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モノクロナ-ル抗体,遺伝子を用いた耐性癌の基礎的な診断と治療に関する研究

Research Project

Project/Area Number 03151028
Research Category

Grant-in-Aid for Cancer Research

Allocation TypeSingle-year Grants
Research InstitutionMie University

Principal Investigator

白川 茂  三重大学, 医学部, 教授 (20026850)

Co-Investigator(Kenkyū-buntansha) 曽根 三郎  徳島大学, 医学部附属病院, 講師 (40145024)
玉置 憲一  東海大学, 医学部, 教授 (50055860)
上田 龍三  愛知県がんセンター研究所, 化学療法部, 部長 (20142169)
下山 正徳  国立がんセンター病院, 薬物療法部, 部長 (50110002)
鶴尾 隆  東京大学, 応用微生物研究所, 教授 (00012667)
Project Period (FY) 1991
Project Status Completed (Fiscal Year 1991)
Budget Amount *help
¥14,600,000 (Direct Cost: ¥14,600,000)
Fiscal Year 1991: ¥14,600,000 (Direct Cost: ¥14,600,000)
Keywords多剤耐性腫瘍 / P糖蛋白(Pーglycoprotein;Pーgp) / 抗Pーgp抗体MRK16 / 抗Pーgp抗体C219 / 多剤耐性遺伝子(mdr1) / mdr1mRNA発現 / ヒトマウスキメラ抗体 / magneticーaffinity cell sorring(MACS)法
Research Abstract

(1)基礎的に抗P糖蛋白(Pーgp)抗体MRK16(鶴尾)の反応性とmdr1遺伝子のmRNA発現程度を培養細胞株で検討し,中等度以上のmRNA発現細胞株でMRK16陽性であった(下山)。(2)ヒト腫瘍nude mouse移植株47株のうち多剤耐性を示す33株中21株でRTーPCR法によりmdr1遺伝子の発現を認め,このうち8株が抗Pーgp抗体C219陽性であった。なおMRK16とC219による固型腫瘍材料の免疫染色至適条件が決定された(玉置)。(3)臨床材料につきmdr1遺伝子発現を6種類のamplimerを用いてRTーPCR法で検索し,amplimerは200〜300bp前後のものが感度が高く,少量の試料で解析可能であった(向山)。(4)白血病,悪性リンパ腫などの造血器腫瘍でのPーgpの関与はin vivoの耐性細胞株で確認された。in vivoの症例検索がなされ,128例の造血器腫瘍でMRK16 F(ab')_2抗体(鶴尾)を用いた間接法で11例陽性,直接法では3例(リンパ腫再発例)の化学療法不応例のみに陽性であった(上田)。また64例の各種白血病症例で同上抗体でのFACS解析陽性例は8例で,うち5例は単球性性格を示し,経過を追跡し得た治療抵抗性8例でmdr1遺伝子発現を経過中に認めたものはPh(+)ALL,MDS各1例で臨床上検出限界に問題が残った(白川)。(5)固型癌については,MRK16の肺癌培養細胞42株の検討では全例陰性であった(上田)が,C219の免疫染色で肺癌,転移性肺腫瘍76例中26例(24%)に陽性(広橋),大腸癌ではC219で高率(68%)に陽性(玉置),また大腸癌,未分化甲状腺癌,肝癌,胎盤など(菅原),乳癌,卵巣癌など(向山)でPTーPCR法によるmdr1mRNAの有意な発現があり,化学療法抵抗性と関連があった。(6)MRK16とMRK17はADCC誘導に際し,リンパ球はMRK16においてのみeffectorとして,単球は両抗体において働くことが判明した。またヒトマウスキメラ抗体の臨床応用への可能性が示唆された(曽根,鶴尾)。(7)MRK16とmagnetic particleをcouplingしたbeadsを用いるmagneticーaffinity cell sorting(MACS)法が開発され,Pーgp発現多剤耐性細胞の分離に成功した。

Report

(1 results)
  • 1991 Annual Research Report
  • Research Products

    (29 results)

All Other

All Publications (29 results)

  • [Publications] Nishikawa M,et al: "Decreased expressin of type II protein kinase C in HL-60 variant cells resistant to induction of cell differentiation by phorbal diester" Cancer Research. 50. 621-626 (1990)

    • Related Report
      1991 Annual Research Report
  • [Publications] Komada F,et al: "Expression of three major protein Kinase C isozymes in various types of human leukemic cells." Cancer Research. 51. 4271-4278 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] 白川 茂,他: "悪性リンパ腫のサルベ-ジ療法ー大細胞型リンパ腫を中心に" 血液・腫瘍科. 22. 55-63 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Mizuno Y,et al: "Detection of multidrug-rosistant protein,P-glycoprotein in childhood leukemia and lymphoma" Eur,J,Pediatr.150. 416-418 (1991)

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      1991 Annual Research Report
  • [Publications] Solary E,et al: "P-glycoprotein expression and in vitro reversion of doxorubicin resistance by verapamil in clinical specimens from acute leukemia and myeloma." Leukemia. 5. 592-597 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Padmanabhan R,et al: "magnetic-affinity cell sorting of human multidrug-resistant cells" J Natl.Cancer Inst.83. 565-569 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Kageyama Y,et al.: "Detection of P-glycoprotein in human urogenital carcinomas and its relationship to epidermal growth factor recoptor expression" Eur,Urol. 20. 58-61 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] 向山 雄人: "臨床におけるpー糖タンパクの発現と多剤耐性克服の試み" BIO medica. 6. 446-451 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] 下山 正徳: "薬剤耐性機構 抗癌剤の多剤耐性(MDR)" 臨床医. 17. 1456-1461 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] 下山 正徳: "抗癌剤の臨床評価法" 最新医学. 46. 1286-1301 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Lymphoma Study Group(1984-1987)(shimoyama M,et al): "Major Prognostic factors of patients with adult T-cell leukemia-lymphoma:A cooperative study" Leukemia Research. 15. 81-90 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Fukuoka M,et al: "Randomized trials of cyclophosphamide,doxorubicin,and vincristine versns cisplation and etoposide versus altemation of these regimens in small-cell lung cancer." J.Natl Cancer Inst.33. 855-861 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Hida T,et al: "Epitope analysis of cluster 1 and NK cell-related monoclonal antibodies" Br.J.Cancer. 63. 24-28 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Nakamura S,et al: "Clinicopathologic study of large cell anaplastic lymphoma (Ki-1 positive large cell lymphoma) among the Japanese" Cancer. 68. 118-129 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Sekido Y,et al: "Preferential expression of c-kit protooncogene transcripts in small cell lung cancer." Cancer Research. 51. 2416-2419 (1991)

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      1991 Annual Research Report
  • [Publications] Hibi K,et al: "Coexpression of the stem cell factor and the c-kit genes in small cell lung cancer." Oncogene. 6. 2291-2296 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] 里 悌子,他: "大腸癌におけるP糖蛋白の発現に関する免疫組織化学的検討" 消化器と免疫. 25. 248-252 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Nomori H,et al: "Tumor cell hetorogeneity and subpopulations with metastatic ability in differentiated adenocarcinoma of the lung." Chest. 99. 934-940 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Shimoyama Y,et al: "Expression of E-and P-cadherin in gastric carcinomas." Cancer Research. 51. 2185-2192 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Tamura G,et al: "Detection of p53 gene mutations in primary gastric cancer by cell sorting and polymerase chain reaction singl-strand conformation polymorphism analysis" Cancer Research. 51. 3056-3058 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] MoriYama M,et al: "Elevated expression of P-glycoprotein in kidner and urinary bladden cancers" Tohoku J.Exp.Med.164. 191-201 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Sugawara I,et al: "Characterization of an etoposide-resistant human K562 cell line,K/eto." Jpn.J.Cancer Res.82. 1035-1043 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Sugawa I,et al: "Primer-dependent amplification of mdr 1 mRNA by polymerase chain reaction" Jpn.J.Cancer Res. 83. (1992)

    • Related Report
      1991 Annual Research Report
  • [Publications] Maeda K,et al: "A novel differentiation antigen on human monocytes that is specifically induced by granulocyte-macrophage colony-stimulating factor ar 1L-3" J.Immunol. 146. 3779-3784 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Nishioka Y,et al: "Down-regulation by interleukin 4 of activation of human alvealar macrophages to the tumor cidal state" cancer Research. 51. 5526-5531 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Sone S,et al: "Macrophage colony-stimulating facter activity in malignant pleural effusions and its augmentation by intrapleural interleukin-2 infusions" Chest. 99. 377-381 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Nishioka Y,et al: "Effector cell analysis of human multidrug-resistant cell killing by mouse-human chimeric antibody against P-glycoprotein" Jpn.J.Cancer Res.

    • Related Report
      1991 Annual Research Report
  • [Publications] Shimoyama M: "Treatment of aggressive T-and B-lymphomas of advanced stage:An overview" In Lymphomas of the Shin Vol.X ed.by Yamada M & Nakajima H, 39-51 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Kojima S,et al: "Cancer Chemotherapy:Challenges for the future.Vol.6,Kimura K,Otak,Carter SK,Santas GW,eds" Excepta Medica,Tokyo, 83-86 (1991)

    • Related Report
      1991 Annual Research Report

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Published: 1991-04-01   Modified: 2016-04-21  

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