Plasma inhibitory activity (PIA): a pharmacodynamic assay reveals insights into the basis for cytotoxic response to FLT3 inhibitors
Plasma inhibitory activity (PIA): a pharmacodynamic assay reveals insights into the basis for cytotoxic response to FLT3 inhibitors
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DOI：
10.1182/blood-2006-04-015743
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发表时间：
2006-11-15
期刊：
影响因子：
20.3
通讯作者：
Small, Donald
中科院分区：
文献类型：
--
作者：
Levis, Mark;Brown, Patrick;Small, Donald
我们开发了一种有用的替代试验，用于监测口服FLT 3抑制剂治疗患者的FLT 3抑制疗效。在接受CEP-701和PKC 412治疗的患者中，FLT 3的血浆抑制活性（PIA）与临床活性相关。使用PIA测定，沿着白血病细胞中的体外磷酸化和细胞毒性测定，我们比较了PKC 412及其代谢产物CGP 52421与CEP-701。虽然两种药物在体外均能有效抑制FLT 3，但CEP-701在FLT 3抑制水平相当时对原代样本的细胞毒性更强。PKC 412似乎比CEP-701更具选择性，因此在体外诱导原发性急性髓性白血病（AML）样品的细胞毒性方面效果较差。然而，PKC 412代谢物CGP 52421的选择性低于其母体化合物PKC 412，并且在相当的FLT 3抑制水平下对原代母细胞样本的细胞毒性更强。血浆抑制活性测定代表了小分子抑制剂开发中有用的相关工具。我们的应用表明，代谢产物CGP 52421可能有助于在接受口服PKC 412的患者中观察到的抗白血病活性的显著部分。此外，我们的研究结果表明，非选择性可能是FLT 3突变AML中FLT 3抑制剂细胞毒性作用的重要组成部分。
We have developed a useful surrogate assay for monitoring the efficacy of FLT3 inhibition in patients treated with oral FLT3 inhibitors. The plasma inhibitory activity (PIA) for FLT3 correlates with clinical activity in patients treated with CEP-701 and PKC412. Using the PIA assay, along with in vitro phosphorylation and cytotoxicity assays in leukemia cells, we compared PKC412 and its metabolite, CGP52421, with CEP-701. While both drugs could effectively inhibit FLT3 in vitro, CEP-701 was more cytotoxic to primary samples at comparable levels of FLT3 inhibition. PKC412 appears to be more selective than CEP-701 and therefore less effective at Inducing cytotoxicity in primary acute myelold leukemia (AML) samples in vitro. However, the PKC412 metabolite CGP52421 is less selective than its parent compound, PKC412, and is more cytotoxic against primary blast samples at comparable levels of FLT3 inhibition. The plasma inhibitory activity assay represents a useful correlative tool in the development of small-molecule inhibitors. Our application of this assay has revealed that the metabolite CGP52421 may contribute a significant portion of the antileukemia activity observed in patients receiving oral PKC412. Additionally, our results suggest that nonselectivity may constitute an important component of the cytotoxic effect of FLT3 inhibitors in FLT3-mutant AML.