モノクロナー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

1993 Fiscal Year Annual Research Report

• Project/Area Number: 05151033
• Research Institution: Mie 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, 助教授 (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 國立がんセンター中央病院, 副院長 (50110002) ; 鶴尾 隆 東京大学, 応用微生物学研究所, 教授 (00012667)
• Keywords: 多剤耐性(MDR)腫瘍 / P糖蛋白(P-gp) / 抗P-gp抗体 / 多剤耐性遺伝子(MDR1) / MDR1mRNA発現 / 血液脳関門 / MDR癌の免疫療法 / cyclosporin A(CsA)誘導体

Research Abstract

1.lethal midiline granulomaを始めとする鼻腔原発‘T'リンパ腫(NL)は予後不良とされているが、NL10例につきP糖蛋白(P-gp)発現を抗体と遺伝子発現から検討した。10例中9例で腫瘍細胞のUIC2陽性、9例中4例にMDR1遺伝子mRNAの発現を認め、通常の悪性リンパ腫に比べて高率であった。2.81例の原発ヒト大腸癌および61例の転移リンパ節を用いてテネイシン(TN)の発現、DNA ploidyおよびP-gp発現を検討した。異数体DNAパターンはTN^-の大腸癌組織(37/61)および転移リンパ節(44/52)に高頻度に認められ、二倍体DNAパターンはTN^+例(50/56)に主に認められ、P-gpの発現は原発TN^+およびTN^-大腸癌(9/81)に認められたが、P-gpとDNA異数体との間に有意な相関はなかった。3.P-gpが脳毛細血管内皮細胞に存在し、脳に移行しにくい抗癌剤VCRに対する血液脳関門として機能していることが、新しく樹立した脳毛細血管内皮細胞株を用いたモデル系により実証された。即ちマウス脳内皮細胞MBECのVCRの細胞内蓄積量をP-gp(+)細胞とP-gp(-)細胞で比較し、前者で抑制されており、P-gp阻害薬のVerapamil(VER)により蓄積量の増大のみ、MBECのP-gpも耐性細胞と同様の抗癌剤輸送機能をもつことが推測された。ヒト脳腫瘍(glioma)でもP-gp/MDR1遺伝子発現は腫瘍細胞自身ではなく、間質の血間内皮細胞の血間内腔側細胞膜上に局在し、脳腫瘍の脳内移植系のVCR,DOX自然耐性に関与していることが考えられた。4.多剤耐性(MDR)癌の免疫療法の上で抗P-gp抗体MRK16を介して単球/mφがMDR癌細胞を障害するが、P-gp阻害剤cyclosporin A(CsA)がMRK16と相乗的にMDR癌細胞の抗癌剤感受性を回復することが判明し、この際CsA誘導体PSC833およびFK-506も単球のADCC活性を増強させるがVERではこの作用はなく、MRK16とCsAとの併用時期の考慮により多剤耐性克服強化への可能性が示唆された。

Research Products

• [Publications] 白川茂,他: "P-糖蛋白質と白血病" Mebio. 10. 21-26 (1993)
• [Publications] 白川茂,他: "mdr1遺伝子(P-糖蛋白)の血液腫瘍における発現とその意義" 医学のあゆみ. 167. 153-156 (1993)
• [Publications] Miwa H,et al: "Expression of MDR1 gene in acute leukemia cells:Association with CD7^+ acute myeloblastic leukemia/acute lymphoblastic leukemia." Blood. 82. 3445-3451 (1993)
• [Publications] Yamaguchi M,et al: "Discordant reaction of Lew 4 and rabbit anti-human CD3ε in sinonasal lymphoma." Int J Hematol. 59. 25-30 (1993)
• [Publications] Naito M,et al: "Enhancement of cellular accumulation of cyclosporine by anti-P-glycoprotein monoclonal antibody MRK-16 and synergistic modulation of multidrug resistance." J Narl Cancer Inst.85. 311-316 (1993)
• [Publications] Naito M,et al: "Enhancement of reversing effect of cyclosporin A on vinoristine resistance by anti-P-glycoprotein monoclonal antibody MRK-16" Jpn J Cancer Res. 84. 489-492 (1993)
• [Publications] Noguchi K,et al: "cDNA expression cloning of the 85-kDa protein overexpressed in adriamycin-resistant cells." Biochem Biophys Res Commun. 192. 88-95 (1993)
• [Publications] Ishii S,et al: "Expression behavior of 85-kDa membrane protein in adriamycin-resistant tumor cells and the inhibition of human tumor growth in athymic mice by MRK-20 monoclonal antibody against the protein." Jpn J Cancer Res. 84. 776-782 (1993)
• [Publications] Sugimoto Y,et al: "Molecular cloning and characterization of the cDNA for the Mr85,000 protein overaxpressed in adriamycin-resistant human tumor cells." Cancer Res. 53. 2538-2543 (1993)
• [Publications] 島田安博,他: "MDR遺伝子と薬剤耐性の克服" 最新医学. 48. 243-249 (1993)
• [Publications] Ohno R,et al: "Randomized study of individnalized induction therapy with or without vincristine,and maintenance-intensification therapy between 4 or 12 courses in adult acute mycloid leukemia." Cancer. 71. 3888-3895 (1993)
• [Publications] Horio Y,et al: "Prognostic significance of P53 mutations and 3p deletions in primary reseoted non-small cell lung cancer." Cancer Res. 53. 1-4 (1993)
• [Publications] Hida T,et al: "Glutathione S-transforase π levels in a panel of lung cancer cell lines and its relation to chemosoncitivity." Jpn J Clin Oncol. 23. 14-19 (1993)
• [Publications] Sekido Y,et al: "Recombinant human stem cell factor mediales chemotaxis of small-cell lung cancer cell lines laberrantly expressing the c-kit protooncogene." Cancer Res. 53. 1709-1714 (1993)
• [Publications] Katoh Y,et al: "Antonomous production of granulocyte-colony stimulating factor in tumor xenografts associated with leukocytesis" Br J Cancer. 68. 715-719 (1993)
• [Publications] Tsuda H.et al: "p-53 mutations and c-erb-2 amplification in intraductal and invasive breast carcinomas of high histologic grade." Jpn J Cancer Res. 84. 394-401 (1993)
• [Publications] Ookawa K,et al: "Concordant p53 and DCC alterations and allelic losses on chromosomes p53 and DCC alterations and allelic losses on chromosomes 13q and 14q associated with liver metastases of colorectal carcinoma." Int.J Cancor. 53. 382-287 (1993)
• [Publications] Uchino S,et al: "p53 mutation in gastric cancer:A genetic model for carcinogenesis is common to gastric and colorectal cancer." Int J Cancer. 54. 759-764 (1993)
• [Publications] Sugawara I,et al: "Relationship among multidrug resistance,terascin expression and DNA ploidy pattern." Jpn J Cancer Res. 84. 703-707 (1993)
• [Publications] 菅原勇,他: "MDR3とそのモノクローナル抗体" 血液・腫瘍科. 27. 9-14 (1993)
• [Publications] Yamashita T,et al: "Multidrug resistance gene and P-glycoprotein expression in anaplastic carcinoma of the thyroid." Cancer Detect Prev. (in press). (1993)
• [Publications] Heike Y,et al: "M-CSF gene transduction in multidrug resistant human cancer cells to enhance anti-P-glycoprotein antibody-dependent macrophage-mediated cytotoxicity." Int J Cancer. 54. 851-857 (1993)
• [Publications] Yano S,et al: "Cyclosporin A enhances susceptibility of multi-drug resistant human cancer cells to anti-P-glycoprotein antibody-dependent cytotoxicity of manocytes,but not of lymphocytes." Jpn J Cancer Res. 85(in press). (1994)
• [Publications] Nakamura A,et al: "Augnmentation by transferrin of 1L-2-inducible killer activity and porforin production in CD8^+ T cells." Clin exp Immunol. 92. 174-179 (1993)
• [Publications] Fukumoto M,et al: "Chromosomal location and structure of amplicons in two human cell lines with coamplification of c-myc and Ki-ras oncogenes." Somat Cell Molecul Genet. 19. 21-28 (1993)
• [Publications] Mizutani Y,et al: "Enhanced antitumor effect of Bacillus Calmctle-Guerin in combination with fibrinagon on vrinary leladder tumor." J Urol. in press. (1993)
• [Publications] Arao S,et al: "Expression of multidrue resistant gene and localization of P-glycoprotein in human primary ovarian cancer." Cancer Res. in press. (1993)
• [Publications] 福本学,他: "MDR発現と臨床" Mebio. 10. 15-20 (1993)
• [Publications] 福本学: "多剤耐性(MDR)の臨床発現" 医学のあゆみ. 167. 150-152 (1993)
• [Publications] Nishii K,et al: "The Mechanism and New Approach on Drug Resistance of Cancer Cells." P-glycoprotein expression in human node.Elesevier Science Publ.Miyazaki T,Takaku F,Sakurada K(eds.), 37-43 (1993)
• [Publications] Miwa H,et al: "ibid.Elesevier Science Publ.Miyazaki T,Takaku F,Sakurada K(eds.)" Expression of MDR1 gene in CD7(+)acute lymphoblastic leukemia., 33-36 (1993)
• [Publications] 島田安博,他: "Annual Review血液1993" III.白血球系 5.MDRとその臨床的意義 高久史麿,宮崎澄雄,斉藤英昭,溝口秀昭(編),中外医学社, 120-126 (1993)
• [Publications] Fukuhara S,et al: "Cancer Chemotherapy:Challenges for the Future.Vol.8.(Kimura K,et al eds.)" Interim analysis of LSG-4 protocol study on the treatment of aggressive non-Hodgkin's lymphomas in Japan.Excernta Medica, 289-294 (1993)
• [Publications] Sugawara I,et al: "The Mechanism and New Approach on Drug Resistance of Cancer Cells.Miyazaki T,Takaku F,Sakurada K(eds.)" Detection of multidrug-resistant cancers at mRNA level by enzymatic gene amplification-with emphasis on comparison with immunohistochemistry and in vitro cytotoxicity test.Excerpta Medica, 55-62 (1993)
• [Publications] Sone S,et al: "Regulation of Human Cancer by Cytokines:Prosontstatus and Future Prospect" Induction of interleukin 2-activated effector activity and its regnlatory mechanisms.Gann Monograph on Cancer Res.Japan Scientific Societies Press,Tokyo, 40(81-93) (1993)