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Development of Gene Targeting Technique Using Radiolabeled Antisense DNA

Research Project

Project/Area Number 10470194
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Radiation science
Research InstitutionKanazawa University

Principal Investigator

TONAMI Norihisa  Kanazawa University Graduate School of Medical Sciences, Professor, 大学院・医学系研究科, 教授 (60019940)

Co-Investigator(Kenkyū-buntansha) SHIBA Kazuhiro  Kanazawa University Radioisotope Center, Associate Professor, アイソトープ総合センター, 助教授 (40143929)
YOKOYAMA Kunihiko  Kanazawa University Hospital, Lecturer, 医学部・附属病院, 講師 (60230661)
Project Period (FY) 1998 – 2000
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥5,300,000 (Direct Cost: ¥5,300,000)
Fiscal Year 2000: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1999: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 1998: ¥2,700,000 (Direct Cost: ¥2,700,000)
Keywordsantisense DNA / oligonucleotide / radioisotope / imaging diagnosis / gene imaging / delivery system / induced hypertension / DNA / ターゲッティング / がん遺伝子
Research Abstract

Using radiolabeled antisense oligonucletides (DNA), lesions of amplified mRNA can be imaged with gamma cameras. For this approach, the stable radiometal chelates, which are appropriate for oligonucletide, is required. We have developed the in vivo model system where nude mice xenografted tumor cells express P-glycoprotein (P-gp). To image multidrug resistant tumors caused by P-gp, we designed the 15mer of antisense DNA sequence for the mdr1 gene coding P-gp. The 5'-end of the oligonucletide was modified with the thiol group and the maleimido-C6-benzyl-EDTA chelate was reacted. The final product was identified as the objective compound by ODS chromatography. Further investigation was warranted. The small molecules like oligonucleotides tend to be cleared very rapidly from the blood and therefore, the absolute tumor uptake of this kind of the tracer is limited. We have tried to increase the tumor uptake of radiolabeled antibodies by modifying the delivery system to the tumor tissue. The combination usage of angiotensin-II, continuously infused at 2μg/kg/min, and a kininase inhibitor, enalapril maleate, 30 μg increased the mouse blood pressure from 95/61 to 153/67. And the tumor uptake was also increased by the factor of 1.62 with little change in normal organ distribution. The autoradiography showed that more homogeneous distribution of the radiolabeled antibody in the tumor because of recanalization of vascular beds and increased vascular permeability. In conclusions, enhanced tumor uptake was achieved by manipulating hemodynamics and vascular permeability of the tumor tissue and this technique can be applied for smaller molecule as the oligonucleotides.

Report

(4 results)
  • 2001 Final Research Report Summary
  • 2000 Annual Research Report
  • 1999 Annual Research Report
  • 1998 Annual Research Report
  • Research Products

    (9 results)

All Other

All Publications (9 results)

  • [Publications] Seigo Kimuya: "Euhanced efficacy of vadioimmunotherapy condicred with systemic chemotherapy and local hypothermia in xengraft model."JpnJ.Cancer Res. 91(5). 573-578 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Seigo Kimuya: "Pharmacological intervention with angiotensin II and kiminess inhibitor for enhanad efficacy of vadio immunie therapy"J Nucl Med. 41(7). 1244-1249 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Seigo Kimuya: "Optimal timiny of administration of Cypathermia in rombinod vadioimmuneherapy"Cancer Biotherapy & Radio pharmaceuticals. 15(4). 373-379 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Seigo Kinuya: "Early response of tumour to radiotherapy should be apsesaed by both uptake and retention of single photon tracers"Nuclear Medicate Communication. 20(7). 581-588 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 横山邦彦: "がんのアイソトープ内用療法"癌と化学療法. 26(6). 768-774 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 横山邦彦: "がんのラジオアイソトープ内用療法の利用の現状と展望"Isotope News. 5. 2-7 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Seigo Kinuya: "Efficacy, toxicity and mode of interaction of combination radio immunotherapy with 5FU in colon cancer xenografts"J Cancer Research Clinical Oncology.

    • Related Report
      1999 Annual Research Report
  • [Publications] 横山邦彦: "がんのアイソトープ内用療法" 癌と化学療法. 26(6). (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] 横山邦彦: "がんのラジオアイソトープ内用療法の利用の現状と展望" Isotope News. 5. (1999)

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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