1997 Fiscal Year Annual Research Report

抗がん剤による骨髄抑制の予測法の確立

Research Project

Project/Area Number	09255241
Research Institution	Kyushu University
Principal Investigator	仁保喜之九州大学, 医学部, 教授 (60091287)
Co-Investigator(Kenkyū-buntansha)	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)
Keywords	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
Research Abstract	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。

Research Products

(22 results)

All Other

All Publications (22 results)

[Publications] Asano Y.: "Effect of(-)-epigallocatechin gallate on leukemic blast cells from patients with acute myelobalstic leukemia." Life Sciences. 60(2). 135-142 (1997)
[Publications] 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)
[Publications] 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)
[Publications] Katayama Y.: "The effects of a simplified method for cryopreservation and thawing procedures on peripheral blood cells." Bone Marrow Transplant.19. 283-287 (1997)
[Publications] Miyamoto T.: "Collection and transplantation autologous peripheral blood stem cells in adults." Jpn.J.Apheresis. 16(1). 50-55 (1997)
[Publications] Ikeda K.: "C5a induces tissue factor activity on endothelial cells." Thromb.Haemost.77(2). 394-398 (1997)
[Publications] 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)
[Publications] Niiro H.: "Regulation by interleukin-10 and interleukin-4 of cyclooxygenase-2 expression in human neutrophils." Blood. 89(5). 1621-1628 (1997)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] 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)
[Publications] Tanaka Y.: "Detection of polymorphisms within the human IL-10 receptor DNA gene sequence by RT-PCR RFLP." Immunogenetics. 46. 439-441 (1997)
[Publications] Gondo H.: "Autologous peripheral blood stem cell transplantation for acute myelogenous leukemia." Bone Marrow Transplant.20. 821-826 (1997)
[Publications] 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)
[Publications] Yamaoka K.: "Activation of STAT5 by lipopolysaccharide through granulocyte-macrophage colonystimulating factor production in human monocytes." J.Immunol.160. 838-845 (1998)
[Publications] Horiuchi T.: "A non-sense mutation at Arg^<95> is predominant in complement 9 deficiency in Japanese." J.Immunol.160. 1509-1513 (1998)
[Publications] 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)
[Publications] Niho Y.: "Fas/Fas ligant and hematopoietic precursor cells." Curr.Opin.Hematol.(in press). (1998)
[Publications] 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 Fiscal Year Annual Research Report

抗がん剤による骨髄抑制の予測法の確立

Principal Investigator

仁保 喜之 九州大学, 医学部, 教授 (60091287)

Research Products

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

[Publications] 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)

[Publications] 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)

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

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

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

[Publications] 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)

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

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

[Publications] 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)

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

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

[Publications] 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)

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

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

[Publications] 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)

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

[Publications] 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)

仁保喜之九州大学, 医学部, 教授 (60091287)