Effects of imatinib and interferon on primitive chronic myeloid leukaemia progenitors
Effects of imatinib and interferon on primitive chronic myeloid leukaemia progenitors
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DOI：
10.1111/j.1365-2141.2005.05606.x
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发表时间：
2005-08-01
影响因子：
6.5
通讯作者：
Jones, RJ
中科院分区：
文献类型：
--
作者：
Angstreich, GR;Matsui, W;Jones, RJ
伊马替尼对慢性粒细胞白血病 (CML) 具有令人印象深刻的活性，但似乎并不能完全根除这种疾病。尽管对干扰素-α (IFN) 的反应比对伊马替尼的反应慢且不那么显着，但即使在停药后，它们也可以持续存在。与伊马替尼不同，IFN 在 CML 中发挥临床活性的具体机制尚不清楚。我们发现，IFN 诱导临床标本中 CML 细胞系 KT-1 和 CML CD34(+) 细胞的 G(1) 细胞周期停滞以及终末分化。骨髓生长因子增强了 IFN 的抗白血病活性，而针对骨髓生长因子的中和抗体则抑制 IFN 的抗白血病活性。接下来，我们直接比较了伊马替尼和 IFN 对新诊断患者的分化型和原始 CML 祖细胞的影响。虽然 IFN 对 CML 粒细胞-巨噬细胞集落形成单位的活性不如伊马替尼，但对负责维持长期培养的原始 CML 祖细胞的毒性明显更大。伊马替尼和干扰素似乎对不同成熟阶段的 CML 祖细胞具有不同的作用，伊马替尼对分化的 CML 祖细胞更有效，而 IFN 对原始 CML 祖细胞更有效。这些药物的不同靶细胞可能解释了它们临床反应的动力学和持久性的差异。 IFN 在 CML 中的临床效果至少部分归因于其分化原始 CML 祖细胞的能力。
Imatinib has impressive activity against chronic myeloid leukaemia (CML), but does not appear to completely eradicate the disease. Although responses to interferon-alpha (IFN) are slower and less dramatic than those to imatinib, they can be durable even after discontinuation of the drug. Unlike imatinib, the specific mechanisms responsible for IFN's clinical activity in CML are unknown. We found that IFN induced a G(1) cell cycle arrest, as well as terminal differentiation, of the CML cell line KT-1 and CML CD34(+) cells from clinical specimens. Myeloid growth factors augmented the antileukaemic activity of IFN, and neutralising antibodies directed against myeloid growth factors inhibited IFN's antileukaemic activity. We next directly compared the effects of imatinib and IFN against differentiated and primitive CML progenitors from newly-diagnosed patients. Although less active against CML granulocyte-macrophage colony forming units than imatinib, IFN was significantly more toxic to primitive CML progenitors responsible for the maintenance of long-term cultures. Imatinib and IFN appear to have divergent effects on CML progenitors at different stages of maturation, with imatinib more active against differentiated CML progenitors and IFN more active against primitive CML progenitors. The different target cells for these agents may explain the disparities in the kinetics and durability of their clinical responses. At least part of the clinical effect of IFN in CML appears to result from its ability to differentiate primitive CML progenitors.