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Basic studies on combination of new hypoxic cell sensitizers and intraoperative radiotherapy for unresectable pancreatic cancer

Research Project

Project/Area Number 11470190
Research Category

Grant-in-Aid for Scientific Research (B).

Allocation TypeSingle-year Grants
Section一般
Research Field Radiation science
Research InstitutionKYOTO UNIVERSITY

Principal Investigator

SHIBAMOTO Yuta  Kyoto University, Graduate School of Medicine, Associate Professor, 医学研究科, 助教授 (20144719)

Co-Investigator(Kenkyū-buntansha) KOKUBO Masaki  Kyoto University, Graduate School of Medicine, Assistant Professor, 医学研究科, 助手 (90283605)
SASAI Keisuke  Kyoto University, Graduate School of Medicine, Associate Professor, 医学研究科, 助教授 (20225858)
Project Period (FY) 1999 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 2000: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 1999: ¥2,000,000 (Direct Cost: ¥2,000,000)
KeywordsRadiosensitizer / Hypoxic cell sensitizer / Pancreatic Cancer / Intraoperative radiotherapy / Daranidazole
Research Abstract

We investigated the radiosensitivity and hypoxic fraction of human pancreatic cancer cells xenografted in nude mice, and the efficacy of a new hypoxic cell radiosensitizer doranidazole against them. Although a clinical study of doranidazole in combination with intraoperative radiotherapy is ongoing in Japan for localized unresectable pancreatic cancer, few data have been reported on these issues.
In vitro, four established human pancreatic cancer cell lines (SUIT-2, PANC-1, MIA PaCa-2 and BxPC-3) and murine SCCVII tumor cells (for comparison) were used. These cells were treated with 0.4 or 1 mM doranidazole for 45 min prior to and during aerobic or hypoxic irradiation, and the cell survival was determined using the colony assay. In vivo, Balb/c nude mice bearing the pancreatic cancers (about 200 mg) on their backs received whole-body irradiation either after cervical dislocation, without physical restraint or anesthesia, or 20 min after intravenous injection of 100 mg/kg (0.4 mmol/kg) o … More r 250 mg/kg (1 mmol/kg) of doranidazole. Following irradiation, the in vivo-in vitro assay was performed. The hypoxic fraction was estimated by the paired survival curve method.
Regarding in vitro radiosensitivity, there were no characteristics common to the four pancreatic cancer cell lines. In vitro, doranidazole had no sensitizing effect under aerobic conditions, but under hypoxic conditions, its sensitizer enhancement ratio (SER) was 1.25-1.3 at 0.4 mM and 1.4-1.55 at 1 mM against the four pancreatic cancer cell lines. These SERs were similar to those obtained in SCCVII cells. In vivo, the hypoxic fraction was 20% (95% CI, 11-38%) in SUIT-2, 14% (6.5-28%) in PANC-1, 10% (5.9-16%) in MIA PaCa-2, and 27% (15-46%) in BxPC-3 tumors. The SER of doranidazole was 1.15-1.3 at the dose of 100 mg/kg and 1.35-1.45 at 250 mg/kg.
In summary, the four xenografted pancreatic cancers had hypoxic fractions of 10-27% (mean : 18%). These results might suggest that the use of a hypoxic cell sensitizer is reasonable in intraoperative radiotherapy for unresectable pancreatic cancer. Doranidazole had definite in vitro and in vivo effects on all pancreatic cancer cell lines, but the SERs were not high enough. Dose escalation should be investigated in future clinical studies. Less

Report

(3 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • Research Products

    (18 results)

All Other

All Publications (18 results)

  • [Publications] Kanamuri S,Shibamoto Y 他: "Tumor response and patterns of failure following intraperative radiotherapy for unresatable pancreatic cancer. Evaluation by computed tomography"Acta Oncologica. 38. 215-220 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Matsuoka H,Shibamoto 他: "In vivo efficacy and pharmacokinetics of a new hypoxic cell radiosensitizer doranidazole in SUIT-2 human pancreatic cancer Xenografted in mouse pancreas"Oncology Reports. 7. 23-26 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kokubo M,Shibamoto Y 他: "Concurrent chemoradiotherapy combined with intraoperative radiotherapy for locally advanced pancreatic cancer : a feasibility study"Oncology Reports. 7. 773-776 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Shibamoto Y 他: "Radiosensitivity of human pancreatic cancer cells in vitro and in vivo and the effect of a new hypoxic cell sensitizer, doranidazole"Radiotherapy and Oncology. 56. 265-270 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kokubo M,Shibamoto Y 他: "Analysis of the clinical benefit of intraoperative radiotherapy in patients undergoing macroscopically curative resection for pancreatic cancer"International Journal of Radiation Oncology Biology physics. 48. 1081-1087 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nemoto K,Shibamoto Y 他: "A phase Ia study of a hypoxic cell sensitizer doranidazole (RP-350) in combination with conventional radiotherapy"Anti-Cancer Drugs. 12. 1-6 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kanamori S, Nishimura Y, Kokubo M, Sasai K, Hiraoka M, Shibamoto Y, Hosotani R, Imamura M, Abe M: "Tumor response and patterns of failure following intraoperative radiotherapy for unresectable pancreatic cancer. Evaluation by computed tomography."Acta Oncol. 38. 215-220 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Matsuoka H, Shibamoto Y, Kubota T, Tsujitani M, Majima T: "In vivo efficacy and pharmacokinetics of a new hypoxic cell radiosensitizer doranidazole in SUIT-2 human pancreatic cancer xenografted in mouse pancreas."Oncol Rep. 7. 23-26 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kokubo M, Nishimura Y, Shibamoto Y, Sasai K, Hosotani R, Imamura M, Hiraoka M: "Concurrent chemoradiotherapy combined with intraoperative radiotherapy for locally advanced pancreatic cancer : a feasibility study."Oncol Rep. 7. 773-776 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Shibamoto Y, Kubota T, Kishii K, Tsujitani M: "Radiosensitivity of human pancreatic cancer cells in vitro and in vivo, and the effect of a new hypoxic cell sensitizer, doranidazole."Radiother Oncol. 56. 265-270 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Kokubo M, Nishimura Y, Shibamoto Y, Sasai K, Kanamori S, Hosotani R, Imamura M, Hiraoka M: "Analysis of the clinical benefit of intraoperative radiotherapy in patients undergoing macroscopically curative resection for pancreatic cancer."Int J Radiat Oncol Biol Phys. 48. 1081-1087 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Nemoto K, Shibamoto Y, Ohmagari J, Baba Y, Ebe E, Ariga H, Takai Y, Ouchi A, Sasai K, Shinozaki M, Tsujitani M, Sakaguchi M, Yamada S, Sakamoto K.: "A phase Ia study of a hypoxic cell sensitizer doranidazole (PR-350) in combination with conventional radiotherapy."Anti-Cancer Drugs. 12. 1-6 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Shibamoto Y 他: "Radiosensitivity of human pancreatic cancer cells in vitro and in vivo, and the effect of a new hypoxic cell sensitizer, doranidazole"Radiotherapy and Oncology. 56・2. 265-270 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kokubo M,Shibamoto Y 他: "Analysis of the clinical benefic of intraoperative radiotherapy in patients undergoing maeroscopically curative resection for pancreatic cancer"International Journal of Rediation Oncology Biology Physics. 48・4. 1081-1087 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Nemoto K,Shibamoto Y 他: "A phase In study of a hypoixic cell sensitizer doranidazole (PR-350) in combination with conventional rediotherapy"Anti-Cancer Drugs. 12・1. 1-6 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Shibamoto Y. 他: "Systemic chemotherapy with vincristine, cyclophosphamide, doxorubicin and prednisolone following radiotherapy for primary central nervous system lymphona: a Phese II study"Journal of Neuro-Oncology. 42・2. 161-167 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Matsuoka H.,Shibamoto Y. 他: "In vivo efficacy and pharmacokinetics of a new hypoxic cell rodiosensitizer doranidazole in SUIT-2 human pancreatic cancer xenografted in mouse pancreas"Oncology Reports. 7・1. 23-26 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Kanamori S.,Shibamoto Y. 他: "Tumor response and patterns of failure following intraoperative radiotherapy for unresectable pancreatic cancer. Evaluation by computed tomography"Acta Oncologica. 38・2. 215-220 (1999)

    • Related Report
      1999 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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