Albella B, Faircloth G, López-Lázaro L, Guzmán C, Jimeno J, Bueren J A
Department of Molecular and Cellular Biology, CIEMAT, Av. Complutense, 22, 28040 Madrid, Spain.
Eur J Cancer. 2002 Jul;38(10):1395-404. doi: 10.1016/s0959-8049(01)00245-3.
Ecteinascidine-743 (ET-743) and aplidine are two marine-derived antineoplastics currently in phase II development. With the aim of evaluating whether in vitro haematopoietic studies can predict the toxicity of these two drugs in patients, human bone marrow (BM) samples were incubated with these drugs under conditions which mimicked the administration exposures used in the clinics. As it was observed in different cancer cell lines, ET-743 was more toxic on an equimolar basis in human hematopoietic progenitors (inhibitory concentration reducing the viability to 50% after 24 h exposures; IC50(24h): 10-50 nM) compared with doxorubicin (IC50(24h) values: 280-460 nM), used as a control anticancer drug. In contrast to the high haematotoxic effects observed for ET-743, similar IC values were obtained for aplidine (IC50(24h): 150-530 nM) compared with doxorubicin. For both ET-743 and aplidine, the megakaryocytic progenitor was the most sensitive, compared with the other haematopoietic progenitors (IC50 values were 3- to 5-fold lower in the CFU-Megs compared with the CFU-GMs). The observation that the Cmax observed in patients treated with the aplidine maximum tolerated dose (MTD) (7.1 nM) was 21-75 fold lower than the IC50(24h) value observed for the different haematopoietic progenitors is highly consistent with the lack of haematotoxicity observed in patients treated with this drug. In the case of ET-743, differences between the Cmax value corresponding to the MTD (2.6 nM) and the in vitro IC50 values corresponding to the different progenitors were much lower (4-19-fold), also consistent with the haematotoxicity that was observed in patients treated at recommended doses (RDs) and MTDs. Although CFU-Megs were more sensitive than CFU-GM progenitors to ET-743 in vitro, clinical data showed that neutropenic events were more frequent than thrombocytopenic episodes. Aiming to further improve the predictive value of in vitro IC values corresponding to the different haematopoietic progenitors, additional refinement parameters derived from pharmacokinetic and animal studies are proposed.
埃博霉素-743（ET-743）和阿利地嗪是两种目前正处于II期开发阶段的海洋来源抗肿瘤药物。为了评估体外造血研究是否能够预测这两种药物对患者的毒性，将人类骨髓（BM）样本与这些药物在模拟临床用药暴露的条件下进行孵育。正如在不同癌细胞系中所观察到的，在等摩尔浓度下，ET-743对人类造血祖细胞的毒性更大（暴露24小时后使活力降低50%的抑制浓度；IC50(24h)：10 - 50 nM），相比之下，用作对照抗癌药物的阿霉素（IC50(24h)值：280 - 460 nM）。与ET-743所观察到的高血液毒性效应相反，阿利地嗪与阿霉素相比获得了相似的IC值（IC50(24h)：150 - 530 nM）。对于ET-743和阿利地嗪而言，与其他造血祖细胞相比，巨核细胞祖细胞最为敏感（CFU-Megs的IC50值比CFU-GMs低3至5倍）。在用阿利地嗪最大耐受剂量（MTD）（7.1 nM）治疗的患者中观察到的Cmax比在不同造血祖细胞中观察到的IC50(24h)值低21至75倍，这一观察结果与用该药物治疗的患者中未观察到血液毒性高度一致。就ET-743而言，对应于MTD的Cmax值（2.6 nM）与对应于不同祖细胞的体外IC50值之间的差异要小得多（4至19倍），这也与在推荐剂量（RDs）和MTDs下治疗的患者中观察到的血液毒性一致。尽管在体外CFU-Megs比CFU-GM祖细胞对ET-743更敏感，但临床数据显示中性粒细胞减少事件比血小板减少发作更频繁。为了进一步提高对应于不同造血祖细胞的体外IC值的预测价值，提出了从药代动力学和动物研究中得出的额外优化参数。
