The third-generation bisphosphonate zoledronate synergistically augments the anti-Ph+ leukemia activity of imatinib mesylate
The third-generation bisphosphonate zoledronate synergistically augments the anti-Ph+ leukemia activity of imatinib mesylate
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DOI：
10.1182/blood-2003-01-0305
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发表时间：
2003-09-15
期刊：
影响因子：
20.3
通讯作者：
Maekawa, T
中科院分区：
文献类型：
--
作者：
Kuroda, J;Kimura, S;Maekawa, T
甲磺酸伊马替尼是Abl酪氨酸激酶的竞争性抑制剂，对慢性粒细胞白血病（CIVIL）的早期阶段非常有效，但在晚期CIVIL和费城染色体阳性（Ph+）急性淋巴细胞白血病中诱导的缓解往往相对短暂。因此，寻找增强甲磺酸伊马替尼抗Ph+作用的药物是必要的。我们研究了甲磺酸伊马替尼和第三代双膦酸盐唑来膦酸盐（ZOL）对Ph+白血病的联合作用，因为ZOL抑制了Bcr/Bcr下游Ras相关蛋白的异戊烯化。首先，我们确定了ZOL在体外对人白血病细胞系的效力，包括2个Ph+和P-糖蛋白过表达的白血病细胞系。ZOL在体内也是有效的，因为它延长了非肥胖糖尿病/严重联合免疫缺陷（NOD/SCID）小鼠的生存期，这些小鼠被给予Ph+ BV 173白血病细胞异种移植物。接下来，我们显示了ZOL和甲磺酸伊马替尼对Ph+细胞系的体外协同作用。ZOL与甲磺酸伊马替尼组合显示出体内协同效应，延长了接种BV 173的小鼠的存活。ZOL在体外仅最低限度地抑制正常造血祖细胞的生长，并且接受ZOL或甲磺酸伊马替尼或两者的小鼠对这些治疗耐受良好。这些发现表明，ZOL是一种有效的抗白血病药物，协同增强甲磺酸伊马替尼的抗Ph+白血病活性。(C)2003年，美国血液学会。
Imatinib mesylate, a competitive inhibitor of Abl tyrosine kinase, is highly effective for the early stages of chronic myelogenous leukemia (CIVIL), but remissions induced in advanced-phase CIVIL and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia tend to be relatively short-lived. Therefore, the search for agents that enhance the anti-Ph+ effect of imatinib mesylate is warranted. We investigated the combined effects of imatinib mesylate and the third-generation bisphosphonate zoledronate (ZOL) on Ph+ leukemias, because ZOL inhibited the prenylation of Ras-related proteins downstream of Bcr/Abl. First, we identified the potency of ZOL in vitro against human leukemic cell lines, including 2 Ph+ and a P-glycoprotein-overexpressing leukemic cell line. ZOL was also effective in vivo because as it prolonged the survival of nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice who were given xenografts with Ph+ BV173 leukemic cells. Next, we showed the in vitro synergistic effects with ZOL and imatinib mesylate for Ph+ cell lines. ZOL combined with imatinib mesylate showed synergistic effects in vivo that prolonged the survival of mice inoculated with BV173. ZOL only minimally inhibited the growth of normal hematopoietic progenitors in vitro, and mice receiving ZOL or imatinib mesylate or both tolerated these treatments well. These findings indicate that ZOL is a potent antileukemic agent that augments synergistically the anti-Ph+ leukemia activity of imatinib mesylate. (C) 2003 by The American Society of Hematology.