放射線照射ならびに温熱に対するストレス応答機構の基礎的解析

• 研究課題/領域番号: 13218015
• 研究種目: 特定領域研究
• 配分区分: 補助金
• 審査区分: 生物系
• 研究機関: 群馬大学
• 研究代表者: 桜井 英幸 群馬大学, 大学院・医学系研究科, 講師 (50235222)
• 研究分担者: 北本 佳住 群馬大学, 医学部, 助手 (20334097) ; 鈴木 義行 群馬大学, 大学院・医学系研究科, 助手 (60334116) ; 石川 仁 群馬大学, 放射線・医学総合研究所, 研究員 (70344918)
• 研究期間 (年度): 2001 – 2004
• 研究課題ステータス: 完了 (2004年度)
• 配分額: 26,000千円 (直接経費: 26,000千円); 2004年度: 6,900千円 (直接経費: 6,900千円); 2003年度: 6,900千円 (直接経費: 6,900千円); 2002年度: 6,100千円 (直接経費: 6,100千円); 2001年度: 6,100千円 (直接経費: 6,100千円)
• キーワード: 放射線 / 温熱 / 熱耐性 / 熱耐性タンパク / 放射線増感 / 低酸素 / 熱耐性蛋白 / 増感 / 肺癌 / 耐熱性 / p53 / HSP

研究概要

放射線照射と温熱による増感機構について解析するとともに,細胞のもつストレス応答シグナルの抑制が,放射線の効果をどのように修飾するかを明らかにすることにより,放射線照射と温熱の有効な併用方法とその分子生物学的機構を解析することを目的とした.また,放射線照射ならびに温熱の効果に影響を与える低酸素ストレスについて,その意義と治療効果への影響を明らかにすることを目的とした.
実験腫瘍を用いた研究では,熱耐性の抑制や放射線照射からの亜致死障害からの回復阻害など,放射線と温熱には互いにその効果を高める機構が存在すると考えられた.薬剤により熱耐性を抑制することにより,温熱の効果のみならず,放射線と温熱の併用効果も増強することが明らかとなった.熱耐性抑制による増感の機序は,HSPの発現抑制と熱感受性のS期細胞の増加が関与していた.臨床では,胸壁浸潤型肺癌や進行直腸癌,難治性肉腫などにおいて,放射線と温熱の併用が有用であることを明らかにした.放射線と温熱の効果に重大な影響を与える低酸素腫瘍の解析においては,子宮頸癌と食道癌を用いて,HIF-1,p53,p21,BAXなどの因子を解析し,HIF-1の高発現が治療効果に影響することを明らかにした.治療前の腫瘍の低酸素状態の非侵襲的定量化が重要な研究課題と考えられたため,種々の低酸素評価法を実験腫瘍を用いて試みた.電極を腫瘍内に挿入し直接酸素濃度を測定する方法や,31P-MRSなどの方法と比較して,低酸素細胞マーカーであるβ-D-IAZGPは,副作用も軽微で,腫瘍の大きさにかかわらず,その取り込みが評価可能であり,臨床上も有用性が高いと考えられた.臨床的な評価としては,子宮頸癌の酸素分圧の低下が実際の治療効果と相関することを明らかにした.また,癌細胞の生存シグナルが腫瘍の悪性度に関係し,シグナルの抑制が治療効果増強につながる可能性があることを見出した.

研究成果

• [雑誌論文] CT-fluoroscopy guided interstitial brachytherapy with image-based treatment planning for unresectable locally recurrent rectal carcinoma (2004)
  • 著者名/発表者名: Sakurai H et al.
  • 雑誌名: Brachytherapy 3 ページ: 220-230
• [雑誌論文] A 104-year-old woman with advanced cervical carcinoma of the uterus (2004)
  • 著者名/発表者名: Sakurai H et al.
  • 雑誌名: Gyn Oncol 92 ページ: 713-715
• [雑誌論文] The prognostic significance of phosphatidylinositol 3-kinase pathway activation in human gliomas (2004)
  • 著者名/発表者名: Chakravarti A et al.
  • 雑誌名: J Clin Oncol 22 ページ: 1926-1933
• [雑誌論文] Expression of hypoxic-inducible factor 1 predicts metastasis-free survival after radiation therapy alone in stage IIIB cervical squamous cell carcinoma (2004)
  • 著者名/発表者名: Ishikawa H et al.
  • 雑誌名: Int J Radiat Oncol Biol Phys 60 ページ: 513-521
• [雑誌論文] Pre-treatment evaluation of combined HIF-1 alpha, p53,and p21 expression is a useful and sensitive indicator of response to radiation and chemotherapy in esophageal cancer (2004)
  • 著者名/発表者名: Sohda M et al.
  • 雑誌名: Int J Cancer 110 ページ: 838-844
• [雑誌論文] Radicicol potentiates heat-induced cell killing in a human oesophageal cancer cell line : the Hsp90 chaperone complex as a new molecular target for enhancement of thermosensitivity. (2004)
  • 著者名/発表者名: Akimoto T et al.
  • 雑誌名: Int J Radiat Biol 80 ページ: 483-492
• [雑誌論文] Selective inhibition of survival signal transduction pathways enhanced radiosensitivity in human esophageal cancer cell lines in vitro (2004)
  • 著者名/発表者名: Akimoto T et al.
  • 雑誌名: Anticancer Res 24 ページ: 811-819
• [雑誌論文] A case of rhabdomyosarcoma of the vagina in an elderly woman (2004)
  • 著者名/発表者名: Suzuki Y et al.
  • 雑誌名: Eur j Gyn Oncol. 25 ページ: 509-511
• [雑誌論文] Immunohistochemical study of cell cycle associated proteins in adenocarcinoma of the uterine cervix treated with radiation therapy alone : p53 status has a strong impact on prognosis (2004)
  • 著者名/発表者名: Suzuki Y et al.
  • 雑誌名: Int J Radiat Oncol Biol Phys 60 ページ: 231-236
• [雑誌論文] Radiation therapy induces the p53(+)p21(-) expression in squamous cell carcinomas of the uterine cervix (2004)
  • 著者名/発表者名: Oka K et al.
  • 雑誌名: Gynecol Oncol. 93 ページ: 340-344
• [雑誌論文] Comparable outcomes of radiation therapy without high-dose methotrexate for patients with primary central nervous system lymphoma (2003)
  • 著者名/発表者名: Ishikawa H et al.
  • 雑誌名: Jpn J Clin Oncol 33 ページ: 443-449
• [雑誌論文] Treatment results of radiotherapy for malignant lymphoma of the orbit and histopathologic review according to the WHO classification (2003)
  • 著者名/発表者名: Hasegawa M et al.
  • 雑誌名: Int J Radiat Oncol Biol Phys 57 ページ: 172-176
• [雑誌論文] Caffeine diminishes cytotoxic effects of paclitaxel on a human lung adenocarcinoma cell line (2003)
  • 著者名/発表者名: Kitamoto Y et al.
  • 雑誌名: Cancer Letter 191 ページ: 101-107
• [雑誌論文] Effect of hyperthermia combined with external radiation therapy in primary non-small lung cancer with direct bony invasion (2003)
  • 著者名/発表者名: Sakurai H et al.
  • 雑誌名: Int J Hyperthermia 18 ページ: 472-483
• [雑誌論文] Correlation between in vivo tumor weight, oxygen pressure, 31P NMR spectroscopy, hypoxic microenvironment marking by β-D-iodinated azomycin galactopyranoside(β-D-IAZGP), and radiation sensitivity (2002)
  • 著者名/発表者名: Saitoh J-I et al.
  • 雑誌名: Int J Radiat Oncol Biol Phys 54 ページ: 903-909
• [雑誌論文] Combined effect of hyperthermia at 42℃ and irradiation dose of 2 Gy on two rat yolk sac tumor cell lines with different radiothermosensitivity in vitro (2002)
  • 著者名/発表者名: Tamaki Y et al.
  • 雑誌名: Anticancer Res 22 ページ: 3143-3148
• [雑誌論文] Signal transduction pathway to low-dose radiation-induced apoptosis in peripheraql PNET cells (2002)
  • 著者名/発表者名: Imai R et al.
  • 雑誌名: Anticancer Res 22 ページ: 2741-2748
• [雑誌論文] Heat shock protein 90(Hsp90) chaperone complex : A molecular target for enhancement of thermosensitivity and radiosensitivity (2002)
  • 著者名/発表者名: Akimoto T et al.
  • 雑誌名: Jpn J Hyperthermic Oncol 18 ページ: 131-142
• [雑誌論文] Analysis of recurrence of squamous cell carcinoma of the uterine cervix after definitive radiation therapy alone -patterns of recurrence, latent periods and prognosis- (2001)
  • 著者名/発表者名: Sakurai H et al.
  • 雑誌名: Int.J.Radiat.Oncol.Biol.Phys 50 ページ: 1136-1144
• [雑誌論文] Clinical application of low dose-rate brachytherapy combined with simultaneous mild temperature hyperthermia (2001)
  • 著者名/発表者名: Sakurai H et al.
  • 雑誌名: Anticancer Res 21 ページ: 679-684
• [雑誌論文] A challenge for Non-small cell lung cancer using hyperthermia (2001)
  • 著者名/発表者名: Sakurai H et al.
  • 雑誌名: Jpn.J.Hyperthermic Oncol 17 ページ: 23-31
  • NAID: 10029675025
• [雑誌論文] Genistein, a tyrosine kinase inhibitor, enhanced radiosensitivity in human esophageal cancer cell lines in vitro : possible involvement of inhibition of survival signal transduction pathways (2001)
  • 著者名/発表者名: Akimoto T et al.
  • 雑誌名: Int.J.Radiation Oncology Biol.Phys 50 ページ: 195-201
• [雑誌論文] The effects of p53 status and human papillomavirus infection on the clinical outcome of patients with stage IIIB cervical carcinoma treated with radiation therapy alone (2001)
  • 著者名/発表者名: Ishikawa H et al.
  • 雑誌名: Cancer 91 ページ: 80-89
• [雑誌論文] High-dose radiation therapy for elderly patients with inoperable or unresectable non-small cell lung canner (2001)
  • 著者名/発表者名: Hayakawa K et al.
  • 雑誌名: Lung Cancer 32 ページ: 81-88
• [雑誌論文] Hyperthermia-induced apoptosis in two rat yolk sac tumor cell lines with different radiothermosensitivity in vitro (2001)
  • 著者名/発表者名: Islam MS et al.
  • 雑誌名: Oncology Reports 8 ページ: 501-507
• [雑誌論文] Biological cell survival mapping for radiofrequency intracavitary hyperthermia combined with simultaneous high dose-rate intracavitary irradiation (2001)
  • 著者名/発表者名: Kurosaki H et al.
  • 雑誌名: Jpn.J.Cancer Res 92 ページ: 95-102
• [雑誌論文] Clinical Outcomes and Prognostic Factors for Patients with Early Esophageal Squamous Cell Carcinoma Treated with Definitive Radiation Therapy Alone
  • 著者名/発表者名: Ishikawa H et al.
  • 雑誌名: J Clin Gastroenterol (in press)
• [雑誌論文] Oxygenated and reoxygenated tumors show better local control in radiation therapy for cervical cancer
  • 著者名/発表者名: Suzuki Y et al.
  • 雑誌名: Int J Gynecol Cancer (in press)
• [文献書誌] Sohda M: "Pretreatment evaluation of combined HIF-1alpha, p53, and p21 expression is a useful and sensitive indicator of response to radiation and chemotherapy in esophageal cancer"Int J Cancer. (in press).
• [文献書誌] Sakurai H: "A 104-year-old woman with advanced cervical carcinoma of the uterus"Gyn Oncol. 92・2. 713-715 (2004)
• [文献書誌] Suzuki Y: "A case of rhabdomyosarcoma of the vagina in an elderly woman"Eur J Gyn Oncol. (in press).
• [文献書誌] Saitoh J-I: "A persistent retroperitoneal synovial sarcoma -Effect of hyperthermia alone-"Jpn J Hyperthermic Oncology. (in press).
• [文献書誌] Ishikawa H: "Comparable outcomes of radiation therapy without high-dose methotrexate for patients with primary central nervous system lymphoma"Jpn J Clin Oncol. 33・9. 443-449 (2003)
• [文献書誌] Hasegawa M: "Treatment results of radiotherapy for malignant lymphoma of the orbit and histopathologic review according to the WHO classification"Int J Radiat Oncol Biol Phys. 57・1. 172-176 (2003)
• [文献書誌] Kitamoto Y: "Caffeine diminishes cytotoxic effects of paclitaxel on a human lung adenocarcinoma cell line"Cancer Letter. 191. 101-107 (2003)
• [文献書誌] Sakurai H: "Effect of hyperthermia combined with external radiation therapy in primary non-small lung cancer with direct bony invasion"Int J Hyperthermia.. 18・5. 472-483 (2002)
• [文献書誌] Saitoh J-I: "Correlation between in vivo tumor weight, oxygen pressure, 31P NMR spectroscopy, hypoxic microenvironment marking by β-D-iodinated azomycin galactopyranoside(β-D-IAZGP), and radiation sensitivity"Int J Radiat Oncolo Biol Phys. 54・3. 23-31 (2001)
• [文献書誌] Tamaki Y: "Combined effect of hyperthermia at 42℃ and irradiation dose of 2 Gy on two rat yolk sac tumor cell lines with different radiothermosensitivity in vitro"Anticancer Res. 22. 3143-3148 (2002)
• [文献書誌] Imai R: "Signal transduction pathway to low-dose radiation-induced apoptosis in peripheraql PNET cells"Anticancer Res. 22. 2741-2748 (2001)
• [文献書誌] Sakurai H: "Analysis of recurrence of squamous cell carcinoma of the uterine cervix after definitive radiation therapy alone patterns of recurrence, latent periods and prognosis"Int.J.Radiat.Oncol.Biol.Phys.. 50・5. 1136-1144 (2001)
• [文献書誌] Sakurai H: "Clinical application of low dose-rate brachytherapy combined with simultaneous mild temperature hyperthermia"Anticancer Res. 21. 679-684 (2001)
• [文献書誌] Sakurai, H: "A challenge for Non-small cell lung cancer using hyperthermia"Jpn.J.Hyperthermic Oncol. 17・1. 23-31 (2001)
• [文献書誌] Akimoto, T: "Genistein, a tyrosine kinase inhibitor, enhanced radiosensitivity in human esophageal cancer cell lines in vitro : possible involvement of inhibition of survival signal transduction pathways"Int.J.Radiation Oncology Biol.Phys.. 50・1. 195-201 (2001)
• [文献書誌] Ishikawa H: "The effects of p53 status and human papillomavirus infection on the clinical outcome of patients with stage IIIB cervical carcinoma treated with radiation therapy Alone"Cancer. 91・1. 80-89 (2001)
• [文献書誌] Hayakawa, K: "High-dose radiation therapy for elderly patients with inoperable or unresectable non- small cell lung cancer"Lung Cancer. 32. 81-88 (2001)
• [文献書誌] Kurosaki H: "Biological cell survival mapping for radiofrequency intracavitary hyperthermia combined with simultaneous high dose-rate intracavitary irradiation"Jpn.J.Cancer Res. 92・1. 95-102 (2001)
• [文献書誌] Kitamoto Y: "Caffeine diminishes cytotoxic effects of paclitaxel on a human lung adenocarcinoma cell line"Cancer Letter. 191・1. 101-7 (2003)
• [文献書誌] Sakurai H: "Effect of hyperthermia combined with external radiation therapy in primary non-small lung cancer with direct bony invasion"Int J Hyperthermia. 18・5. 472-483 (2002)
• [文献書誌] Akimoto T: "Heat shock protein 90(Hsp90) chaperone complex : A molecular target for enhancement of thermosensitivity and radiosensitivity"Jpn J Hyperthermic Oncol.. 18. 131-142 (2002)
• [文献書誌] Saitoh J-I: "Correlation between in vivo tumor weight, oxygen pressure, 31P NMR spectroscopy, hypoxic microenvironment marking by β-D-iodinated azomycin galactopyranoside(β-D-IAZGP), and radiation sensitivity"Int J Radiat Oncol Biol Phys. 54・3. 903-909 (2002)
• [文献書誌] Tamaki Y: "Combined effect of hyperthermia at 42℃ and irradiation dose of 2 Gy on two rat yolk sac tumor cell lines with different radiothermosensitivity in vitro"Anticancer Res. 22. 3143-8 (2002)
• [文献書誌] Imai R: "Signal transduction pathway to low-dose radiation-induced apoptosis in peripheraql PNET cells"Anticancer Res. 22. 2741-8 (2002)
• [文献書誌] Sakurai H: "Analysis of recurrence of squamous cell carcinoma of the uterine cervix after definitive radiation therapy alone -patterns of recurrence, latent periods and prognosis-"Int. J. Radiat. Oncol. Biol. Phys.. 50・5. 1136-1144 (2001)
• [文献書誌] Sakurai H: "Clinical application of low dose-rate brachytherapy combined with simulataneous mild temperature hyperthermia"Anticancer Res.. 21. 679-684 (2001)
• [文献書誌] Sakurai H: "A challenge for Non-small cell lung cancer using hyperthermia"Jpn. J. Hyperthermic Oncol.. 171. 23-31 (2001)
• [文献書誌] Akimoto T: "Genistein, a tyrosine kinase inhibitor, enhanced radiosensitivity in human esophageal cancer cell lines in vitro : possible involvement of inhibition of survival signal transduction pathways"Int. J. Radiat. Oncol. Biol. Phys.. 50・1. 195-201 (2001)
• [文献書誌] Ishikawa H: "The effects of p53 status and human papillomavirus infection on the clinical outcome of patients with stage IIIB cervical carcinoma treated with radiation therapy alone"Cancer. 91・1. 80-89 (2001)
• [文献書誌] Hayakawa K: "High-dose radiation therapy for elderly patients woth inoperable or unresectable non-small cell lung cancer"Lung Cancer. 32. 81-88 (2001)
• [文献書誌] Islam MS: "Hyperthermia-induced apoptosis in two rat yolk sac tumor cell lines with different radiothermosensitivity in vitro"Oncology Reports. 8. 501-407 (2001)
• [文献書誌] Kurosaki H: "Biological cell survival mapping for radiofrequency intracavitary hyperthermia combined with simultaneous high dose-rate intracavitary irradiation"Jpn. J. Cancer Res. 92・1. 95-102 (2001)
• [文献書誌] Tsukiyama I: "Multi-institutional phase I and II trial of simultaneous intra-cavitary hyperthermia and brachytherapy for advanced esophageal cancer"J Brachytherapy International. 17. 299-308 (2001)
• [文献書誌] Imai R: "Small cell lung cancer with a brain metastasis controlled for 5 years : a case report"Jpn J Clin Oncol. 31・3. 116-118 (2001)
• [文献書誌] Fujita K: "The combined effect of preoperative hyperthermia and radiation therapy on advanced rectal cancer"Jpn J of Hyperthermic Oncol.. 17・3. 151-159 (2001)
• [文献書誌] Mogi A: "Intrathoracic thermochemotherapy for the treatment of post-operative malignant pleural effusion in primary lung carcinoma-Report of a cese"Jpn J OF Hyperthermic Oncol.. 17・3. 159-164 (2001)
• [文献書誌] Sakurai H: "Analysis of recurrence of squamous cell carcinoma of the uterine cervix after definitive radiation therapy alone patterns of recurrence, latent periods and prognosis"Int. J. Radiat. Oncol. Biol. Phys.. 50・5. 1136-1144 (2001)
• [文献書誌] Sakurai H: "Clinical application of low dose-rate brachytherapy combined with simultaneous mild temperature hyperthermia"Anticancer Res.. 21. 679-684 (2001)
• [文献書誌] Sakurai H: "A challenge for Non-small cell lung cancer using hyperthermia"Jpn. J. Hyperthermic Oncol.. 171. 23-31 (2001)
• [文献書誌] Akimoto T: "Genistein, a tyrosine kinase inhibitor, enhanced radiosensitivity in human esophageal cancer cell lines in vitro : possible involvement of inhibition of survival signal transduction pathway"Int. J. Radiat. Oncol. Biol. Phys.. 50・1. 195-201 (2001)
• [文献書誌] Ishikawa H: "The effects of p53 status and human papillomavirus infection on the clinical outcome of patients with stage IIIB cervical carcinoma treated with radiation therapy alone"Cancer. 91・1. 80-89 (2001)
• [文献書誌] Hayakawa K: "High-dose radiation therapy for elderly patients woth inoperable or unresectable non-small cell lung canner"Lung Cancer. 32. 81-88 (2001)
• [文献書誌] Islam MS: "Hyperthermia-induced apoptosis in two rat yolk sac tumor cell lines with different radiothermosensitivity in vitro"Oncology Reports. 8. 501-407 (2001)
• [文献書誌] Kurosaki H: "Biological cell survival mapping for radiofrequency intracavitary hyperthermia combined with simultaneous high dose-rate intracavitary irradiation"Jpn. J. Cancer Res. 92・1. 95-102 (2001)
• [文献書誌] Tsukiyama I: "Multi-institutional phase I and II trial of simultaneous intra-cavitary hyperthermia and brachytherapy for advanced esophageal cancer"J Brachytherapy International. (in press).
• [文献書誌] Imai R: "Small cell lung cancer with a brain metastasis controlled for 5 years : a case report"Jpn J Clin Oncol. 31・3. 116-118 (2001)
• [文献書誌] Fujita K: "The combined effect of preoperative hyperthermia and radiation therapy on advanced rectal cancer"Jpn J of Hyperthermic Oncol.. 17・3. 151-159 (2001)
• [文献書誌] Mogi A: "Intrathoracic thermochemotherapy for the treatment of post-operative malignant pleural effusion in primary lung carcinoma-Report of a cese"Jpn J of Hyperthermic Oncol.. 17・3. 159-164 (2001)