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Development of anti-lung cancer drugs overcoming drug resistance mediated by new molecules a drug efflux pump, breast cancer resistance protein (BCRP), and topoisomerase-I inhibitor

Research Project

Project/Area Number 14570557
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Respiratory organ internal medicine
Research InstitutionKawasaki Medical School (2004)
Nagasaki University (2002-2003)

Principal Investigator

OKA Mikio  Kawasaki Medical School, Department of Medicine, Professor, 医学部, 教授 (40223995)

Co-Investigator(Kenkyū-buntansha) SODA Hiroshi  Nagasaki University, Department of Medidne, Associate Professor, 医学部, 助教授 (60244042)
Project Period (FY) 2002 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2004: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2003: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2002: ¥1,400,000 (Direct Cost: ¥1,400,000)
KeywordsDrug Resistance / Cancer Chemotherapy / Lang Cancer / Drug Transporter Protpin / Topoisomerase Inhibitor / Histone Deareryinse Inhibitor / Telomerase / Breast Cancer Resistance Protein / 茎剤輸送蛋白
Research Abstract

We have explored that breast cancer resistance protein (BCRP)/ABCG2 of a half ABC transporter is a relatively specific transporter for topoisomerase I inhibitors of anti-lung cancer drugs (Biochem Biophys Research Commun 280:1216-1223, 2001). In addition, we have reported that BCRP/ABCG2 interacted directly with drugs and then immediately exported them out of cells, by using plasma membrane vesicles ovemxpressing BCRP (BiochemBiophys Res Commun 288:827-832, 2001). These findings were the first reports in biochemical analyses of BCRP.Thereafter, to explore the clinical role of BCRP/ABCG2 in lung cancer, we did expression and functional analyses of BCRP in clinical specimens and culture cells of non-small cell lung cancer (NSCLC). The results were that the levels of BCRP mRNA expression in the cell lines were significantly correlated with the BCRP function and the sensitivity to SN-38 and topotecan of topoisomerase I inhibitors, and that some NSCLC tissues expressed sufficient levels of … More the BCRP mRNA to confer drug resistance in vitro (Clin Cancer Res 9:3052-3057, 2003).
Based on the above findings, to develop new anticancer drugs overcoming BCRP-mediated drug resistance, we synthesized about thirty of new derivatives of SN-38. These derivatives were biochemically tested whether they overcame the resistance by using plasma membrane vesicles. Consequently, we demonstrated that low-polarity camptothecin derivatives were potent lead compounds to overcome the resistance, and provided a practical approach to discover new drugs (Int J Cancer 110:921-927, 2004). On the other hand, to reverse BCRP-mediated drug resistance, we examined the reversal effects of novobiocin, a coumermycin antibiotic, in BCRP-over expressing cancer cells. Novobiocin significantly increased intracellular topotecan accumulation by competitive inhibition of BCRP function (Int J Cancer 108:146-151,2004). The findings suggested that novobiocin effectively overcame BCRP-mediated drug resistance at clinically acceptable concentrations. Very interestingly, we demonstrated that gefitinib of a novel molecular target drug for lung cancer reversed BCRP-mediated drug resistance in cancer cells and that gefitinib was a substrate for BCRP (Cancer Res 65:1541-1546, 2005). However, we found that gefitinib itself was not tranported by BCRP, using plasma membrane vesicles expressing BCRP.
FR901228 is a novel his tone deacetylase (HDAC) inhibitor and shows antitumor effects in various cancer cells. We demonstrated that FR901228 inhibited proliferation of small-cell lung cancer cells and drug-resistant sublines very effectively at very low concentrations (Int J Cancer 104:238-242, 2003). Thereafter, we suggested that FR901228 induced caspase-dependent apoptosis via the mitochondrial pathway rather than the death receptor pathway (Mol Cancer Ther 3:1397-1402, 2004). Considering the possible contributions of BCL-2 and BCL-XL to multidug resistance, FR901228 is a promising agent in the treatment of refractory as well as primary small-cell lung cancer. Less

Report

(4 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • Research Products

    (54 results)

All 2006 2005 2004 2003 2002 Other

All Journal Article (39 results) Book (3 results) Publications (12 results)

  • [Journal Article] BCRP/ABCGII levels account for the resistance to topoisomerase I inhibitors2006

    • Author(s)
      Nagashima S, Oka M. et al.
    • Journal Title

      Cancer Chemotherapy and Pharmacology 58

      Pages: 594-600

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Phase II study of irinotecan combined with carboplatin in previously untrea2006

    • Author(s)
      Kinoshita A, Fukuda M, Oka M, et al.
    • Journal Title

      British Journal of Cancer 94

      Pages: 1267-1271

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] BCRP/ABCG2 levels account for the resistance to topoisomerase I inhibitors and reversal effects by gefitinib in non-small cell lung cancer.2006

    • Author(s)
      Nagashima S, Soda H, Oka M, ef al.
    • Journal Title

      Cancer Chemother Pharmacol 58

      Pages: 594-600

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Phase II study of irinotecan combined with carboplatin in previously untreated small-cell lung cancer.2006

    • Author(s)
      Kinoshita A, Soda H, Oka M, ef al.
    • Journal Title

      British Journal of Cancer 94

      Pages: 1267-1271

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Gefitinib (Iressa,ZD1839), an EGFR tyrosine kinase inhibitor, reverses brea2005

    • Author(s)
      Nakamura Y, Oka M. et al.
    • Journal Title

      Cancer Research 65

      Pages: 1541-1546

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] 抗がん剤とABCトランスポーター2005

    • Author(s)
      岡 三喜男, 福田 実, 早田 宏
    • Journal Title

      癌と化学療法 32

      Pages: 585-592

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Gefitinib, and EGFR tyrosine kinase inhibitor, directly inhibits the function o2005

    • Author(s)
      Kitazaki T, Oka M. et al.
    • Journal Title

      Lung Cancer 49

      Pages: 337-347

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Gefitinib ("Iressa", ZD1839), an epidermal growth factor receptor tyrosine kinase inhibitor, reverses breast cancer resistance protein/ABCG2-mediated drug resistance.2005

    • Author(s)
      Nakamura Y, Oka M, Soda H, ef al.
    • Journal Title

      Cancer Research 65

      Pages: 1541-1546

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Gefitinib, an EGFR tyrosine kinase inhibitor, directly inhibits the function of P-glycoprotein in multidrug resistant cancer cells.2005

    • Author(s)
      Kitazaki T, Oka M, Soda H, ef al.
    • Journal Title

      Lung Cancer 49

      Pages: 337-347

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Gefitinib (Iressa, ZD1839), an EGFR tyrosine kinase inhibitor, reverses breast cancer resistance protein/ABCG2-mediated drug resistance2005

    • Author(s)
      Nakamura Y, Oka M, et al.
    • Journal Title

      Cancer Research 65

      Pages: 1541-1546

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Reversal of breast cancer resistance protein (BCRP/ACBG2)-mediated drug resistanc2004

    • Author(s)
      Shiozawa K, Oka M. et al.
    • Journal Title

      International Journal of Cancer 108

      Pages: 146-151

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Novel camptothecin analogues that circumvent ABCG2-associated drug resistance in2004

    • Author(s)
      Yoshikawa M, Oka M. et al.
    • Journal Title

      International Journal of Cancer 110

      Pages: 921-927

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Phase II study of irinotecan combined with carboplatin in previously untreated non-s2004

    • Author(s)
      Fukuda M, Oka M. et al.
    • Journal Title

      Cancer Chemotherapy and Pharmacology 54

      Pages: 573-577

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The histone deacetylase inhibitor FR901228 induces caspase-dependent apop2004

    • Author(s)
      Doi S, Soda H, Oka M, et al.
    • Journal Title

      Molecular Cancer Therapeutics 3

      Pages: 1397-1402

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Reversal of breast cancer resistance protein (BCRP/ABCG2)-mediated drug resistance by novobiocin, acoumermycin antibiotic.2004

    • Author(s)
      Shiozawa K, Oka M, Soda H, ef al.
    • Journal Title

      International Journal of Cancer 108

      Pages: 146-151

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Novel camptothecin analogues that circumvent ABCG2-associated drug resistance in human tumor cells.2004

    • Author(s)
      Yoshikawa M, Oka M, ef al.
    • Journal Title

      International Journal of Cancer 110

      Pages: 921-927

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Phase II study of irinotecan combined with carboplatin in previously untreated non-small-cell lung cancer.2004

    • Author(s)
      Fukuda M, Oka M, Soda H, ef al.
    • Journal Title

      Cancer Chemotherapy and Pharmacology 54

      Pages: 573-577

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The histone deacetylase inhibitor FR901228 induces caspase-dependent apoptosis via the mitochondrial pathway in small cell lung cancer cells.2004

    • Author(s)
      Doi S, Soda H, Oka M, ef al.
    • Journal Title

      Molecular Cancer Therapeutics 3

      Pages: 1397-1402

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Reversal of breast cancer resistance protein (BCRP/ABCG2)-mediated drug resistance by novobiocin, a coumermycin antibiotic2004

    • Author(s)
      Shiozawa K, Oka M, et al.
    • Journal Title

      International Journal of Cancer 108

      Pages: 146-151

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Novel camptothecin analogues that circumvent ABCG2-associated drug resistance in human tumor cells2004

    • Author(s)
      Yoshikawa M, Oka M, et al.
    • Journal Title

      International Journal of Cancer 110

      Pages: 921-927

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Phase II study of irinotecan combined with carboplatin in previously untreated non-small cell lung cancer2004

    • Author(s)
      Fukuda M, Oka M, et al.
    • Journal Title

      Cancer Chemotherapy and Pharmacology 54

      Pages: 573-577

    • Related Report
      2004 Annual Research Report
  • [Journal Article] The histone deacetylase inhibitor FR901228 induces caspase-dependent apoptosis via the mitochondrial pathway in small cell lung cancer cells2004

    • Author(s)
      Doi S, Oka M, et al.
    • Journal Title

      Molecular Cancer Therapeutics 3

      Pages: 1397-1402

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Antiproliferative effects of the histone deacetylase inhibitor FR901228 on small-cell lung cancer lines and drug-resistant sublines2003

    • Author(s)
      Tsurutani J, Soda H, Oka M, et al.
    • Journal Title

      International Journal of Cancer 104

      Pages: 238-242

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Expression and functional analyses of breast cancer resistance protein in lung cance2003

    • Author(s)
      Kawabata S, Oka M, et al.
    • Journal Title

      Clinical Cancer Research 9

      Pages: 3025-3057

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Expression of heat shock protein (Hsp) 70 and Hsp 40 in colorectal cance2003

    • Author(s)
      Kanazawa Y, Oka M, et al.
    • Journal Title

      Medical Oncology 20

      Pages: 157-164

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Expression of heat shock protein (Hsp) 70 and Hsp 40 in gastric cancer2003

    • Author(s)
      Isomoto H, Oka M. et al.
    • Journal Title

      Cancer Letter 198

      Pages: 219-228

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Antiproliferative effects of the histone deacetylase inhibitor FR901228 on small-cell lung cancer lines and drug-resistant sublines.2003

    • Author(s)
      Tsurutani J, Oka M, Soda H, ef al.
    • Journal Title

      International Journal of Cancer 104

      Pages: 238-242

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Expression and functional analyses of breast cancer resistance protein in lung cancer.2003

    • Author(s)
      Kawabata S, Oka M, Soda H, ef al.
    • Journal Title

      Clinical Cancer Research 9

      Pages: 3052-3057

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Expression of heat shock protein (Hsp) 70 and Hsp 40 in colorectal cancer.2003

    • Author(s)
      Kanazawa Y, Oka M, ef al.
    • Journal Title

      Medical Oncology 20

      Pages: 157-164

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Expression of heat shock protein (Hsp) 70 and Hsp 40 in gastric cancer.2003

    • Author(s)
      Isomoto H, Oka M, ef al.
    • Journal Title

      Cancer Letter 198

      Pages: 219-228

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Phase I study of irinotecan and cisplatin with concurrent split-course radiotherapy2002

    • Author(s)
      Oka M, Fukuda M, Soda H, et al.
    • Journal Title

      European Journal of Cancer 38

      Pages: 1998-2004

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Phase I and pharmacokinetic study of paclitaxel and irinotecan for patients with2002

    • Author(s)
      Kasai T, Oka M, Soda H, et al.
    • Journal Title

      European Journal of Cancer 38

      Pages: 1871-1878

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Histone deacetylase inhibitors suppress telomerase reverse transcriptase mRNA2002

    • Author(s)
      Suenaga M, Soda H, Oka M, et al.
    • Journal Title

      International Journal of Cancer 97

      Pages: 621-625

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Mutational analysis of the beta-tublin gene in ling cancer2002

    • Author(s)
      Tsurutani J, Komiya T, Oka M. et al.
    • Journal Title

      Lung Cancer 35

      Pages: 11-16

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] 肺癌の抗癌剤耐性の分子機構2002

    • Author(s)
      岡 三喜男
    • Journal Title

      呼吸 21

      Pages: 779-787

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Phase I study of irinotecan and cisplatin with concurrent split-course radiotherapy in limited-disease small-cell lung cancer.2002

    • Author(s)
      Oka M, Soda H, ef al.
    • Journal Title

      European Journal of Cancer 38

      Pages: 1998-2004

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Phase I and pharmacokinetic study of paclitaxel and irinotecan for patients with advanced non-small cell lung cancer.2002

    • Author(s)
      Kasai T, Oka M, Soda H, et al.
    • Journal Title

      European Journal of Cancer 38

      Pages: 1871-1878

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Histone deacetylase inhibitors suppress telomerase reverse transcriptase mRNA expression in prostate cancer cells.2002

    • Author(s)
      Suenaga M, Soda H, Oka M, ef al.
    • Journal Title

      International Journal of Cancer 97

      Pages: 621-625

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Mutational analysis of the beta-tubulin gene in lung cancer.2002

    • Author(s)
      Tsurutani J, Oka M, et al.
    • Journal Title

      Lung Cancer 35

      Pages: 11-16

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Book] 癌化学療法Update(西條長宏, 鶴尾隆、編集)2005

    • Author(s)
      岡 三喜男, 福田 実, 早田 宏
    • Total Pages
      524
    • Publisher
      中外医学社
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Book] EBM呼吸器疾患の治療 2006-2007(永井厚志, 吉澤靖之、編)2005

    • Author(s)
      福田 実, 早田 宏, 岡 三喜男
    • Total Pages
      574
    • Publisher
      中外医学社
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Book] プラクテイカル内科シリーズ 肺癌 改訂第2版(福岡正博, 西條長宏、編集)2003

    • Author(s)
      岡 三喜男(分担執筆)
    • Total Pages
      273
    • Publisher
      南江堂
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] Kawabata S, Oka M, et al.: "Expression and functional analyses of breast cancer resistance protein in lung cancer"Clinical Cancer Research. 9. 3025-3057 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Shiozawa K, Oka M, et al.: "Reversal of breast cancer resistance protein (BCRP/ABCG2)-mediated drug resistance by novobiocin. a coumermycin antibiotic"International Journal of Cancer. 108. 146-151 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yoshikawa M, Oka M, et al.: "Novel camptothecin analogues that circumvent ABCG2-associated drug resistance in human tumor cells"International Journal of Cancer. 印刷中. (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Fukuda M, Oka M, et al.: "Phase II study of irinotecan combined with carboplatin in previously untreated non-small cell lung cancer"Cancer Chemotherapy and Pharmacology. 印刷中. (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kanazawa Y, Oka M, et al.: "Expression of heat shock protein (Hsp) 70 and Hsp 40 in colorectal cancer"Medical Oncology. 20. 157-164 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Isomoto H, Oka M, et al.: "Expression of heat shock protein (Hsp) 70 and Hsp 40 in gastric cancer"Cancer Letter. 198. 219-228 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Oka M, Fukuda M, Soda H, et al.: "Phase I study of irinotecan and cisplatin with concurrent split-course radiotherapy in limited-disease small-cell lung cancer"European Journal of Cancer. 38. 1998-2004 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kasai T, Oka M, Soda H, et al.: "Phase I and pharmacokinetic study of paclitaxel and irinotecan for patients with advanced non-small cell lung cancer"European Journal of Cancer. 38. 1871-1878 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Suenaga M, Soda H, Oka M, et al.: "Histone deacetylase inhibitors suppress telomerase reverse transcriptase mRNA expression in prostate cancer"International Journal of Cancer. 97. 621-625 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tsurutani J, Komiya T, Oka M, et al.: "Mutational analysis of the beta-tublin gene in lung cancer"Lung Cancer. 35. 11-16 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tsurutani J, Soda H, Oka M, et al.: "Antiproliferative effects of the histone deacetylase inhibitor FR901228 on small-cell lung cancer cell lines and drug-resistant sublines"International Journal of Cancer. (印刷中). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] 岡 三喜男: "肺癌の抗癌剤耐性の分子機構"呼吸. 21. 779-787 (2002)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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