Targeting RAS for leukemia therapy

靶向 RAS 治疗白血病

• 批准号: 15591005
• 负责人: KIMURA Shinya
• 金额: $ 1.79万
• 依托单位: Kyoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591005/
• 关键词: RAS related proteins; bisphosphonates; zoledronate; imatinib mesykate; p53; p-glycoprotein; YM529; γδ T cell; 白血病; 分子標的; RAS; BCR-ABL; Zoledronate; imatinib mesylate; zoledronate; imatinib mysylate

We have studied about targeting RAS related proteins for leukemia therapy with grant-in-aid for scientific research (C)(2) and have reported as follows :1)The third generation bisphosphonate(BP) zoledronate(ZOL) is a potent anti-leukemic agent that augments synergistically the anti-Ph^+ leukemia activity of imatinib.2)ZOL is effective on the cell lines which p53 function are reduced, suggesting the p53-independent anti-tumor activities of ZOL. ZOL is also effective on p-glycoprotein over expressing leukemic cell line. These findings suggest that ZOL may be an attractive agent for treating cancers, including chemoresistant cases.3)ZOL acts synergistically when administered concurrently with cytarabine (Ara-C) in some leukemic cell lines. Furthermore, one day of ZOL pre-treatment augmented the sensitivity of imatinib and Ara-C.4)Another third generation BP, YM529 has also anti-leukemic effects both in vitro and in vivo.5)ZOL and YM529 shows anti-tumor effects not only against leukemia but also lung cancer, renal cell cancer, prostate cancer cell lines. ZOL augments synergistically the anti-lung cancer activity of paclitaxel and YM529 augments synergistically the anti-renal cell cancer activity of interferon-α.6)ZOL stimulates the proliferation of γδ. T cells and that pre-treatment with ZOL greatly enhances the cytotoxic activity of γδ T cells against target cells.Based on our these studies, clinical trials for imatinib plus ZOL against chronic myeloid leukemia and Ph^+ acute lymphoblastic leukemia have started in United Kingdom and Germany, suggesting that these studies contribute translational research. We are currently preparing for a clinical trial on imatinib plus ZOL in Japan

我们利用科研助学金研究了靶向RAS相关蛋白用于白血病治疗的研究(C)(2)，报道如下：1)第三代双膦酸唑来膦酸盐(ZOL)是一种有效的抗白血病药物，能协同增强伊马替尼的抗Ph~+白血病活性。2)ZOL对P53功能降低的细胞株有效，提示ZOL的抗肿瘤活性不依赖于P53。Zol对高表达P-糖蛋白的白血病细胞株也有一定的作用。这些发现表明，ZOL可能是一种有吸引力的治疗癌症的药物，包括化疗耐药病例。3)在一些白血病细胞株中，ZOL与阿糖胞苷(Ara-C)同时给予时具有协同作用。此外，ZOL预治疗一天增加了伊马替尼和Ara-C.4的敏感性)另一代BP，YM529在体内外也具有抗白血病作用。5)ZOL和YM529不仅对白血病有抗肿瘤作用，而且对肺癌、肾细胞癌、前列腺癌细胞株也有抗肿瘤作用。Zol协同增强紫杉醇的抗肺癌活性，YM529协同增强干扰素-α的抗肾细胞癌活性。6)Zol刺激γδ的增殖。在我们这些研究的基础上，伊马替尼联合左旋咪唑治疗慢性粒细胞白血病和Ph^+急性淋巴细胞白血病的临床试验已经在英国和德国开始，这表明这些研究有助于翻译研究。我们目前正准备在日本进行伊马替尼加ZOL的临床试验

项目成果

Kuroda J: "p53-independent anti-tumor effect of the nitrogen-containing bisphosphonate zoledronic acid"Cancer Science. 95(2). 186-192 (2004)

Kuroda J：“含氮双膦酸盐唑来膦酸的 p53 独立抗肿瘤作用”癌症科学。

The anti-leukemic efficacy of the third generation bisphosphonate ONO5920/YM529.

第三代双膦酸盐ONO5920/YM529的抗白血病功效。

• 发表时间: 2005
• 期刊: Leuk Res 29
• 作者: Segawa H;Kimura S;Kuroda J;Sato K;Nogawa M;Yuasa T;Yokota A;Hodohara K;Fujiyama Y;Maekawa T.
• 通讯作者: Maekawa T.

Zoledronic acid mediates Ras-independent growth inhibition of prostate cancer cells.

唑来膦酸介导前列腺癌细胞的 Ras 独立生长抑制。

• 发表时间: 2005
• 期刊: Oncol Res 15
• 作者: Nogawa M;Yuasa T;Kimura S;Kuroda J;Segawa H;Sato K;Koizumi M;Maekawa T.
• 通讯作者: Maekawa T.

血液疾患のEBM(慢性骨髄性白血病の項目を担当)

血液病循证医学（负责慢性粒细胞白血病）

• 发表时间: 2004
• 作者: Sato K;Kimura S;Segawa H;Yokota A;Matsumoto S;Kuroda J;Nogawa M;Yuasa T;Kiyono Y;Wada H;Maekawa T.;木村晋也;木村晋也
• 通讯作者: 木村晋也

Zoledronic acid mediates Ras-independent growth inhibition of prostate cancer cells

唑来膦酸介导前列腺癌细胞的 Ras 独立生长抑制

• 发表时间: 2005
• 期刊: Oncology Research 15
• 作者: Kunihiro Tsukasaki;Sakae Tanosaki;Sven DeVos;Wolf K.Hofmann;William Wachsman;Adrian F.Gombart;Johannes Krebs;Anna Jauch;Claus R.Bartram;Kazuhiro Nagai;Masao Tomonaga;Jonathan W.Said;H.Phillip Koeffler;Tsukasaki K;Segawa H;Sato K;Nogawa M
• 通讯作者: Nogawa M