Angstreich Greg R, Matsui William, Huff Carol Ann, Vala Milada S, Barber James, Hawkins Anita L, Griffin Constance A, Smith B Douglas, Jones Richard J
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, MD, USA.
Br J Haematol. 2005 Aug;130(3):373-81. doi: 10.1111/j.1365-2141.2005.05606.x.
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 G1 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.
伊马替尼对慢性粒细胞白血病（CML）具有显著疗效，但似乎无法完全根除该疾病。虽然干扰素-α（IFN）的反应比伊马替尼慢且不那么显著，但即使在停药后仍可持续有效。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可诱导CML细胞系KT-1以及临床标本中的CML CD34+细胞发生G1期细胞周期阻滞和终末分化。髓系生长因子增强了IFN的抗白血病活性，而针对髓系生长因子的中和抗体则抑制了IFN的抗白血病活性。接下来，我们直接比较了伊马替尼和IFN对新诊断患者中分化型和原始型CML祖细胞的作用。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，但对维持长期培养负责的原始CML祖细胞毒性显著更大。伊马替尼和IFN对不同成熟阶段的CML祖细胞似乎有不同的作用，伊马替尼对分化型CML祖细胞更有效，而IFN对原始型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续性差异。IFN在CML中的临床效果至少部分源于其分化原始CML祖细胞的能力。
