa, Y.: "Expression of FRA16D/WWOX and FRA3B/FHIT Genes in Hematopoietic Malignancies"Mol.Cancer Res.. 1. 940-947 (2003)
  • Description: 「研究成果報告書概要(欧文)」より