1994 Fiscal Year Annual Research Report

多剤耐性遺伝子の関与しない抗癌剤の感受性を左右する因子の解明に関する研究

Research Project

Project/Area Number	06282268
Research Institution	National Cancer Center Research Institute and Research Center for Innovative Oncology, National Cancer Center Hospital East
Principal Investigator	西條長宏国立がんセンター, 薬効試験部, 部長 (00215526)
Co-Investigator(Kenkyū-buntansha)	平家勇司国立がんセンター, 薬効試験部, 研究員 (90260322) 西尾和人国立がんセンター, 薬効試験部, 研究員 (10208134)
Keywords	抗がん剤 / 多剤耐性
Research Abstract	P糖蛋白の関与しない多剤耐性機構を分子レベルで明らかにする事を究極の目的とした。細胞のリン酸化の状態が薬剤感受性に関わりもつ事実は従来から散発的にはあるものの直接的な証明は乏しい。本研究ではPKCのactivatorであるTPAと、phosphataseのinhibitorのokadaic acid(OA)に対する耐性株を樹立しその特性を分析するとともに克服法の開発を試みた。 1.TPA耐性K562細胞(K562/TPA)はP糖蛋白の関与しない多剤耐性細胞であり、細胞内薬剤蓄積の低下はみられない。K562/TPAではアドリアマイシン(ADM)は主に細胞質へ分布し核にはわずかに認められたにすぎなかった。チロシンキナーゼ阻害剤genisteinにより抗癌剤のK562/TPAに対する細胞傷害能は上昇するとともに細胞内へのADMの蓄積も増加した。又ADMなどによるDNAの単鎖切断も増加し、genisteinにより薬剤耐性を克服しうると示唆された。シグナル伝達機構に作用する物質が薬剤耐性を修飾しうる事実は、耐性克服に重要な示唆をもたらした。 2.抗癌剤耐性細胞はprotein phoshatase(PP)阻害剤であるokadaic acid(OA)に対しても耐性化した。OAに対する耐性機構を解明するため、肺小細胞癌株H69よりOA耐性株(H69/OA)を樹立した。H69/OAにおけるPP活性は有意に低く、PP(PP1,PP2Aとも)はOAによる抑制に対し抵抗性を示した。OAによるH69/OA100のp34^<cdc2>kinaseの脱リン酸化は、抑制されていた。OAによるG2/M blockはPP阻害を介したp34^<cdc2>kinaseのtyrosine residueへの作用によって誘導されると示唆された。H69/OA100ではOAによるp34^<cdc2>kinaseのtyrosine residueの脱リン酸化が阻害されるためG2/M blockがおこらないと示唆された。PPは細胞周期の調節に重要な役割を果していると示された。

Research Products
(16 results)

All Other

All Publications (16 results)

[Publications] Kubo,S.O.: "Apoptosis induced by etoposide small-cell lung cancer cell lines.Cacct Chemother." Pharmacol.33. 385-390 (1994)
[Publications] Kubota,N.: "Characterization of an etoposide-resistant human ovarican cancer cell line." Cancer Chemother.Pharmacol.34. 183-190 (1994)
[Publications] Ohmori,T.: "Ouabain resistant non-small-cell lung cancer cell line shows collateral sensitivity to cisdiamminedichloroplatinum(II)(CDDP)." Int.J.Cancer. 57. 111-116 (1994)
[Publications] Ogasawara,H.: "KW-2189,a novel cyclopropylpyrroloindole,is activated by carboxyl esterase and induces DNA-strand breaks." Jpn.J.Cancer Res.85. 418-425 (1994)
[Publications] Takeda,Y.: "Reversal of multidrug resistance by tyrosine-kinase inhibitors in a non-p-glycoprotein-mediated multidrug-resistant cell line." Int.J.Cancer. 57. 229-239 (1994)
[Publications] Ohta,S.: "Characterization of a taxol-resistant human small-cell lung cancer cell lines." Jpn.J.Cancer Res.85. 290-297 (1994)
[Publications] Yang,Y.,Woo,E.: "Human metallothionein isoform gene expression in cisplatin-sensitive and resistant cells." Molecular Pharmacol.45. 453-460 (1994)
[Publications] Oshita,F.: "Rapid polymerase chain reaction assay to detect variation in the extent of gene-specific damage betweem cisplatin-or Vp-16-resistant and sensitive lung cancer cell lines." Jpn.J.Cancer Res.85. 669-673 (1994)
[Publications] Takeda,Y.: "Establishment of aHuman Small-Cell Lung-Cancer Subline Resistant to Okadaic Acid." Int.J.Cancer.58. 882-890 (1994)
[Publications] Kondo,H.: "In vitro and in vivo effects of cisplatin and etoposide in combination on small cell lung cancer cell lines." Jpn.J.Cancer Res.85. 1050-1056 (1994)
[Publications] Kjima,T.: "Establishment of CPT-11 resistant human ovarian cancer cell Line." Anticancer Res.14. 799-804 (1994)
[Publications] Saijo,N.: "7-Ethyl-10〔4-(1-piperidino)-1-piperidino〕carbonylowy camptothecin;mechanism of resistance and clinical trials." Cancer.Chemother.Pharmacol.34. 112-117 (1994)
[Publications] Bojanowski,K.: "Effect of suramin on p34^<cdc2>kinase in vitro and in extracts from human H69 cells:evidence for a double mechanism of action." Biochem.Bioph.Res.Commun.203. 1574-1580 (1994)
[Publications] Nishio,K.: "Genistein,a tyrosine Kinase Inhibitor,Decreased the affinity of p56^<lek>to β-chain of interleukin-2receptor in human natural killer(NK)-rich cells and decreased NK-mediated cytotoxicity(43811)." PSEBM. 207. 227-233 (1994)
[Publications] Nishio,M.: "Overexpression of cisplatin-inducible proteins that are recognized by anti-HMG antibody in cisplatin-resistant human lung cancer cell line." Cellular Pharmacol.1. 251-255 (1994)
[Publications] Kunikane,H.: "Flow cytometric analysis of cellular adriamycin accumulation in small-cell lung cancer cell lines:correlation of P-glycoprotein expression,cytotoxicity and intracellular distribution." Cellular Pharmacol.1. 293-300 (1994)

1994 Fiscal Year Annual Research Report

多剤耐性遺伝子の関与しない抗癌剤の感受性を左右する因子の解明に関する研究

Principal Investigator

西條 長宏 国立がんセンター, 薬効試験部, 部長 (00215526)

Research Products

[Publications] Kubo,S.O.: "Apoptosis induced by etoposide small-cell lung cancer cell lines.Cacct Chemother." Pharmacol.33. 385-390 (1994)

[Publications] Kubota,N.: "Characterization of an etoposide-resistant human ovarican cancer cell line." Cancer Chemother.Pharmacol.34. 183-190 (1994)

[Publications] Ohmori,T.: "Ouabain resistant non-small-cell lung cancer cell line shows collateral sensitivity to cisdiamminedichloroplatinum(II)(CDDP)." Int.J.Cancer. 57. 111-116 (1994)

[Publications] Ogasawara,H.: "KW-2189,a novel cyclopropylpyrroloindole,is activated by carboxyl esterase and induces DNA-strand breaks." Jpn.J.Cancer Res.85. 418-425 (1994)

[Publications] Takeda,Y.: "Reversal of multidrug resistance by tyrosine-kinase inhibitors in a non-p-glycoprotein-mediated multidrug-resistant cell line." Int.J.Cancer. 57. 229-239 (1994)

[Publications] Ohta,S.: "Characterization of a taxol-resistant human small-cell lung cancer cell lines." Jpn.J.Cancer Res.85. 290-297 (1994)

[Publications] Yang,Y.,Woo,E.: "Human metallothionein isoform gene expression in cisplatin-sensitive and resistant cells." Molecular Pharmacol.45. 453-460 (1994)

[Publications] Oshita,F.: "Rapid polymerase chain reaction assay to detect variation in the extent of gene-specific damage betweem cisplatin-or Vp-16-resistant and sensitive lung cancer cell lines." Jpn.J.Cancer Res.85. 669-673 (1994)

[Publications] Takeda,Y.: "Establishment of aHuman Small-Cell Lung-Cancer Subline Resistant to Okadaic Acid." Int.J.Cancer.58. 882-890 (1994)

[Publications] Kondo,H.: "In vitro and in vivo effects of cisplatin and etoposide in combination on small cell lung cancer cell lines." Jpn.J.Cancer Res.85. 1050-1056 (1994)

[Publications] Kjima,T.: "Establishment of CPT-11 resistant human ovarian cancer cell Line." Anticancer Res.14. 799-804 (1994)

[Publications] Saijo,N.: "7-Ethyl-10〔4-(1-piperidino)-1-piperidino〕carbonylowy camptothecin;mechanism of resistance and clinical trials." Cancer.Chemother.Pharmacol.34. 112-117 (1994)

[Publications] Bojanowski,K.: "Effect of suramin on p34^<cdc2>kinase in vitro and in extracts from human H69 cells:evidence for a double mechanism of action." Biochem.Bioph.Res.Commun.203. 1574-1580 (1994)

[Publications] Nishio,K.: "Genistein,a tyrosine Kinase Inhibitor,Decreased the affinity of p56^<lek>to β-chain of interleukin-2receptor in human natural killer(NK)-rich cells and decreased NK-mediated cytotoxicity(43811)." PSEBM. 207. 227-233 (1994)

[Publications] Nishio,M.: "Overexpression of cisplatin-inducible proteins that are recognized by anti-HMG antibody in cisplatin-resistant human lung cancer cell line." Cellular Pharmacol.1. 251-255 (1994)

[Publications] Kunikane,H.: "Flow cytometric analysis of cellular adriamycin accumulation in small-cell lung cancer cell lines:correlation of P-glycoprotein expression,cytotoxicity and intracellular distribution." Cellular Pharmacol.1. 293-300 (1994)

西條長宏国立がんセンター, 薬効試験部, 部長 (00215526)