薬剤感受性と血管新生の分子標的から見たがんの診断と治療

• Project/Area Number: 12217105
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Kurume University (2003-2004); Kyushu University (2000-2002)
• Principal Investigator: 桑野 信彦 久留米大学, 医学部, 教授 (80037431)
• Project Period (FY): 2000 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥59,300,000 (Direct Cost: ¥59,300,000); Fiscal Year 2004: ¥12,700,000 (Direct Cost: ¥12,700,000); Fiscal Year 2003: ¥12,700,000 (Direct Cost: ¥12,700,000); Fiscal Year 2002: ¥10,000,000 (Direct Cost: ¥10,000,000); Fiscal Year 2001: ¥11,900,000 (Direct Cost: ¥11,900,000); Fiscal Year 2000: ¥12,000,000 (Direct Cost: ¥12,000,000)
• Keywords: 抗がん剤感受性 / 分子標的 / オーダーメイド医療 / ABCトランスポーター / YB-1 / がん血管新生 / 抗血管新生療法 / 腫瘍関連マクロファージ / 薬剤感受性 / 血管新生 / 分子標的治療 / 個別化治療 / トランスレーショナルリサーチ / MRP1 / MRP4 / MRP2 / DAP-Kinase / SU5416 / Iressa / MRP3 / 腸肝循環 / 多剤耐性 / 抗血管新生剤 / 分子標的薬剤 / ZD1839 / 転移・血管新生 / 抗がん剤耐性 / 単球 / マクロファージ / TNFα / IL1 / IL4 / IL13

Research Abstract

がん治療の最適化療法の実践にむけての基盤づくりは極めて重要である。そのために我々は本研究で、抗がん剤の感受性とがんの血管新生の分子機序のメカニズムを明らかにしながら、有用な分子標的を提示しがん治療薬の開発とがん治療の個別化へ貢献することにした。その結果、2002年から現在までに以下の知見を得た。
1.抗がん剤の感受性を制御する分子標的に関して:以下の成果を得た。
(1)我々が初めて単離したABCトランスポーターMRP2やMRP3認識する抗がん剤と関連する構造ドメインを明らかにし、さらに肝や腸の癌部位での発現上昇を観察した。
(2)P-糖蛋白質/MDR1に関しては、がんでの発現にプロモーターCpGサイトのメチル化の有無やYB-1の核内局在が臨床がんの発現上昇や多剤耐性に関与していた。
(3)YB-1はp53やPCNAと結合することやその核内局在ががん患者の予後に関連することやYB-1の翻訳制御への関与を明らかにした。
(4)EGFレセプターの変異にかえて肺癌細胞の増殖や細胞死にEGF/EGFレセプターのシグナルがどれだけ緊密に依存しているかが、ゲフィチニブ(イレッサ)の感受性に重要であった。
2.がんの血管新生に影響を与える間質応答に関して以下の成果を得た。
(1)VEGF受容体を標的とする阻害剤SU5416はFltだけでなくFlt-1のシグナルも阻害すること、更にゲフィチニブが血管新生を阻害する活性を示すことは幾つかのモデル系で明らかにした。
(2)TNF-αやIL-1βなどの炎症性サイトカインによって誘導される血管新生(炎症性血管新生)では可溶VCAMやインテグリンまたシクロオキシゲナーゼ2の活性化が重要な鍵をにぎっていた。
(3)炎症性サイトカインによって誘導される血管新生にはマクロファージの誘導が重要であることを標的薬剤を用いて明らかにしている。

Research Products

• [Journal Article] Cisplatin resistance and transcription factors. (2005)
  • Author(s): Torigoe, T.
  • Journal Title: Curr. Med. Chem. Anti-Cancer Agents 3 Pages: 15-27
• [Journal Article] PKCδ and MAPK mediate G_1 arrest induced by PMA in SKBR-3 breast cancer cells. (2005)
  • Author(s): Yokoyama, G.
  • Journal Title: Biochem. Biophys. Res. Commun. 325 Pages: 720-726
• [Journal Article] Characterization of 5'-untranslated region of YB-1 mRNA and autaregulation of translation by YB-1 protein. (2004)
  • Author(s): Fukuda, T.
  • Journal Title: Nucleic Acid Res. 32 Pages: 611-622
• [Journal Article] Cyclooxygenase 2 is a key enzyme for inflammatory cytokinase-induced angiogenesis. (2004)
  • Author(s): Kuwano, T.
  • Journal Title: FASEB J. 18 Pages: 300-310
• [Journal Article] Sensitivity to gefitinib (Iressa : ZD1839) in non-small cell lung cancer cell lines correlates with dependence on the EGF receptor/ERK1/2 and EGF receptor/AKT pathway for proliferation. (2004)
  • Author(s): Ono, M.
  • Journal Title: Males. Cancer Therapeutics 3 Pages: 465-472
• [Journal Article] Targeted disruption of one allele of the Y-box binding-1 (YB-1) gene in mouse embryonic stem cell and increased sensitivity to cisplatin and mitomycin C. (2004)
  • Author(s): Shibahara, K.
  • Journal Title: Cancer Science 95 Pages: 348-353
• [Journal Article] IL-1β represses multidrug resistance protein2 gene expression through inactivation of IRF3 in HepG2 cells. (2004)
  • Author(s): Hisaeda, K.
  • Journal Title: Hepatology 39 Pages: 1574-1582
• [Journal Article] Direct inhibition of EGF receptor activation in vascular endotheliab cells by gefitinib ('Iressa', ZD1839). (2004)
  • Author(s): Hirata, A.
  • Journal Title: Cancer Science 95 Pages: 614-618
• [Journal Article] N-myc downstream-regulated gene 1 expression in injured sciatic nerves. (2004)
  • Author(s): Hirata, K.
  • Journal Title: GLIA 47 Pages: 325-334
• [Journal Article] The role of nuclear YB-1 as a global marker in drug resistance. (2004)
  • Author(s): Kuwana, M.
  • Journal Title: Molec. Cancer Therapeutics 3 Pages: 1458-1492
• [Journal Article] HER2 overexpression increases sensitivity to gefitinib, an EGF receptor tyrosine kinase inhibitor thrnugh inhibition of HER2/HER3 heterodimer formation in lung cancer cells.
  • Author(s): Hirata, A.
  • Journal Title: Cancer Res. in press
• [Journal Article] The critical role of inflammatory cell infiltration in tumor angiogenesis-a target for antitumor drug development?
  • Author(s): Kuwano, M.
  • Journal Title: In "New Angiogenesis Research" by Nova Science Publishers. Inc. New York in press
• [Journal Article] ATP-binding cassette superfamily transporter gene expression in human soft tissue sarcomas.
  • Author(s): Oda, Y.
  • Journal Title: Int. J. Cancer in press
• [Journal Article] Cooperative cell-growth inhibition by combination treatment with ZD1839 (Iressa) and trastuzumab (Herceptin) in non-small-cell lung cancer.
  • Author(s): Nakamura, H.
  • Journal Title: Cancer Lett. in press
• [Journal Article] Anti-myeloma effects of a novel synthetic retinoid Am80 (Tamibarotene) through inhibition of angiogenesis.
  • Author(s): Sanda, T.
  • Journal Title: Leukemia in press
• [Book] 消化器がんの化学療法2004 消化器がんの分子標的治療 (2004)
  • Author(s): 三島麻衣
  • Publisher: 日本メディカルセンター
• [Patent(Industrial Property Rights)] MDR1遣伝子の5制御領域におけるSNPs (2004)
  • Inventor(s): 桑野信彦, 和田守正
  • Industrial Property Rights Holder: 桑野信彦, 和田守正
  • Industrial Property Number: 2003-332584
  • Filing Date: 2004-06-18
• [Patent(Industrial Property Rights)] ヒトcMQAT遺伝子とそのcDNA (1996)
  • Inventor(s): 桑野信彦, 和田守正
  • Industrial Property Rights Holder: 桑野信彦, 和田守正
  • Filing Date: 1996-09-30
  • Acquisition Date: 1998-04-21
• [Publications] Hisaeda, K.: "IL-1β represses multidrug resistance protein2 gene expression through inactivation of IRF3 in HepG2 cells."Hepatology. (in press). (2004)
• [Publications] Shibahara, K.: "Targeted disruption of one allele of the Y-box binding-1 (YB-1) gene in mouse embryonic stem cell and increased sensitivity to isplatin and mitomycin C."Cancer Science. (in press). (2004)
• [Publications] Ono, M.: "Sensitivity to gefitinib (Iressa : ZD1839) in non-small cell lung cancer cell lines correlates with dependence on the EGF receptor/ERK1/2 and EGF receptor/AKT pathway for proliferation."Molecular Cancer Therapeutics. (in press). (2004)
• [Publications] Kuwano, T.: "Cyclooxygenase 2 is a key enzyme for inflammatory cytokinase-induced angiogenesis."The FASEB Journal. 18. 300-310 (2004)
• [Publications] Fukuda, T.: "Characterization of 5'-untranslated region of YB-1 mRNA and autoregulation of translation by YB-1 protein."Nucleic Acid Research. 32. 611-622 (2004)
• [Publications] Taniguchi, S.: "Genetic polymorphism at 5' regulatory region of multidrug resistance 1 (MDR1) and its association with interindividual variation of expression level in the colon."Molecular Cancer Therapeutics. 2. 1351-1359 (2003)
• [Publications] Wakisaka, Y.: "Cellular distribution of NDRG1 protein in the rat kidney and brain during normal postnatal development."The Journal of Histochemistry & Cytochemistry. 51. 1515-1525 (2003)
• [Publications] Mochida, Y.: "The role of P-glycoprotein in intestinal tumorigenesis : disruption of mdrla suppresses polyp formation in Apc^<Min/+> mice."Carcinogenesis. 24. 1219-1224 (2003)
• [Publications] Kohno, K.: "The pleiotropic functions of the Y-box-binding protein, YB-1."Bio Essays. 25. 691-698 (2003)
• [Publications] Saji, H.: "Nuclear expression of YB-1 protein correlates with P-glycoprotein expression in human breast carcinoma."Cancer Letters. 190. 191-197 (2003)
• [Publications] Konno, T.: "Identification of domains participating in the substrate specificity and subcellular localization of the multidrug resistance proteins MRP1 and MRP2."The Journal of Biological Chemistry. 278. 22908-22917 (2003)
• [Publications] Oda, Y.: "Nuclear expression of Y-box-binding protein-I correlates with P-glycoprotein and topoisomerase II alpha expression, and with poor prognosis in synovial sarcoma."Journal of Pathology. 199. 251-258 (2003)
• [Publications] Masuda, K.: "Downregulation of CAP43 gene by von Hippel-Lindau tumor suppressor protein in human renal cancer cells."International Journal of Cancer. 105. 803-810 (2003)
• [Publications] Nakao, S.: "Synergistic effect of TNF-α in soluble VCAM-1-induced angiogenesis through α_4 integrins."The Journal of Immunology. 170. 5704-5711 (2003)
• [Publications] Kuwano, M.: "The basic and clinical implications of ABC transporters, Y-box-binding protein-1(YB-1)and angiogenesis-related factors in human malignancies."Cancer Science. 94. 9-14 (2003)
• [Publications] 三島 麻衣: "消化器がんの化学療法2004"日本メディカルセンター(印刷中). (2004)
• [Publications] Chen, Z.S., et al.: "Analysis of methotrexate and folate transport by multidrug resistance protein 4 (ABCC4) : MRP4 is a component of the methotrexate efflux system"Cancer Res.. 62. 3144-3150 (2002)
• [Publications] Tada, Y., et al.: "The association of hypermethylation of multiple genes including DAP-kinase with recurrence in superficial bladder cancers"Cencer Res.. 62. 4048-4053 (2002)
• [Publications] Hashimoto, K., et al.: "Trafficking and functional defects by mutations of the ATP-binding domains in MRP2 in patients with Dubin-Johnson syndrome"Hepatology. 36. 1236-1245 (2002)
• [Publications] Ashizuka, M., et al.: "Novel translational control through Iron-responsive element by interaction of multifunctional protein YB-1 and IRP2"Mol. Cell Biol.. 22. 6375-6383 (2002)
• [Publications] Itokawa, T.et al.: "Antiangiogenic Effect by SU5416 Is Partly Attributable to Inhibition of Flt-1 Receptor Signaling"Mol. Cancer Ther.. 1. 295-302 (2002)
• [Publications] Hirata, A., et al.: "ZD1839 (Iressa) induces antiangiogenic effects through inhibition of epidermal growth factor receptor tyrosine kinase"Cancer Res.. 62. 2554-2560 (2002)
• [Publications] 和田守正, 内海健, 桑野信彦: "MRP2/cMOATの生理機能と変異・遺伝子多型"医薬ジャーナル社. 9 (2001)
• [Publications] Nagayama, J. et al.: "Retrovirus insertion and transcriptional activation of the multidrug resistance(mdrla) gene in leukemias treated by a chemotherapeutic agent in vivo"Blood. 97. 759-766 (2001)
• [Publications] Goto, H. et al.: "Gamma interferon-dependent induction of thymidine phosphorylase/platelet derived endothelial growth factor through gamma-activated sequence-like element in human macrophages"Cancer Res.. 61. 469-473 (2001)
• [Publications] Haga, S. et al.: "Involvement of the multidrug resistance protein 3 in drug sensitivity and its expression in human glioma"Cancer Res.. 92. 211-219 (2001)
• [Publications] Nishie, A. et al.: "High expression of the cap43 gene in infiltrating macrophages of human renal cell carcinomas"Glin. Cancer Res.. 7. 2145-2151 (2001)
• [Publications] Hinoshita, E. et al.: "Decreased expression of an ATP-binding cassette transporter, MRP2, in human livers with hepatitis C virus infection"J. Hepatol.. 35. 765-773 (2001)
• [Publications] Harris, M.J. et al.: "Identification of the apical membrane-targeting signal of the multidrug resistance-associated protein 2 (MRP2/MOAT)"J. Biol. Chem.. 276. 20876-20881 (2001)
• [Publications] Migita, T. et al.: "The accumulation of angiostatin-like fragments in human prostate carcinoma"Clin. Cancer Res.. 7. 2750-2756 (2001)
• [Publications] Shibahara, K. et al.: "Nuclear expression of the Y-box binding protein, YB-1, as a novel marker of disease progression in non-small-cell lung cancer"Glin. Cancer Res.. 7. 3151-3155 (2001)
• [Publications] Inokuchi, A. et al.: "Enhanced expression of human multidrug resistance protein 3 by bile salt in human enterocytes : a transcriptional control of plausible bile acid transporter"J. Biol. Chem.. 276. 46822-46829 (2001)
• [Publications] Tada, Y. et al.: "Increased expression of multidrug resistance-associated proteins in bladder cancer during clinical course and drug resistance to doxorubicin"Int. J. Cancer. (in press). (2001)
• [Publications] Hirata, T. et al.: "ZD1839 (' Iressa' ) induces antiangiogenic effects through inhibition of EGFR tyrosine kinase"Cancer Res.. (in press). (2002)
• [Publications] Tada, Y. et al.: "The association of hypermethylation if multiple genes including DAP-kinase with recurrencce in superficial bladder cancers"Cancer Res.. (in press). (2002)
• [Publications] Nagayama,J., et. al: "Retrovirus insertion and transcriptional activation of the multidrug resistance (mdrla) gene in letukemias treated by a chemotherapeutic agent in vivo."Blood. 97. 759-766 (2001)
• [Publications] Goto,H. et. al: "Gamma interferon-dependent induction of thymidine phosphorylasc/platelet derived endothelial growth factor through gamma-activated sequence-like element in human macrophages."Cancer Res.. 61. 469-473 (2001)
• [Publications] Tada,Y., et. al: "MDR1 overexpression and altered degree of methylation at the promoter region in bladder cancer during chemotherapeutic treatment."Clinical Cancer Res.. 6. 4618-462* (2000)
• [Publications] Hinoshita,E.,et. al: "Increased expression of an ATP-binding cassette superfamily transporter, multidrug resistance protein 2, in human colorectal carcinomas."Clinical Cancer Res.. 6. 2401-2407 (2000)
• [Publications] Fukushi,J., et. al: "The activity of soluble VCAM-1 in angiogenesis stimulated by IL-4 and IL-13."J. Immunol.. 165. 2818-2823 (2000)