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Radiolytic Reduction Activating Prodrugs Possessing 5-Fluorouracil-Releasing Ability : Radiation Sensitizing Effect on Mouse Tumors

Research Project

Project/Area Number 09557069
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Radiation science
Research InstitutionKYOTO UNIVERSITY

Principal Investigator

NISHIMOTO Sei-ichi  Kyoto University, Energy and Hydrocarbon Chemistry Professor, 工学研究科, 教授 (10115909)

Co-Investigator(Kenkyū-buntansha) TAKAHASHI Masaji  Kyoto University, Chest Disease Research Professor, 胸部疾患研究所, 教授 (00026931)
SHIBAMOTO Yuta  Kyoto University, Frontier Medical Sciences Associate Professor, 再生医科学研究所, 助教授 (20144719)
ZHOU Ling  Kyoto University, Energy and Hydrocarbon Chemistry Instructor, 工学研究科, 助手 (50293890)
Project Period (FY) 1997 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥11,900,000 (Direct Cost: ¥11,900,000)
Fiscal Year 1999: ¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 1998: ¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 1997: ¥5,800,000 (Direct Cost: ¥5,800,000)
KeywordsRadiation Activating Prodrug / Radiolytic Reduction / 5-Fluorouracil / 2-Oxoalkyl Substituted Derivatives / Cytotoxicity / Pharmacokinetics / Intracellular Drug Release / in vivo Sensitzing Effect / 放射線活性化プロドラック / N(1)-C(5)結合ニ量体
Research Abstract

Radiolytic reduction activating prodrugs consisting of 5-fluorouracil (5FU) and 2-oxoalkyl substituents at N1, that show no antitumor activity, but release 5FU as a well-specified antitumor agent within hypoxic cells upon irradiation, were studied to obtain a structure-activity relationship for radiotherapy of cancer. The followings are results in the several assays for determining their potential of clinical application.
(1) Among a series of radiolytic reduction activating prodrugs, several 5FU derivatives bearing certain 2-oxoalkyl substituents that showed higher 5FU-releasing reactivity in the radiation chemical assay were synthesized on a large scale to submit for in vivo assay using mouse tumors.
(2) The survival fractions of SCCVII tumor cells suspended in the pre-irradiated (7.5-22.5 Gy) culture medium were evaluated to correlate with the incubation time, by which a quantitative relationship between the cytotoxicity and the amount of 5FU released was obtained.
(3) The cytotoxicity … More and the in vitro radiosensitizing activity toward SCCVII tumor cells were evaluated under oxic and hypoxic conditions dosages of prodrugs, which were correlated with intracelluar concentration of 5FU released upon irradiation. The structure-cytotoxicity and structure-activity relationships derived from the in vitro data were utilized as a guiding principle for molecular design and synthetic study.
(4) The ICィイD250ィエD2 values of a series of prodrugs were evaluated to correlate with molecular structures and in vitro radiosensitizing activity.
(5) Pharmacokinetic analyses were performed to evaluate drug concentrations in plasma and tumor tissues after i.v. injection, using mice bearing SCCVII or EMT6 solid tumors. The time-dependent itratumor concentrations of 5FU released were also analyzed under various timings of irradiation, thereby correlating with the 5FU-releasing ability of prodrugs. These analyses provided a guiding principle for molecular design of better prodrugs with respect to the pharmacokinetic characteristics. Less

Report

(4 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • 1997 Annual Research Report
  • Research Products

    (44 results)

All Other

All Publications (44 results)

  • [Publications] 西本清一: "Radical Anions from 5-Fluorouracil Derivatives. A Theoretical Study of their Cleavage and Orbital Isomerism"Journal of Molecular Structure: THEOCHEM. 499(1-3). 151-160 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 芝本雄太: "A novel Class of Antitumor Prodrug, 1-(2-Oxopropyl)-5-Fluorouracil (OFU001) that Releases 5-Fluorouracil upon Hypoxic Irradiation"Japanese Journal of Cancer Research. 91(4) 印刷中. (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 西本清一: "Stereoisomeric C5-C5'-Linked Dihydrothymine Dimers Produced by Radiolytic One-Electron Reduction of Thymine Derivatives in Anoxic Aqueous Solution: Structural Characteristics in Reference to Cyclobutane Photodimers"Journal of Orgamic Chemistry. 64(14). 5100-5108 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 西本清一: "Radiation-Induced and Photosensitized Splitting of C5-C5'-Linked Dihydrothymine Dimers: Product and Laser Flash Photolysis Studies on the Oxidative Splitting Mechanism"Journal of Physical Chemistry A. 103(42). 8413-8420 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 周玲: "Evidences for Adduct Formation between Intracellular Non-Protein Thiols and Nitroazoles Possessing an α,β-Unsaturated Carbonyl Side Chain and the Effects on Radiosensitization of Hypoxic Cells"Bioorganic & Medicinal Chemistry. 7. 2591-2598 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 周玲: "Bifunctional 2-Naphthyl Propargylic Sulfones Exhibiting High DNA Intercalating and Alkylatinf Activity"Bioorganic & Medicinal Chemistry Letters. 9. 2789-2794 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 周玲: "Synthesis and DNA Cleavage Study of a 10-Membered Ring Enediyne Formed via Allylic Rearrangement"Journal of Organic Chemistry. 64(3). 682-683 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 芝本雄太: "A Phase II Study of Concurrent Accelerated Hyperfractionated Radiotherapy and Carboplatin/Oral Etoposide for Elderly Patients with Stage III Non-Small-Cell Lung Cancer"International Journal of Radiation Oncology・Biology・physics. 44. 343-348 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 芝本雄太: "The influence of DNA Ploidy of a Human Tumor Cell Line on the Frequencies of Micronuclei or Chromosome Aberrations after Irradiation"Mutation Research. 418. 49-57 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 西本清一: "Hydroxyl Radical-Induced Cross-Linking of Thymine and Lysine: Identification of the Orimary Structure and Mechanism"Bioorganic & Medicinal Chemistry Letters. 8. 865-870 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 周玲: "Remarkable Tethering Effect on DNA Cleavage of Propargylic Sulfone Conjugates with Intercalating Moieties"Bioorganic & Medicinal Chemistry Letters. 8(2). 169-174 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 高橋正治: "Proliferative Activity and Micronucleus Frequency after Radiation of Lung Cancer Cells as Assessed by the Cytokinesis-Block Method and their Relationship to Clinical Outcome"Clinical Cancer Research. 4. 677-682 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 芝本雄太: "Absence of Thoracic Radiation Myelitis after Hyperfractionated Radiation Therapy with and without Concurrent Chemotherapy for Stage III Non-Small-Cell Lung Cancer"International Journal of Radiation Oncology・Biology・physics. 40. 343-346 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 芝本雄太: "A Phase I/II Study of a Hypoxic Cell Radiosensitizer KU-2285 in Combination with Intraoperative Radiotherapy"British Journal of Cancer. 76. 1474-1479 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Borosky, G. L.; Nishimoto, S, Pierini, A. B.: "Radical Anions from 5-Fluorouracil Derivatives. A Theoretical Study of their Cleavage and Orbital Isomerism"J. Mol. Struct. THEOCHEM. 499. 151-160 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Shibamoto, Y.; Zhou, L. ;Hatta, H. ; Mori, M.; Nishimoto, S.: "A Novel Class of Antitumor Prodrug, 1-(2-Oxopropyl)-5-Fluorouracil(OFU001) that Releases 5-Fluorouracil upon Hypoxic Irradiation."Jpn. J. Cancer Res. 91, (in press,). (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ito, T.; Shinohara, H.; Hatta, H.; Nishimoto, S.: "Stereoisomeric C5-C5'-Linked Dihydrothymine dimers Produced by Radiolytic One-Electron Reduction of Thymine Derivatives in Anoxic Aqueous Solution: Structural Characteristics in Reference to Cyclobutane Photodimers."J. Org. Chem.. 64. 5100-5108 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ito, T.; Shinohara, H.; Hatta, H.; Fujita, S.; Nishimoto, S: "Radiation-Induced and Photosensitized Splitting of C5-C5'-Linked Dihydrothymine Dimers: Product and Laser Flash Photolysis Studies on the Oxidative Splitting Mechanism."J. Phys. Chem. A. 103. 8413-8420 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Zhou, L.; Ino, A.; Dai, W.-M.; Nishimoto, S: "Evidences for Adduct Formation between Intracellular Non-Protein Thiols and Nitroazoles Possessing an α,β-Unsaturated Carbonyl Side Chain and the Effects on Radiosensitization of Hypoxic Cells."BioMed Chem. 7. 2591-2598 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Dai, W.-M.; Chow, C.-W.; Zhou, L,; Ishii, A.; Lau, C. W.; Li, Q.; Hamaguchi, W.; Nishimoto, S: "Bifunctional 2-Naphthyl Propargylic Sulfones Exhibiting High DNA Intercalating and Alkylating Activity."BioMed Chem. Lett.. 9. 2789-2794 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Dai, W.-M.; Li, Q.; Fong, K.-C.; Law, C.-W.; Zhou, L.; Hamaguchi, W.; Nishimoto, s: "Synthesis and DNA Cleavage Study of a 10-Membered Ring Enediyne Formed via Allylic Rearrangement."J. Org. Chem.. 64. 682-683 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Jeremic, B.; Shibamoto, y.; Milicic, B.; Milisavljevic, s.; Nikolic, N.; Dagovic, A.; Aleksandrovic, J.; Radosavljevic-Asic, G: "A Phase II Study of Concurrent Accelerated Hyperfractionated Radiotherapy and Carboplatin/Oral Etoposide for Elderly Patients with Stage III Non-Small-Cell Lung Cancer"Int. J. Radiat. Oncol. Biolo. Phys. 44. 343-348 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Takagi, T.; Sasai, K.; Shibamoto, Y.; Akagi, K.; Oya, N.; Shibata, T.; Kim. J.; Hiraoka, M: "The influence of DNA Ploidy of a Human Tumor Cell Line on the Frequencies of Micronuclei or Chromosome Aberrations after Irradiation"Mutat. Res.. 418. 49-57 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Morimoto, S.; Hatta, H.; Fujita, s.; Matsuyama, T.; Ueno, T.; Nishimoto, S: "Hydroxyl Radical-Induced Cross-Linking of Thymine and Lysine: Identification of the Orimary Structure and Mechanism"BioMed Chem. Lett. 8. 865-870 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Dai, W.-M.; Li, Q.; Fong, K.-C.; Chow, C.-W.; Zhou, l.; Hamaguchi, W.; Nishimoto, S: "Remarkable Tethering Effect on DNA Cleavage of Propargylic Sulfone Conjugates with Intercalating Moieties"BioMed Chem. Lett. 8. 169-174 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Shibamoto, Y.; Ike, O.; Mizuno, H.; Fukuse, T.; Hitomi, H.; Takahashi, ,: "Proliferative Activity and Micronucleus Frequency after Radiation of Lung Cancer Cells as Assessed by the Cytokinesis-Block Method and their Relationship to Clinical Outcome"Clin. Cancer Res. 4. 677-682 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Jeremic, B.; Shibamoto, Y.; Milicic, B.; Acimovic, l.; Milisavljevic, S: "Absence of Thoracic Radiation Myelitis after Hyperfractionated Radiation Therapy with and without Concurrent Chemotherapy for Stage III Non-Small-Cell Lung Cancer."Int. J. Radiat. Oncol. Biolo. Phys. 40. 343-346 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Shibamoto, Y.; Oshsio, G.; Hosotani, R.; Nishimura, Y.; Manabe, T.; Imamura, M.; Abe, M: "A Phase I/II Study of a Hypoxic Cell Radiosensitizer KU-2285 in Combination with Intraoperative Raditherapy"Br. J. Cancer. 76. 1474-1479 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] 西本清一: "Radical Anions from 5-Fluorouracil Derivatives. A Theoretical Study of their Cleavage and Orbital Isomerism"Journal of Molecular Structure:THEOCHEM. 499・1-3. 151-160 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] 西本清一: "Stereoisomeric C5-C5'-Linked Dihydrothymine Dimers Produced by Radiolytic One-Electron Reduction of Thymine Derivatives in Anoxic Aqueous Solution: Structural Characteristics in Reference to Cyclobutane Photodimers"Journal of Organic Chemistry. 64・14. 5100-5108 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 西本清一: "Radiation-Induced and Photosensitized Splitting of C5-C5'-Linked Dihydrothymine Dimers: Product and Laser Flash Photolysis Studies on the Oxidative Splitting Mechanism"Journal of Physical Chemistry A. 103・42. 8413-8420 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 周 玲: "Evidences for Adduct Formation between Intracellular Non-Protein Thiols and Nitroazoles Possessing an α,β-Unsaturated Carbonyl Side Chain and the Effects on Radiosensitization of Hypoxic Cells"Bioorganic & Medicinal Chemistry. 7. 2591-2598 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 周 玲: "Bifunctional 2-Naphthyl Propargylic Sulfones Exhibiting High DNA Intercalating and Alkylating Activity"Bioorganic & Medicinal Chemistry Letters. 9. 2789-2794 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 芝本雄太: "A Novel Class of Antitumor Prodrug, 1-(2-Oxopropyl)-5-Fluorouracil (OFU001) that Releases 5-Fluorouracil upon Hypoxic Irradiation"Japanese Journal of Cancer Research. 91・4(印刷中). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] 西本精一: "Stereoisomeric C5-C5′-Linked Dihydrothymine Dimers produced by Radiolytic One-Electron Reduction of Thymine Derivatives in Anoxic Aqueous Solution : Structural Characteristics in Reference to Cyclobutane Photodimers" Journal of Organic Chemistry. 64(受理). (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] 周 玲: "Synthesis and DNA Cleavage Study of a 10-Membered Ring Enediyne Formed via Allylic Rearrangement" Journal of Organic Chemistry. 64・3. 682-683 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] 芝本雄太: "The influence of DNA Ploidy of a Human Tumor Cell Line on the Frequencies of Micronuclei or Chromosome Aberrations after Irradiation" Mutatation Research. 418. 49-57 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 芝本雄太: "A Phase II Study of Concurrent Accelerated Hyperfractionated Radiotherapy and Carboplatin/Oral Etoposide for Elderly Patients with Stage III Non-Small-Cell Lung Cancer" International Journal of Radiation Oncology-Biology・Physics. 43(印刷中). (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] 西本清一: "Hydroxyl Radical-Induced Cross-Linking of Thymine and Lysine : Identification of the Orimary Structure and Mechanism" Bioorganic & Medicinal Chemistry Letter. 8. 印刷中 (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] 周 玲: "Remarkable Tethering Effect on DNA Cleavage of Propargylic Sulfone Conjugates with Intercalating Moieties" Bioorganic & Medicinal Chemistry Letter. 8・2. 169-174 (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] 高橋正治: "Proliferative activity and micronucleus frequency after radiation of lung cancer cells assessed by the cytokinesis-block method and their relationship to clinical outcome" Clinical Cancer Research. 4. 677-682 (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] 高橋正治: "Oral vehicle administration before radiation causes radioprotection of murine SCCVII tumors" Oncology Report. 4. 787-789 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] 芝本雄太: "Absence of thoracic radiation myelitis after hyperfractionated radiation therapy with and without concurrent chemotherapy for Stage III non-small-cell lung cancer" International Journal of Radiation Oncology・Biology・Physics. 40. 343-346 (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] 芝本雄太: "A phase I/II study of a hypoxic cell radiosensitizer KU-2285 in combination with intraoperative radiotherapy" British Journal of Cancer. 76. 1474-1479 (1997)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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