2000 Fiscal Year Annual Research Report

癌抑制遺伝子導入による放射線・温熱治療の増感

Research Project

Project/Area Number	12470189
Research Institution	Nara Medical University
Principal Investigator	大西武雄奈良県立医科大学, 医学部, 教授 (60094554)
Keywords	遺伝子治療 / p53 / 放射線 / 温熱 / 抗癌剤 / アポトーシス / 遺伝子導入 / DNAラダー
Research Abstract	【目的】p53蛋白質は細胞に与えられたストレスに応じて活性化されアポトーシスを誘導する。このp53蛋白質の働きを利用することにより効率の良い癌治療が期待できる。従ってp53細胞あるいはp53遺伝子欠損細胞に対しては、正常型p53遺伝子導入と放射線・温熱・抗癌剤との併用が治療効果の向上につながる。本研究では過剰発現させたp53を放射線・温熱・抗癌剤により活性化し効率良くアポトーシスを誘導し癌細胞を殺すことを目的とした。【方法】変異型p53保有ヒト甲状腺未分化癌8305c細胞に温度感受性変異型p53(codon 143,Val→Ala)を導入し、32℃培養条件で正常型p53蛋白質を過剰発現させた場合と37℃培養条件で変異型p53蛋白質を過剰発現させた場合で放射線・温熱・CDDP感受性をコロニー形成法で比較した。また、ヘキスト染色法及びDNA ladder検出法でアポトーシスの解析を行った。【結果】8305c細胞を32℃培養条件で正常型p53蛋白質を過剰発現させた場合、放射線・温熱・CDDP感受性が高くなり、アポトーシス小体の経時的な増加とDNAラダーの出現が認められた。【考察】32℃培養条件で見られた放射線・温熱・CDDPによるアポトーシス増強はp53遺伝子導入により過剰発現させた正常型p53蛋白質が内在する変異型p53蛋白質に対しドミナントに働いたためと思われる。【結論】変異型p53を持つあるいはp53遺伝子欠損癌細胞においても、p53遺伝子導入により正常型p53蛋白質が持つ機能を発揮させ、正常型p53蛋白質を持つ癌細胞と同程度の放射線・温熱・抗癌剤による殺細胞効果が期待できる可能性が示唆された。

Research Products
(19 results)

All Other

All Publications (19 results)

[Publications] Harima,Y., et al.: "Polymorphism of the WAF1 gene is related to susceptibility to cervical cancer in Japanese women."Int.J.Mol.Medicine. (in press). (2001)
[Publications] Harima,Y., et al.: "Mutation of the PTEN gene in advanced cervical cancer correlated with tumor progression and poor outcome after radiotherapy."Int.J.Oncol.. (in press). (2001)
[Publications] Matsumoto,H., et al.: "Induction of radioresistance by a nitric oxide-mediated bystander effect."Radiat. Res.. 155. 387-396 (2001)
[Publications] Ohnishi,K., et al.: "Glycerol restores p53 dependent radiosensitivity of human head and neck cancer cells bearing mutant."Br.J.Cancer. 83. 1735-1739 (2000)
[Publications] Kubota,N., et al.: "Wortmannin sensitizes human glioblastoma cell lines carrying mutant or wild type TP53 gene to radiation."Cancer Lett.. 161. 141-147 (2000)
[Publications] Oka,A., et al.: "Determination of p53-mediated transactivationl ability in radiation-treated cervical cancer."Cencer Detect.Prevent.. 24. 275-282 (2000)
[Publications] Kanata,H., et al.: "CDDP induces p53-dependent apotosis in tongue cancer cells."Int.J.Oncol.. 17. 513-518 (2000)
[Publications] Xie,X., et al.: "p53 status plays no role in radiosensitizing effects of SN-38, a camptothecin derivative."Cancer Chemother.Pharmacol.. 45. 362-368 (2000)
[Publications] Ohnishi,T., et al.: "Heat-induced accumulation of p53 and hsp72 is suppressed in lung fibroblasts from SCID mouse."Int.J.Radiat.Biol.. 76. 711-715 (2000)
[Publications] Ota,I., et al.: "Transfection with mutant p53 gene inhibits heat-induced apoptosis in a head and neck cell line of human squamous cell carcinoma."Int.J.Radiat.Oncol.Biol.Phys.. 47. 495-501 (2000)
[Publications] Takahashi,A., et al.: "The dependence of p53 on the radiation enhancement of thermosensitivity at different LET."Int.J.Radiat.Oncol.Biol.Phys.. 47. 489-494 (2000)
[Publications] Takahashi,A., et al.: "Induction of WAF1 accumulation by carbon-ion beam and α-particle irradiation in human glioblastoma cultured cells."Int.J.Radiat.Biol.. 76. 335-341 (2000)
[Publications] Ohtsubo,T., et al.: "Effect of acidic environment and p53 on apoptosis induction by hyperthermia."Int.J.Hyperthermia. 16. 481-491 (2000)
[Publications] Matsumoto,H., et al.: "Induction of radioresistance to accelerated carbon-ion beams in recipient cells by nitric oxide excreted from irradiated cells of human glioblastoma."Int.J.Radiat.Biol.. 76. 1649-1657 (2000)
[Publications] Matsumoto,H., et al.: "Interactive effects of nitric oxide and p53 on cellular thermosensitivity."Jpn.J.Hyperthermic Oncol.. 16. 69-82 (2000)
[Publications] Harima,Y., et al.: "Loss of heterozygosity on chromosome 6p21.2 as a potential marker for recurrence after radiotherapy of human cervical cancer."Clinical Cancer Res.. 6. 1079-1085 (2000)
[Publications] Harima,Y., et al.: "Bax and Bcl-2 protein expression following radiation therapy versus radiation plus thermoradiotherapy in stage IIIb cervical carcinoma."Cancer. 88. 131-137 (2000)
[Publications] 太田一郎他: "癌放射線療法2000"篠原出版(印刷中). (2001)
[Publications] 桐田忠昭他: "脳の科学"星和書店(印刷中). (2001)

2000 Fiscal Year Annual Research Report

癌抑制遺伝子導入による放射線・温熱治療の増感

Principal Investigator

大西 武雄 奈良県立医科大学, 医学部, 教授 (60094554)

Research Products

[Publications] Harima,Y., et al.: "Polymorphism of the WAF1 gene is related to susceptibility to cervical cancer in Japanese women."Int.J.Mol.Medicine. (in press). (2001)

[Publications] Harima,Y., et al.: "Mutation of the PTEN gene in advanced cervical cancer correlated with tumor progression and poor outcome after radiotherapy."Int.J.Oncol.. (in press). (2001)

[Publications] Matsumoto,H., et al.: "Induction of radioresistance by a nitric oxide-mediated bystander effect."Radiat. Res.. 155. 387-396 (2001)

[Publications] Ohnishi,K., et al.: "Glycerol restores p53 dependent radiosensitivity of human head and neck cancer cells bearing mutant."Br.J.Cancer. 83. 1735-1739 (2000)

[Publications] Kubota,N., et al.: "Wortmannin sensitizes human glioblastoma cell lines carrying mutant or wild type TP53 gene to radiation."Cancer Lett.. 161. 141-147 (2000)

[Publications] Oka,A., et al.: "Determination of p53-mediated transactivationl ability in radiation-treated cervical cancer."Cencer Detect.Prevent.. 24. 275-282 (2000)

[Publications] Kanata,H., et al.: "CDDP induces p53-dependent apotosis in tongue cancer cells."Int.J.Oncol.. 17. 513-518 (2000)

[Publications] Xie,X., et al.: "p53 status plays no role in radiosensitizing effects of SN-38, a camptothecin derivative."Cancer Chemother.Pharmacol.. 45. 362-368 (2000)

[Publications] Ohnishi,T., et al.: "Heat-induced accumulation of p53 and hsp72 is suppressed in lung fibroblasts from SCID mouse."Int.J.Radiat.Biol.. 76. 711-715 (2000)

[Publications] Ota,I., et al.: "Transfection with mutant p53 gene inhibits heat-induced apoptosis in a head and neck cell line of human squamous cell carcinoma."Int.J.Radiat.Oncol.Biol.Phys.. 47. 495-501 (2000)

[Publications] Takahashi,A., et al.: "The dependence of p53 on the radiation enhancement of thermosensitivity at different LET."Int.J.Radiat.Oncol.Biol.Phys.. 47. 489-494 (2000)

[Publications] Takahashi,A., et al.: "Induction of WAF1 accumulation by carbon-ion beam and α-particle irradiation in human glioblastoma cultured cells."Int.J.Radiat.Biol.. 76. 335-341 (2000)

[Publications] Ohtsubo,T., et al.: "Effect of acidic environment and p53 on apoptosis induction by hyperthermia."Int.J.Hyperthermia. 16. 481-491 (2000)

[Publications] Matsumoto,H., et al.: "Induction of radioresistance to accelerated carbon-ion beams in recipient cells by nitric oxide excreted from irradiated cells of human glioblastoma."Int.J.Radiat.Biol.. 76. 1649-1657 (2000)

[Publications] Matsumoto,H., et al.: "Interactive effects of nitric oxide and p53 on cellular thermosensitivity."Jpn.J.Hyperthermic Oncol.. 16. 69-82 (2000)

[Publications] Harima,Y., et al.: "Loss of heterozygosity on chromosome 6p21.2 as a potential marker for recurrence after radiotherapy of human cervical cancer."Clinical Cancer Res.. 6. 1079-1085 (2000)

[Publications] Harima,Y., et al.: "Bax and Bcl-2 protein expression following radiation therapy versus radiation plus thermoradiotherapy in stage IIIb cervical carcinoma."Cancer. 88. 131-137 (2000)

[Publications] 太田一郎 他: "癌放射線療法2000"篠原出版(印刷中). (2001)

[Publications] 桐田忠昭 他: "脳の科学"星和書店(印刷中). (2001)

大西武雄奈良県立医科大学, 医学部, 教授 (60094554)

[Publications] 太田一郎他: "癌放射線療法2000"篠原出版(印刷中). (2001)

[Publications] 桐田忠昭他: "脳の科学"星和書店(印刷中). (2001)