1997 年度実績報告書

抗がん剤による骨髄抑制の予測法の確立

研究課題

研究課題/領域番号	09255241
研究機関	九州大学
研究代表者	仁保喜之九州大学, 医学部, 教授 (60091287)
研究分担者	浅野嘉延九州大学, 医学部, 助手 (60271110) 権藤久司九州大学, 医学部, 助手 (10253428) 岡村孝九州大学, 医学部, 助手 (30136436) 岡村精一九州大学, 医学部, 講師 (20136435)
キーワード	抗がん剤感受性試験 / 造血幹細胞 / CD34陽性細胞 / G-CSF / 可溶性G-CSF受容体 / 造血抑制性サイトカイン / IL-10 / Etoposide
研究概要	抗がん剤による骨髄抑制は造血幹細胞の障害に起因するため、抗がん剤感受性を試験管内で判定するためには、造血幹細胞の増殖能を保持する培養系に抗がん剤を暴露し、その前後で造血コロニー形成の変化を観察する方法が最適と思われる。そこで、抗がん剤感受性試験に適した培養系の基礎的検討として、造血幹細胞を含有するCD34陽性細胞の性状を検討した。CD34陽性細胞には系統特異的な形質を有する細胞集団が混在しており、系統特異的な造血刺激性サイトカイン(Epo、G-CSF、TPO)の作用で細胞増殖と同時に分化成熟が刺激され、機能的Fas抗原の発現によりアポトーシスが誘導された。さらに、造血抑制性サイトカイン(TNF-α、IFN-γ)もCD34陽性細胞のアポトーシスを誘導することが判明した。実際の抗がん剤感受性試験では、迅速かつ簡便性が必要であるため骨髄単核細胞を標的とした培養系が望まれる。骨髄単核細胞を液体培養すると上清中に高濃度のG-CSFを産生した。造血幹細胞の分化成熟によるアポトーシスを防止するためには、この内因性G-CSFの作用を阻害する必要がある。そこで、G-CSF受容体の細胞外領域とIgG Fc領域のキメラ蛋白を用いて、可溶性G-CSF受容体がG-CSFの活性を完全に阻害することを証明した。また、骨髄単核細胞からの造血抑制性サイトカインの産生を、IL-10が完全に阻害することも明らかにした。以上の実験結果を活用し、造血幹細胞の増殖能を保持する骨髄単核細胞の培養系を抗がん剤感受性試験へ応用する試みを行っている。先行試験では、造血コロニー形成を50%抑制するEtoposideの濃度は症例間で差異があり(1-10μg/ml)、この濃度と実際にEtoposideを患者に投与した際の骨髄抑制との相関を検討中である。

研究成果

(22件)

すべてその他

すべて文献書誌 (22件)

[文献書誌] Asano Y.: "Effect of(-)-epigallocatechin gallate on leukemic blast cells from patients with acute myelobalstic leukemia." Life Sciences. 60(2). 135-142 (1997)
[文献書誌] Higuchi M.: "Membrane tumor necrosis factor- α(TNF- α )expressed on HTL-I-infected T cells mediates a costimulatory signal for B cell activation-characterization of membrane TNF-α." Clin.Immunol.Immunopath.82(2). 133-140 (1997)
[文献書誌] Takenaka K.: "Increased incidence of cytomegalovirus(CMV)infection and CMV-associated disease after allogeneic bone marrow transplantation from unrelated donors." Bone Marrow Transplant.19. 241-248 (1997)
[文献書誌] Katayama Y.: "The effects of a simplified method for cryopreservation and thawing procedures on peripheral blood cells." Bone Marrow Transplant.19. 283-287 (1997)
[文献書誌] Miyamoto T.: "Collection and transplantation autologous peripheral blood stem cells in adults." Jpn.J.Apheresis. 16(1). 50-55 (1997)
[文献書誌] Ikeda K.: "C5a induces tissue factor activity on endothelial cells." Thromb.Haemost.77(2). 394-398 (1997)
[文献書誌] Miyamoto T.: "Significance of quantitative analysis of AML1/ETO transcripts in peripheral blood stem cells from t(8;21)." Leukemia & Lymphoma. 25. 69-75 (1997)
[文献書誌] Niiro H.: "Regulation by interleukin-10 and interleukin-4 of cyclooxygenase-2 expression in human neutrophils." Blood. 89(5). 1621-1628 (1997)
[文献書誌] Kanaji T.: "Molecular and genetic analysis of two patients with Bernard-Soulier syndrome - identification of new mutations in glycoprotein Ib α gene." Thromb.Haemost.77. 1055-1061 (1997)
[文献書誌] Akashi T.: "Direct evidence for the contribution of B cells to the progression of insulitis and the development of diabetes in non-obese diabetic mice." Int.Immunol.9(8). 1159-1164 (1997)
[文献書誌] Asano Y.: "Effect of the chimeric soluble granulocyte colony-stimulating factor receptor on the proliferation of leukemic blast cells." Cancer Res.57. 3395-3397 (1997)
[文献書誌] Fujishima H.: "Inhibition by 5-fluorouracil of ERCC1 and γ-glutamylcysteine synthetase messenger RNA expression in a cisplatin resistant HST-1 human squamous carcinoma cell line." Oncology Res.9. 167-172 (1997)
[文献書誌] Shigematsu H.: "Role of the vav proto-oncogene product(Vav)in erythropoietin-mediated cell proliferation and phosphatidylinositol 3-kinase activity." J.Biol.Chem.272(22). 14334-14340 (1997)
[文献書誌] Yoshizawa S.: "A thermolabile β2-macroglycoprotein(TMG)and the antibody against TMG in patients with systemic lupus erythematosus." Clinica Chimica Acta. 264. 219-225 (1997)
[文献書誌] Tanaka Y.: "Detection of polymorphisms within the human IL-10 receptor DNA gene sequence by RT-PCR RFLP." Immunogenetics. 46. 439-441 (1997)
[文献書誌] Gondo H.: "Autologous peripheral blood stem cell transplantation for acute myelogenous leukemia." Bone Marrow Transplant.20. 821-826 (1997)
[文献書誌] Asano Y.: "IL-10 inhibits the autocrine growth of leukemic blast cells from patients with acute myeloblastic leukemia." Int.J.Hematol.66. 445-450 (1997)
[文献書誌] Yamaoka K.: "Activation of STAT5 by lipopolysaccharide through granulocyte-macrophage colonystimulating factor production in human monocytes." J.Immunol.160. 838-845 (1998)
[文献書誌] Horiuchi T.: "A non-sense mutation at Arg^<95> is predominant in complement 9 deficiency in Japanese." J.Immunol.160. 1509-1513 (1998)
[文献書誌] Shibata S.: "Analysis of the granulocyte colony-stimulating factor receptor gene structure using PCR-SSCP in the myeloidlLeukemia and myelodysplastic syndrome." Eur.J.Haematol.(in press). (1998)
[文献書誌] Niho Y.: "Fas/Fas ligant and hematopoietic precursor cells." Curr.Opin.Hematol.(in press). (1998)
[文献書誌] Asano Y.: "Action of interleukein-3 on the proliferation of leukemic progenitor cells from patients with acute myeloblastic leukemia." Clin.Lab.Haematol.(in press). (1998)

1997 年度 実績報告書

抗がん剤による骨髄抑制の予測法の確立

研究代表者

仁保 喜之 九州大学, 医学部, 教授 (60091287)

研究成果

[文献書誌] Asano Y.: "Effect of(-)-epigallocatechin gallate on leukemic blast cells from patients with acute myelobalstic leukemia." Life Sciences. 60(2). 135-142 (1997)

[文献書誌] Higuchi M.: "Membrane tumor necrosis factor- α(TNF- α )expressed on HTL-I-infected T cells mediates a costimulatory signal for B cell activation-characterization of membrane TNF-α." Clin.Immunol.Immunopath.82(2). 133-140 (1997)

[文献書誌] Takenaka K.: "Increased incidence of cytomegalovirus(CMV)infection and CMV-associated disease after allogeneic bone marrow transplantation from unrelated donors." Bone Marrow Transplant.19. 241-248 (1997)

[文献書誌] Katayama Y.: "The effects of a simplified method for cryopreservation and thawing procedures on peripheral blood cells." Bone Marrow Transplant.19. 283-287 (1997)

[文献書誌] Miyamoto T.: "Collection and transplantation autologous peripheral blood stem cells in adults." Jpn.J.Apheresis. 16(1). 50-55 (1997)

[文献書誌] Ikeda K.: "C5a induces tissue factor activity on endothelial cells." Thromb.Haemost.77(2). 394-398 (1997)

[文献書誌] Miyamoto T.: "Significance of quantitative analysis of AML1/ETO transcripts in peripheral blood stem cells from t(8;21)." Leukemia & Lymphoma. 25. 69-75 (1997)

[文献書誌] Niiro H.: "Regulation by interleukin-10 and interleukin-4 of cyclooxygenase-2 expression in human neutrophils." Blood. 89(5). 1621-1628 (1997)

[文献書誌] Kanaji T.: "Molecular and genetic analysis of two patients with Bernard-Soulier syndrome - identification of new mutations in glycoprotein Ib α gene." Thromb.Haemost.77. 1055-1061 (1997)

[文献書誌] Akashi T.: "Direct evidence for the contribution of B cells to the progression of insulitis and the development of diabetes in non-obese diabetic mice." Int.Immunol.9(8). 1159-1164 (1997)

[文献書誌] Asano Y.: "Effect of the chimeric soluble granulocyte colony-stimulating factor receptor on the proliferation of leukemic blast cells." Cancer Res.57. 3395-3397 (1997)

[文献書誌] Fujishima H.: "Inhibition by 5-fluorouracil of ERCC1 and γ-glutamylcysteine synthetase messenger RNA expression in a cisplatin resistant HST-1 human squamous carcinoma cell line." Oncology Res.9. 167-172 (1997)

[文献書誌] Shigematsu H.: "Role of the vav proto-oncogene product(Vav)in erythropoietin-mediated cell proliferation and phosphatidylinositol 3-kinase activity." J.Biol.Chem.272(22). 14334-14340 (1997)

[文献書誌] Yoshizawa S.: "A thermolabile β2-macroglycoprotein(TMG)and the antibody against TMG in patients with systemic lupus erythematosus." Clinica Chimica Acta. 264. 219-225 (1997)

[文献書誌] Tanaka Y.: "Detection of polymorphisms within the human IL-10 receptor DNA gene sequence by RT-PCR RFLP." Immunogenetics. 46. 439-441 (1997)

[文献書誌] Gondo H.: "Autologous peripheral blood stem cell transplantation for acute myelogenous leukemia." Bone Marrow Transplant.20. 821-826 (1997)

[文献書誌] Asano Y.: "IL-10 inhibits the autocrine growth of leukemic blast cells from patients with acute myeloblastic leukemia." Int.J.Hematol.66. 445-450 (1997)

[文献書誌] Yamaoka K.: "Activation of STAT5 by lipopolysaccharide through granulocyte-macrophage colonystimulating factor production in human monocytes." J.Immunol.160. 838-845 (1998)

[文献書誌] Horiuchi T.: "A non-sense mutation at Arg^<95> is predominant in complement 9 deficiency in Japanese." J.Immunol.160. 1509-1513 (1998)

[文献書誌] Shibata S.: "Analysis of the granulocyte colony-stimulating factor receptor gene structure using PCR-SSCP in the myeloidlLeukemia and myelodysplastic syndrome." Eur.J.Haematol.(in press). (1998)

[文献書誌] Niho Y.: "Fas/Fas ligant and hematopoietic precursor cells." Curr.Opin.Hematol.(in press). (1998)

[文献書誌] Asano Y.: "Action of interleukein-3 on the proliferation of leukemic progenitor cells from patients with acute myeloblastic leukemia." Clin.Lab.Haematol.(in press). (1998)

1997 年度実績報告書

仁保喜之九州大学, 医学部, 教授 (60091287)