Boyd A W, Sullivan J R
Blood. 1984 Feb;63(2):384-92.
A variety of chemical agents have been shown to induce differentiation in in vitro cultured neoplastic cell lines. We noted that blast cells in the peripheral blood of acute nonlymphoid leukemia patients treated with the drug Harringtonine appeared to undergo morphological changes that suggested differentiation. In view of the relatively minimal myelotoxicity of Harringtonine, we hypothesized that harringtonine was acting by differentiation-induction, which concomitantly arrested cell division. We tested this hypothesis using two different experimental approaches. First, the promyelocytic leukemic cell line, HL-60, was cultured with Harringtonine and shown to differentiate into a cell, which, by functional cell surface marker and morphological criteria, closely resembled normal monocytes. Furthermore, these changes were accompanied, and indeed slightly preceded by, loss of proliferative capacity. Second, to prove that the leukemic blasts were the cells undergoing the changes observed in vivo, freshly isolated leukemia cell populations were cultured with Harringtonine, and morphological changes paralleling those seen in the patients were observed. Thus, the antileukemic effect of Harringtonine appeared to be due to diversion of the proliferating blast cells into a differentiation pathway, which, as in normal myeloid cells, resulted in the arrest of proliferation.
多种化学试剂已被证明能在体外培养的肿瘤细胞系中诱导分化。我们注意到，用三尖杉酯碱治疗的急性非淋巴细胞白血病患者外周血中的原始细胞似乎发生了提示分化的形态学变化。鉴于三尖杉酯碱相对较小的骨髓毒性，我们推测三尖杉酯碱通过诱导分化起作用，同时阻止细胞分裂。我们使用两种不同的实验方法来验证这一假设。首先，早幼粒细胞白血病细胞系HL-60用三尖杉酯碱培养，并显示分化为一种细胞，根据功能性细胞表面标志物和形态学标准，该细胞与正常单核细胞非常相似。此外，这些变化伴随着增殖能力的丧失，实际上增殖能力的丧失还略早于此。其次，为了证明白血病原始细胞是体内发生所观察到变化的细胞，将新鲜分离的白血病细胞群体用三尖杉酯碱培养，观察到与患者体内所见相似的形态学变化。因此，三尖杉酯碱的抗白血病作用似乎是由于增殖的原始细胞转向分化途径，这与正常髓细胞一样，导致增殖停止。
