1998 Fiscal Year Final Research Report Summary
Establishment of Antisense Therapy for Hematological Mailg-nancies Targeted Their Rearranged Genes.
| Project/Area Number |
09671094
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | The University of Tokyo |
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Principal Investigator |
MAEKAWA Taira The Institute of Medical Science, The University of Tokyo, Assistant Professor, 医科学研究所, 講師 (80229286)
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| Co-Investigator(Kenkyū-buntansha) |
MURAKAMI Akira Kyoto Institute of Technology, Professor, 繊維学部, 教授 (60210001)
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| Project Period (FY) |
1997 – 1998
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| Keywords | antisense / hematological malignancy / leukemia / gene rearrangement / cell therapy |
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| Research Abstract |
In this research project, we have clarified followings concerning the mechanism of suppression of the proliferation of human leukemic cells by antisense oligodeoxynucleotides (AS ODN) for rearranged and over-expressed oncogenes.
1) BCR-ABL AS ODN could effectively suppress the proliferation of chronic myeloid leukemia (CML) cells by the induction of apoptosis of these leukemia cells. c-myc AS ODN could inhibit the proliferation of human leukemia cells HL6O, and the abrupt up-regulation of number of leukemia cells in G_1/S boundary. c-myc AS ODN also inhibited the proliferation of synovial cells from patients with rheumatoid arthritits and induced the apoptosis through Fas/Fas ligand system.
2) We have established the synthesis and purification methods of AS ODN with chimeric backbone structure of phosphorothioate and phosphodiester linkages. The first three linkages of both 5'- and 3'-end are synthesized by phosphorothioate chemistry. We have shown these chimeric analogues were resistant to the degradation by nuclease.
3) The above chimeric analogue have much less non-specific effects or aptamer effects that are often encountered when AS ODNs with all-phosphorothioate linkages are used.
4) We have shown that AS ODNs with chimeric backbones against Bcl-2, c-myc, erythropoietin receptor, and stromal-derived factor 1 effectively work as functional antisense molecules, and we have found the novel target antisense sequence to reduce the Bcl-2 expression.
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[Publications] Kishi, K., Toba, K., Azegami, T., Tsukada, N., Uesugi, Y., Masuko, M., Niwano, H., Hashimoto, S., Sakaue, M., Furukawa, T., Koike, T., Takahashi, H., Maekawa, T., Abe, T., Aizawa, Y.: "Hematopoietic cytokine-dependent differentiation to eosinophils and neutrophils in a newly established acute promyelocytic leukemia cell line with t(15 ; 17)." Exp Hematol. 26. 135-142 (1998)
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「研究成果報告書概要(欧文)」より
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[Publications] Nishihara, M., Wada, Y., Ogami, K., Ebihara, Y., Ishii, T., Tsuji, K., Ueno, H., Asano, S., Nakahata, T., Maekawa, T.: "A combination of stem cell factor and granulocytecolony-stimulating factor enhances the growth of human progenitor B cells supported by murine stromal cell line MS-5." Eur J Immunol. 28(3). 855-864 (1998)
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「研究成果報告書概要(欧文)」より
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[Publications] Chikayama, S., Kimura, S., Kobayashi, Y., Abe, T., Maekawa, T., Kondo, M.: "Effects of daunorubicin on cell growth, cell cycle and induction of apoptosis in HL-60 cells." Haematologia. 29(2). 115-121 (1998)
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「研究成果報告書概要(欧文)」より
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[Publications] Hashiramoto, A., Sano, H., Maekawa, T., Kawahito, Y., Kimura, S., Kusaka, Y., Wilder, R.L., Henkart, P.A., Kato, H., Kondo, M., Nakajima, H: "Induction of apoptosis and Fas downregulation by c-myc antisense oligodeoxy-nucleotides in rheumatoid synoviocytes." Arthrit Rheuma. (in press).
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「研究成果報告書概要(欧文)」より
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