2002 Fiscal Year Annual Research Report

新規アンプリファイヤーによる抗がん剤の細胞死誘導増強と協奏的DNA認識機構の解明

Research Project

Project/Area Number	14030037
Research Institution	Mie University
Principal Investigator	川西正祐三重大学, 医学部, 教授 (10025637)
Co-Investigator(Kenkyū-buntansha)	平工雄介三重大学, 医学部, 助手 (30324510) 及川伸二三重大学, 医学部, 講師 (10277006)
Keywords	アンプリファイヤー / ディスタマイシンA / C1027 / DNA切断 / 塩基特異性 / 分子認識 / アポトーシス / テロメア
Research Abstract	多くの抗がん剤はDNAを切断し、アポトーシスを誘導することによりがん細胞を死滅させる。しかし、化学療法において、抗がん剤の副作用や薬剤耐性の発現は極めて重要な問題である。アンプリファイヤーとは、DNAに結合してその構造を変化させ、抗がん剤の作用を増強する薬剤である。アンプリファイヤーの開発により、少量の抗がん剤で副作用を軽減しながら、有効ながん治療を行うことが可能になる。本研究では、特にエンジイン系抗がん剤C1027によるDNA切断およびアポトーシスに対するDNA結合物質(マイナーグループ結合物質)ディスタマイシンAの増強効果について解析した。C1027によるヒト培養細胞のアポトーシスは、ディスタマイシンAの添加により増強された。ヒト遺伝子DNAにおいて、C1027単独ではAあるいはTの連続した配列で二重鎖切断を起こしたが、ディスタマイシンAにより特に5'-AGGG-3'/3'-TCCC-5'の配列における切断が顕著に増強された(下線はDNA切断が増強された塩基を示す)。さらに、ディスタマイシンAはヒトテロメア繰り返し配列(5'-TTAGGG-3')を含むDNAにおいても5'-AGGG-3'配列でDNA切断を増強するという注目すべき知見を得た。以上の結果から、ディスタマイシンAとC1027はヘテロダイマーを形成してGC-richな配列、特にテロメア配列を標的として特異的に認識し、DNA切断を増強してアポトーシスを増強すると考えられる。本研究では、ディスタマイシンAのようなDNA結合物質、特にマイナーグルーブ結合物質をアンプリファイヤーとして、テロメアなどのミニサテライトを標的とした新たながん化学療法に臨床応用するための基盤となる知見が得られた。

Research Products

(20 results)

All Other

All Publications (20 results)

[Publications] S.Oikawa: "Oxidative damage to cellular and isolated DNA by homocysteine : implications for carcinogenesis"Oncogene. (in press). (2003)
[Publications] K.Hirakawa: "Base oxidation at 5' site of GG sequence in double-stranded DNA induced by UVA in the presence of xanthone analogues : relationship between the DNA-damaging abilities of photosensitizers and their HOMO energies"Photochem Photobiol. (in press). (2003)
[Publications] K.Hirakawa: "Carcinogenic semicarbazide induces sequence-specific DNA damage through the generation of reactive oxygen species and the derived organic radicals"Mutat. Res. (in press). (2003)
[Publications] K.Hirakawa: "Sequence-specific DNA damage induced by ultraviolet A-irradiated folic acid via its photolysis product"Arch. Biochem. Biophys. 410. 261-268 (2003)
[Publications] H.Mizutani: "Mechanism of apoptosis induced by a new topoisomerase inhibitor through the generation of hydrogen peroxide"J. Biol. Chem. 277. 30684-30689 (2002)
[Publications] Y.Hiraku: "Distamycin A, a minor groove binder, changes enediyne-induced DNA cleavage sites and enhances apoptosis"Nucl. Acids Res.. Suppl.2. 95-96 (2002)
[Publications] K.Sakano: "Metabolism of carcinogenic urethane to nitric oxide is involved in oxidative DNA damage"Free Radic. Biol. Med. 33. 703-714 (2002)
[Publications] Y.Hiraku: "Determination of intracellular glutathione and thiols by high performance liquid chromatography with a gold electrode at the femtomole level : comparison with a spectroscopic assay"Biochim. Biophys. Acta. 1570. 47-52 (2002)
[Publications] S.Kawanishi: "The role of metals in site-specific DNA damage with reference to carcinogenesis"Free Radic. Biol. Med. 32. 822-832 (2002)
[Publications] M.Murata: "Oxidation of 5'-site guanine at GG and GGG sequences induced by a metabolite of carcinogenic heterocyclic amine PhIP in the presence of Cu(II) and NADH"Carcinogenesis. 23. 855-860 (2002)
[Publications] S.Ohnishi: "Oxidative DNA Damage Induced by a Metabolite of 2-Naphthylamine, a Smoking-related Bladder Carcinogen"Jpn. J. Cancer Res. 93. 736-743 (2002)
[Publications] S.Homma-Takeda: "2,4,6-trinitrotoluene-induced reproductive toxicity via oxidative DNA damage by its metabolite"Free Radic. Res. 36. 555-566 (2002)
[Publications] K.Midorikawa: "Hydroxylation of deoxyguanosine at 5' site of GG and GGG sequences in double-stranded DNA induced by carbamoyl radicals"Free Radic. Res. 36. 667-675 (2002)
[Publications] S.Oikawa: "Site-specific hydroxylation at polyguanosine in double-stranded DNA by nickel(II) in the presence of SH compounds : comparison with singlet oxygen-induced DNA damage"Chem. Res. Toxicol. 15. 1017-1022 (2002)
[Publications] K.Sakano: "Metal-mediated DNA damage induced by curcumin in the presence of human cytochrome P450 isozymes"Arch. Biochem. Biophys. 405. 223-230 (2002)
[Publications] M.Kawanishi: "Epstein-Barr virus BHRF1 functions downstream of Bid cleavage and upstream of mitochondrial dysfunction to inhibit TRAIL-induced apoptosis in BJAB cells"Biochem Biophys Res Commun. 297. 682-687 (2002)
[Publications] M.Murata: "Oxidative DNA damage by a common metabolite of carcinogenic nitrofluorene and N-acetylaminofluorene"Int J Cancer. 102. 311-317 (2002)
[Publications] S.Kawanishi: "Distinct mechanisms of oxidative DNA damage induced by carcinogenic nickel subsulfide and nickel oxides"Environ Health Perspect. 110. 789S-791S (2002)
[Publications] K.Hirakawa: "Photohydrolysis of methotrexate produces pteridine, which induces poly-G-specific DNA damage through photoinduced electron transfer"Photochem Photobiol. 76. 467-472 (2002)
[Publications] 及川伸二: "職と生活習慣病"昭和堂(菅原努監修). 213 (2003)

2002 Fiscal Year Annual Research Report

新規アンプリファイヤーによる抗がん剤の細胞死誘導増強と協奏的DNA認識機構の解明

Principal Investigator

川西 正祐 三重大学, 医学部, 教授 (10025637)

Research Products

[Publications] S.Oikawa: "Oxidative damage to cellular and isolated DNA by homocysteine : implications for carcinogenesis"Oncogene. (in press). (2003)

[Publications] K.Hirakawa: "Base oxidation at 5' site of GG sequence in double-stranded DNA induced by UVA in the presence of xanthone analogues : relationship between the DNA-damaging abilities of photosensitizers and their HOMO energies"Photochem Photobiol. (in press). (2003)

[Publications] K.Hirakawa: "Carcinogenic semicarbazide induces sequence-specific DNA damage through the generation of reactive oxygen species and the derived organic radicals"Mutat. Res. (in press). (2003)

[Publications] K.Hirakawa: "Sequence-specific DNA damage induced by ultraviolet A-irradiated folic acid via its photolysis product"Arch. Biochem. Biophys. 410. 261-268 (2003)

[Publications] H.Mizutani: "Mechanism of apoptosis induced by a new topoisomerase inhibitor through the generation of hydrogen peroxide"J. Biol. Chem. 277. 30684-30689 (2002)

[Publications] Y.Hiraku: "Distamycin A, a minor groove binder, changes enediyne-induced DNA cleavage sites and enhances apoptosis"Nucl. Acids Res.. Suppl.2. 95-96 (2002)

[Publications] K.Sakano: "Metabolism of carcinogenic urethane to nitric oxide is involved in oxidative DNA damage"Free Radic. Biol. Med. 33. 703-714 (2002)

[Publications] Y.Hiraku: "Determination of intracellular glutathione and thiols by high performance liquid chromatography with a gold electrode at the femtomole level : comparison with a spectroscopic assay"Biochim. Biophys. Acta. 1570. 47-52 (2002)

[Publications] S.Kawanishi: "The role of metals in site-specific DNA damage with reference to carcinogenesis"Free Radic. Biol. Med. 32. 822-832 (2002)

[Publications] M.Murata: "Oxidation of 5'-site guanine at GG and GGG sequences induced by a metabolite of carcinogenic heterocyclic amine PhIP in the presence of Cu(II) and NADH"Carcinogenesis. 23. 855-860 (2002)

[Publications] S.Ohnishi: "Oxidative DNA Damage Induced by a Metabolite of 2-Naphthylamine, a Smoking-related Bladder Carcinogen"Jpn. J. Cancer Res. 93. 736-743 (2002)

[Publications] S.Homma-Takeda: "2,4,6-trinitrotoluene-induced reproductive toxicity via oxidative DNA damage by its metabolite"Free Radic. Res. 36. 555-566 (2002)

[Publications] K.Midorikawa: "Hydroxylation of deoxyguanosine at 5' site of GG and GGG sequences in double-stranded DNA induced by carbamoyl radicals"Free Radic. Res. 36. 667-675 (2002)

[Publications] S.Oikawa: "Site-specific hydroxylation at polyguanosine in double-stranded DNA by nickel(II) in the presence of SH compounds : comparison with singlet oxygen-induced DNA damage"Chem. Res. Toxicol. 15. 1017-1022 (2002)

[Publications] K.Sakano: "Metal-mediated DNA damage induced by curcumin in the presence of human cytochrome P450 isozymes"Arch. Biochem. Biophys. 405. 223-230 (2002)

[Publications] M.Kawanishi: "Epstein-Barr virus BHRF1 functions downstream of Bid cleavage and upstream of mitochondrial dysfunction to inhibit TRAIL-induced apoptosis in BJAB cells"Biochem Biophys Res Commun. 297. 682-687 (2002)

[Publications] M.Murata: "Oxidative DNA damage by a common metabolite of carcinogenic nitrofluorene and N-acetylaminofluorene"Int J Cancer. 102. 311-317 (2002)

[Publications] S.Kawanishi: "Distinct mechanisms of oxidative DNA damage induced by carcinogenic nickel subsulfide and nickel oxides"Environ Health Perspect. 110. 789S-791S (2002)

[Publications] K.Hirakawa: "Photohydrolysis of methotrexate produces pteridine, which induces poly-G-specific DNA damage through photoinduced electron transfer"Photochem Photobiol. 76. 467-472 (2002)

[Publications] 及川伸二: "職と生活習慣病"昭和堂(菅原努監修). 213 (2003)

川西正祐三重大学, 医学部, 教授 (10025637)