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ANALYSIS OF GENES RELATED TO ALKYLATING AGENT-RESISTANCE IN IN VIVO-ESTABLISHED DRUG-RESISTANT CELL LINE EXPRESSED ONLY WHEN GROWN AS MULTICELLULAR SPHEROIDS IN VITRO

Research Project

Project/Area Number 12671613
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Obstetrics and gynecology
Research InstitutionKyushu University

Principal Investigator

KOBAYASHI Hiroaki  Kyushu Univ. Hospital, Dept. of OB & Gyn, Lecturer, 医学部・附属病院, 助手 (70260700)

Co-Investigator(Kenkyū-buntansha) HIRAKAWA Toshio  Kyushu Univ. Hospital, Dept. of OB & Gyn, Senior Lecturer, 医学部・附属病院, 講師 (20218770)
SONODA Kenzo  Kyushu Univ. Hospital, Dept. of OB & Gyn, Assistant Prof., 医学部・附属病院, 助手 (30294929)
FUKUSHIMA Koutarou  Kyushu Univ. Hospital, Dept. of OB & Gyn, Assistant Prof., 医学部・附属病院, 助手 (40304779)
Project Period (FY) 2000 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2001: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2000: ¥1,700,000 (Direct Cost: ¥1,700,000)
Keywordsalkylating agent-resistance / multicellular spheroid / three-dimensional cell culture / differential display method / 3次元培養 / ディファレンシヤル・ディスプレイ法 / アルデヒド・デヒドロゲナーゼ
Research Abstract

In vivo-established alkylating agent-resistant variants of the EMT-6 mouse mammary tumor cell line could express drug resistance only in tumor-bearing animals but not in monolayer cell culture systems (Teicher et al.., Science, 1990). We subsequently demonstrated that these in vivo-established drug-resistant variants could reproduce drug resistance even in vitro, but only when grown as three-dimensional cellular aggregates, and that only the drug-resistant sublines, unlike the drug-sensitive sublines, were capable of forming highly compact cellular spheroids (Kobayashi et al., PNAS, 1993). To detect the genes relevant to the above-mentioned drug resistance mechanism, based on the response of a cell population (i.e. 'multicellular resistance') as opposed to (uni)cellular resistance mechanisms, we used a differential display method and compared the levels of gene expression between drug sensitive and resistant sublines under monolayer or three-dimensional cell culture conditions. Forty-e … More ight expression sequence tags, which were highly expressed only in the drug resistant variants grown three-dimensionally, were collected and analyzed. Subsequent RT-PCR analyses, revealed five genes expressed differentially: (1) aldehyde dehydrogenase-3 gene, (2) glutathione S-transferase mu gene, (3) prolyl 4-hydroxylase alpha gene, (4) mouse VL30 retro-element gene, (5) mouse 18S and 28S rRNA, 5'hypervariable (Vr) region gene. Assuming that the cellular architecture of 'compact spheroid' enhances the expression of these genes in in vivo-established drug resistant variants, there is the possibility of a linkage between a tumor cell-tumor cell interaction in multicellular structure and resistance to alkylating agents through controllable gene expression. Another possibility is that the in vivo drug exposure induces/enhances the above-mentioned candidate gene(s) expression at first, and then a subsequent upregulation of gene(s) expression occurs in particular molecule(s) which enables the compact spheroid formation. Ovarian cancer seems to be a good candidate to evaluate these hypothesis because it exists as a spheroid in a patient ascites and further studies are underway. Less

Report

(3 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • Research Products

    (14 results)

All Other

All Publications (14 results)

  • [Publications] K.Sonoda et al.: "The Clinical Significance of Tumor-Associated Antigen RCAS1 Expression in the Normal, Hyperplastic, and Malignant Uterine Endometrium"Gynecologic Oncology. 79. 424-429 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] K.Fukushima et al.: "Cytotoxic Effects of Soluble Factor in Preeclamptic Sera on Human Trophoblasts"American Journal of Reproductive Immunology. 46. 245-251 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] 萩原 聖子: "卵巣癌化学療法に続発した低ナトリウム血症の1例"日本産科婦人科学会雑誌. 53. 1079-1083 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] 小林 裕明: "卵巣癌に対する化学療法はCAPかパクリタキセルか.-当科における卵巣癌化学療法としてのCEP療法とTJ療法の比較"日本産科婦人科学会九州連合地方部会雑誌. 53. 87-92 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] S.Ogawa et al.: "Prognostic significance of microvessel density, vascular cuffing and vascular endothelial growth factor expression in ovarian carcinoma : a special review for clear cell adenocarcinoma"Cancer Letters. (In press). (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] K.Sonoda et al: "The Clinical Significance of Tumor-Associated Antigen RCAS1 Expression in the Normal, Hyperplastic, and Malignant Uterine Endometrium"Gynecologic Oncology. 79. 424-429 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] K.Fukushima et al.: "Cytotoxic Effects of Soluble Factor in Preeclamptic Sera on Human Trophoblasts"American Journal of Reproductive Immunology. 46. 254-251 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] S. Ogawa et. al.: "Prognostic significance of microvessel density, vascular cuffing and vascular endothelial growth factor expression in ovarian carcinoma: a special review for clear cell adenocarcinoma"Cancer Letters. (in press). (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] K.Sonoda et al.: "The Clinical Significance of Tumor-Associated Antigen RCAS1 Expression in the Normal, Hyperplastic, and Malignant Uterine Endometrium"Gynecologic Oncology. 79. 424-429 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] K.Fukushima et al.: "Cytotoxic Effects of Soluble Factor in Preeclamptic Sera on Human Trophoblasts"American Journal of Reproductive Immunology. 46. 245-251 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 萩原 聖子: "卵巣癌化学療法に続発した低ナトリウム血症の1例"日本産婦人科学会雑誌. 53. 1079-1083 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 小林 裕明: "卵巣癌に対する化学療法はCAPかパクリタキセルか.-当科における卵巣癌化学療法としてのCEP療法とTJ療法の比較"日本産婦人科学会九州連合地方部会雑誌. 53. 87-92 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] S.Ogawa et al.: "Prognostic significance of microvessel density, vascular cuffing and vascular endothelial growth factor expression in ovarian carcinoma : a special review for clear cell adenocarcinoma"Cancer Letters. (In press). (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] K Sonoda. et al.: "The clinical significance of tumor-associated antigen RCAS1 expression in the normal, hyperplastic and malignant uterine endometrium"Gynecologic Oncology. 79. 424-429 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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