2000 Fiscal Year Annual Research Report

腫瘍増殖、浸潤、転移を抑制する新規薬剤の開発

Research Project

Project/Area Number	12217121
Research Category	Grant-in-Aid for Scientific Research on Priority Areas (C)
Research Institution	Kagoshima University
Principal Investigator	秋山伸一鹿児島大学, 医学部, 教授 (60117413)
Co-Investigator(Kenkyū-buntansha)	小松正治鹿児島大学, 医学部, 助手原口みさ子鹿児島大学, 医学部, 助手 (10244229) 古川龍彦鹿児島大学, 医学部, 助手 (40219100)
Keywords	チミジンホスホリラーゼ / 血管新生 / アポトーシス / 2-デオキシ-D-リボース / 2-デオキシ-L-リボース / HIF-1α / ノックアウトマウス
Research Abstract	1.TPI,2-deoxy-riboseによる血管新生、腫瘍増殖、浸潤、転移の抑制。TPが腫瘍の浸潤、転移に関与しているか、TP阻害剤、TPIが腫瘍の浸潤、転移を抑制するかを調べた。KB/TP細胞の遊走能、浸潤能はKB細胞に比べて高く、TPIはKB/TP細胞の遊走能、浸潤能をKB細胞のレベルにまで低下させた。ヌードマウスを用いた転移実験では、KB/TP細胞の転移能はKB細胞に比べて高く、TPIはKB/TP細胞の転移を強く抑制した。これらの結果からTPIの転移抑制剤としての可能性を示した。背部皮下法によりKB細胞とKB/TP細胞の血管新生能を調べるとKB/TP細胞の血管新生能が有為に高いが、2-deoxy-L-riboseはKB/TP細胞の血管新生能をKB細胞のレベルにまで抑制した。 2.アポトーシス耐性の機構。2-deoxy-D-riboseは低酸素下でのHL60細胞のアポトーシスを抑制したが、2-deoxy-L-riboseがその作用を阻害した。低酸素下ではカスパーゼ9、3の活性が上昇したが、2-deoxy-D-riboseはその上昇を抑制した。低酸素下で誘導されるHIF-1αの発現を2-deoxy-D-riboseが強く抑制した。低酸素条件下では、bcl-2,bcl-XL発現レベルの低下、Baxの発現亢進、ミトコンドリアから細胞質ヘのチトクロームCの放出の増加が認められたが、2-deoxy-D-riboseはこれらをすべて阻害した。 3.TPノックアウトマウスの作成と解析。TPノックアウトマウスはみかけ上正常で体重増加も順調であり、雌雄ともに妊娠可能であった。現在8月齢であるが健康で体重増加も野性型との間に差はみられない。今後長期的な観察が必要であると考えられる。マウスのUPはチミジンの分解を触媒するので、TP、UPのダブルノックアウトマウスを作製し実験を行っている。

Research Products
(16 results)

All Other

All Publications (16 results)

[Publications] Jun-ichirou Arima: "Expression of thymidine phosphorylase as an indicator of poor prognosis in human transitional cell carcinoma."Cancer,. 88. 1131-1138 (2000)
[Publications] Masaharu Komatsu: "Copper transporting P-type ATPase (ATP7B) is associated with cisplatin resistance."Cancer Res.,. 60. 1312-1316 (2000)
[Publications] Xiao-Qin Ren,: "Functional comparison between YCF1 and MRP1 expressed in Sf21 insect cells."Biochem.Biophys.Res.Commun.,. 270. 608-615 (2000)
[Publications] Sunji Shimaoka: "Role of thymidine phosphorylase expression in the invasion of gastric carcinomas."Cancer,. 88. 2220-2227 (2000)
[Publications] Jun'ichi Kobayashi,: "Multidrug resistance reversal activity of taxoids from taxus cuspidata in KB-C2 and 2780AD Cell."Cancer Res.,. 91. 638-642 (2000)
[Publications] Sonshin Takao: "Suppression of metastatasis by thymidine phosphorylase Inhibitor."Cancer Res.,. 60. 5345-5348 (2000)
[Publications] Hiroshi Okumura,: "Apoptosis and cell proliferation in esophageal sqamous cell carcinoma treated by chemotherapy."Cancer Lett.,. 158. 211-216 (2000)
[Publications] Hiroshi Okumura,: "Reversal of P-glycoprotein and multidrug-resistance protein-mediated drug resistance in KB cells by 5-O-benzoylated taxinine K."Mol.Pharmacol.,. 58. 1563-4569 (2000)
[Publications] Nobutoshi Murakami,: "New multidrug resistance modulators from atractylodis lanceae rhisoma."Bioorg.Med.Chem.Leet.. 10. 2629-2632 (2000)
[Publications] Nobutoshi Murakami: "Synthesis and evalutation of 4-deacetoxyagosterol A as an MDR-modulator."Bioorg.Med.Chem.Leet.,. 10. 2521-2524 (2000)
[Publications] Kengo Nishimoto: "The role of thymidine phosphorylase in the pathogenesis of allergic rhinitis."Acta Otolaryngol.. 120. 644-648 (2000)
[Publications] Masaki Kitazono,: "Reversal of LRP-associated drug resistance in colon carcinoma SW-620 cells."Int.J.Cancer,. 91. 126-131 (2000)
[Publications] Hisatsugu Goto: "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] Tatsuhiko Furukawa,: "Thymidine phosphorylase, a new molecular target for anit-cancer therapy."Current Topics in Biochemical Research. (in press).
[Publications] Hirofumi Hirano: "Angiogenic effect of thymidine phosphorylase of macrophages in glioblastma."J.Neurosurg.. (in press).
[Publications] Zhe-Sheng Chen,: "Reversal of drug resistance mediated by multidrug resistance protein (MRP)1 by dual effects of agosterol A on MRP function."Int.J.Cancer.,. (in press).

2000 Fiscal Year Annual Research Report

腫瘍増殖、浸潤、転移を抑制する新規薬剤の開発

Principal Investigator

秋山 伸一 鹿児島大学, 医学部, 教授 (60117413)

Research Products

[Publications] Jun-ichirou Arima: "Expression of thymidine phosphorylase as an indicator of poor prognosis in human transitional cell carcinoma."Cancer,. 88. 1131-1138 (2000)

[Publications] Masaharu Komatsu: "Copper transporting P-type ATPase (ATP7B) is associated with cisplatin resistance."Cancer Res.,. 60. 1312-1316 (2000)

[Publications] Xiao-Qin Ren,: "Functional comparison between YCF1 and MRP1 expressed in Sf21 insect cells."Biochem.Biophys.Res.Commun.,. 270. 608-615 (2000)

[Publications] Sunji Shimaoka: "Role of thymidine phosphorylase expression in the invasion of gastric carcinomas."Cancer,. 88. 2220-2227 (2000)

[Publications] Jun'ichi Kobayashi,: "Multidrug resistance reversal activity of taxoids from taxus cuspidata in KB-C2 and 2780AD Cell."Cancer Res.,. 91. 638-642 (2000)

[Publications] Sonshin Takao: "Suppression of metastatasis by thymidine phosphorylase Inhibitor."Cancer Res.,. 60. 5345-5348 (2000)

[Publications] Hiroshi Okumura,: "Apoptosis and cell proliferation in esophageal sqamous cell carcinoma treated by chemotherapy."Cancer Lett.,. 158. 211-216 (2000)

[Publications] Hiroshi Okumura,: "Reversal of P-glycoprotein and multidrug-resistance protein-mediated drug resistance in KB cells by 5-O-benzoylated taxinine K."Mol.Pharmacol.,. 58. 1563-4569 (2000)

[Publications] Nobutoshi Murakami,: "New multidrug resistance modulators from atractylodis lanceae rhisoma."Bioorg.Med.Chem.Leet.. 10. 2629-2632 (2000)

[Publications] Nobutoshi Murakami: "Synthesis and evalutation of 4-deacetoxyagosterol A as an MDR-modulator."Bioorg.Med.Chem.Leet.,. 10. 2521-2524 (2000)

[Publications] Kengo Nishimoto: "The role of thymidine phosphorylase in the pathogenesis of allergic rhinitis."Acta Otolaryngol.. 120. 644-648 (2000)

[Publications] Masaki Kitazono,: "Reversal of LRP-associated drug resistance in colon carcinoma SW-620 cells."Int.J.Cancer,. 91. 126-131 (2000)

[Publications] Hisatsugu Goto: "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] Tatsuhiko Furukawa,: "Thymidine phosphorylase, a new molecular target for anit-cancer therapy."Current Topics in Biochemical Research. (in press).

[Publications] Hirofumi Hirano: "Angiogenic effect of thymidine phosphorylase of macrophages in glioblastma."J.Neurosurg.. (in press).

[Publications] Zhe-Sheng Chen,: "Reversal of drug resistance mediated by multidrug resistance protein (MRP)1 by dual effects of agosterol A on MRP function."Int.J.Cancer.,. (in press).

秋山伸一鹿児島大学, 医学部, 教授 (60117413)