2001 年度実績報告書

薬剤感受性と耐性克服の分子生物学的研究

研究課題

研究課題/領域番号	12217165
研究機関	国立がんセンター
研究代表者	西尾和人国立がんセンター, 研究所・薬効試験部, 室長 (10208134)
キーワード	遺伝子発現解析 / 分子標的薬 / ファルネシルトランスフェラーゼ / EGFR / ZD1839 / アポトーシス / Ras / MAPK
研究概要	分子標的薬の抗腫瘍効果規定因子の決定と分子標的薬の作用機序を明らかにする、臨床試験において標的分子の発現測定をおこない、ヒトの体内で標的とする分子に作用しているか否かを明らかにする目的で以下の研究を実施した。 I.分子標的薬(ファルネシルトランスフェラーゼ阻害剤等)の投与をうけた患者の末梢血単核球の遺伝子発現変動解析により分子標的薬の評価を行った。機能的に類推可能な既知遺伝子から構成するcDNAフィルターアレイを作成し、遺伝子発現解析を行った。同薬剤投与前後の患者末梢血単核球の遺伝子発現変動を比較検討することで、本剤がヒトの体内で適切と標的(Ras関連遺伝子、Rhoファミリー関連遺伝子)に容量依存的に作用していること、また選択した遺伝子がサロゲート遺伝子となる可能性が示された。 II.分子標的薬(EGFR特異的チロシンキナーゼ阻害剤ZD1839)の抗腫瘍効果規定因子の検討を、ヒト非小細胞肺癌株(高感受性および低感受性株)を用いておこなった。EGFR発現量およびその自己リン酸化に加えて、AKTシグナルとMAPKカスケードのバランスがEGFR特異的チロシンキナーゼ阻害剤の感受性・耐性を左右する要因として明らかになった。また、感受性株においては、ZD1839接触によるカスペース3、9の活性化とアポトーシス誘導がおこり、AKT、MAPKカスケードを通じたアポトーシスの経路が抗腫瘍効果発現の一因子であると示された。

研究成果

(23件)

すべてその他

すべて文献書誌 (23件)

[文献書誌] Yoshida, M., et al.: "Antitumor action of the PKC activator gnidimacrin through cdk2 inhibition"Int. J. Cancer. 94・3. 348-352 (2001)
[文献書誌] Zhang, J., et al.: "Differential osteopontin expression in lung cancer"Cancer Lett.. 171・2. 215-222 (2001)
[文献書誌] Saijo, N., et al.: "New strategies for cancer therapy in the 21st century"Cancer Chemother. Pharmacol.. 48・Suppl 1. S102-106 (2001)
[文献書誌] Yoshida, M., et al.: "Induction of MRP5 and SMRP mRNA by adriamycin exposure and its overexpression in human lung cancer cells resistant to adriamycin"Int. J. Cancer. 94・3. 432-437 (2001)
[文献書誌] Fukuoka, K., et al.: "Mechanism of the radiosensitization induced by vinorelbine in human non-small cell lung cancer cells"Lung Cancer. 34・3. 451-460 (2001)
[文献書誌] Tatsumi, Y., et al.: "Enhancement of in vivo antitumor activity of a novel antimitotic 1-phenylpropenone derivative, AM-132, by tumor necrosis factor-α or interleukin-6"Jpn. J. Cancer Res.. 92・7. 768-777 (2001)
[文献書誌] Usuda, J., et al.: "Increased cytotoxic effects of photodynamic therapy in IL-6 gene transfected cells via enhanced apoptosis"Int. J. Cancer. 93・4. 475-480 (2001)
[文献書誌] Natsume, T., et al.: "Gene expression profiling of exposure to TZT-1027, a novel microtubule-interfering agent in non-small cell lung cancer PC-14 cells and astrocytes"Invest. New Drugs. 19・4. 293-301 (2001)
[文献書誌] Nakamura, T., et al.: "Reversal of cisplatin resistance by the 1,4-benzothiazepine derivative, JTV-519"Jpn. J. Cancer Res.. 92・6. 597-602 (2001)
[文献書誌] Kanzawa, F., et al.: "In vitro synergistic interactions between the cisplatin analogue nedaplatin and the DNA topoisomerase I inhibitor irinotecan and the mechanism of this interaction"Clin. Cancer Res.. 7・1. 202-209 (2001)
[文献書誌] Tsunoda, T., et al.: "Upregulated expression of angiogenesis genes and down regulation of cell cycle genes in human colorectal cancer tissue determined by cDNA macroarray"Anticancer Res.. 21・1A. 137-144 (2001)
[文献書誌] Shimizu, M., et al.: "CPT-11 alters the circadian rhythm of dihydropyrimidine dehydrogenase mRNA in mouse liver"Jpn. J. Cancer Res.. 92・5. 554-561 (2001)
[文献書誌] Suzuki, T., et al.: "The MRP family and anticancer drug metabolism current drug"Met. Curr. Drug Met.. 2・4. 367-377 (2001)
[文献書誌] Fukuoka, K., et al.: "Mechanisms of action of the novel sulfonamide anticancer agent E7070 on cell cycle progression in human non-small cell lung cancer cells"Invest. New Drugs. 19・3. 219-227 (2001)
[文献書誌] Nishio, K. et al.: "Oncoprotein 18 overexpression increases the sensitivity to vindesine in the human lung carcinoma cells"Cancer. 91・8. 1494-1499 (2001)
[文献書誌] Natsume, T., et al.: "Enhanced antitumor activities of TZT-1027 against TNF-α or IL-6 secreting Lewis lung carcinoma in vivo"Cancer Chemother. Pharmacol.. 49・1. 35-47 (2002)
[文献書誌] Koh, Y., et al.: "Decreased expression of α2,8 sialyltransferase and increased expression of β1,4 N-acetylgalactosaminyltransferase in gastrointestinal cancers"Proc. Soc. Exp. Biol. Med.. 227・3. 196-200 (2002)
[文献書誌] Naruse, I., et al.: "Antitumor activity of the selective epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)Iressa^<TM>(ZD1839) in a EGFR-expressing multidrug resistant cell line in vitro and in vivo"Int. J. Cancer. 98・2. 310-315 (2002)
[文献書誌] Naruse, I., et al.: "Enhanced anti-tumor effect of trastuzumab in combination with cisplatin"Int. J. Cancer. (In press).
[文献書誌] Fukuoka, K., et al.: "Mechanism of vinorelbine-induced radiosensitization of human small cell lung cancer cells"Cancer Chemother. Pharmacol.. (In press).
[文献書誌] Takahashi, F., et al.: "Osteopontin induces angiogenesis of murine neuroblastoma cells in mice"Int. J. Cancer. (In press).
[文献書誌] Kanzawa, F., et al.: "In vitro effects of combinations of cis-amminedichloro(2-methylpyridine)platinum (α)(ZD0473) with other novel anticancer drugs on the growth of SBC-3, a human small cell lung cancer cell line"Lung Cancer. (In press).
[文献書誌] Koh, Y., et al.: "Mechanisms of action of cancer chemotherapeutic agents : topoisomerase inhibitors. In "Cancer Handbook""Reference Nature Publishing Group. 5 (2002)

2001 年度 実績報告書

薬剤感受性と耐性克服の分子生物学的研究

研究代表者

西尾 和人 国立がんセンター, 研究所・薬効試験部, 室長 (10208134)

研究成果

[文献書誌] Yoshida, M., et al.: "Antitumor action of the PKC activator gnidimacrin through cdk2 inhibition"Int. J. Cancer. 94・3. 348-352 (2001)

[文献書誌] Zhang, J., et al.: "Differential osteopontin expression in lung cancer"Cancer Lett.. 171・2. 215-222 (2001)

[文献書誌] Saijo, N., et al.: "New strategies for cancer therapy in the 21st century"Cancer Chemother. Pharmacol.. 48・Suppl 1. S102-106 (2001)

[文献書誌] Yoshida, M., et al.: "Induction of MRP5 and SMRP mRNA by adriamycin exposure and its overexpression in human lung cancer cells resistant to adriamycin"Int. J. Cancer. 94・3. 432-437 (2001)

[文献書誌] Fukuoka, K., et al.: "Mechanism of the radiosensitization induced by vinorelbine in human non-small cell lung cancer cells"Lung Cancer. 34・3. 451-460 (2001)

[文献書誌] Tatsumi, Y., et al.: "Enhancement of in vivo antitumor activity of a novel antimitotic 1-phenylpropenone derivative, AM-132, by tumor necrosis factor-α or interleukin-6"Jpn. J. Cancer Res.. 92・7. 768-777 (2001)

[文献書誌] Usuda, J., et al.: "Increased cytotoxic effects of photodynamic therapy in IL-6 gene transfected cells via enhanced apoptosis"Int. J. Cancer. 93・4. 475-480 (2001)

[文献書誌] Natsume, T., et al.: "Gene expression profiling of exposure to TZT-1027, a novel microtubule-interfering agent in non-small cell lung cancer PC-14 cells and astrocytes"Invest. New Drugs. 19・4. 293-301 (2001)

[文献書誌] Nakamura, T., et al.: "Reversal of cisplatin resistance by the 1,4-benzothiazepine derivative, JTV-519"Jpn. J. Cancer Res.. 92・6. 597-602 (2001)

[文献書誌] Kanzawa, F., et al.: "In vitro synergistic interactions between the cisplatin analogue nedaplatin and the DNA topoisomerase I inhibitor irinotecan and the mechanism of this interaction"Clin. Cancer Res.. 7・1. 202-209 (2001)

[文献書誌] Tsunoda, T., et al.: "Upregulated expression of angiogenesis genes and down regulation of cell cycle genes in human colorectal cancer tissue determined by cDNA macroarray"Anticancer Res.. 21・1A. 137-144 (2001)

[文献書誌] Shimizu, M., et al.: "CPT-11 alters the circadian rhythm of dihydropyrimidine dehydrogenase mRNA in mouse liver"Jpn. J. Cancer Res.. 92・5. 554-561 (2001)

[文献書誌] Suzuki, T., et al.: "The MRP family and anticancer drug metabolism current drug"Met. Curr. Drug Met.. 2・4. 367-377 (2001)

[文献書誌] Fukuoka, K., et al.: "Mechanisms of action of the novel sulfonamide anticancer agent E7070 on cell cycle progression in human non-small cell lung cancer cells"Invest. New Drugs. 19・3. 219-227 (2001)

[文献書誌] Nishio, K. et al.: "Oncoprotein 18 overexpression increases the sensitivity to vindesine in the human lung carcinoma cells"Cancer. 91・8. 1494-1499 (2001)

[文献書誌] Natsume, T., et al.: "Enhanced antitumor activities of TZT-1027 against TNF-α or IL-6 secreting Lewis lung carcinoma in vivo"Cancer Chemother. Pharmacol.. 49・1. 35-47 (2002)

[文献書誌] Koh, Y., et al.: "Decreased expression of α2,8 sialyltransferase and increased expression of β1,4 N-acetylgalactosaminyltransferase in gastrointestinal cancers"Proc. Soc. Exp. Biol. Med.. 227・3. 196-200 (2002)

[文献書誌] Naruse, I., et al.: "Antitumor activity of the selective epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)Iressa^<TM>(ZD1839) in a EGFR-expressing multidrug resistant cell line in vitro and in vivo"Int. J. Cancer. 98・2. 310-315 (2002)

[文献書誌] Naruse, I., et al.: "Enhanced anti-tumor effect of trastuzumab in combination with cisplatin"Int. J. Cancer. (In press).

[文献書誌] Fukuoka, K., et al.: "Mechanism of vinorelbine-induced radiosensitization of human small cell lung cancer cells"Cancer Chemother. Pharmacol.. (In press).

[文献書誌] Takahashi, F., et al.: "Osteopontin induces angiogenesis of murine neuroblastoma cells in mice"Int. J. Cancer. (In press).

[文献書誌] Kanzawa, F., et al.: "In vitro effects of combinations of cis-amminedichloro(2-methylpyridine)platinum (α)(ZD0473) with other novel anticancer drugs on the growth of SBC-3, a human small cell lung cancer cell line"Lung Cancer. (In press).

[文献書誌] Koh, Y., et al.: "Mechanisms of action of cancer chemotherapeutic agents : topoisomerase inhibitors. In "Cancer Handbook""Reference Nature Publishing Group. 5 (2002)

2001 年度実績報告書

西尾和人国立がんセンター, 研究所・薬効試験部, 室長 (10208134)