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首页> 外文期刊>Biochemical Pharmacology >The alkylating prodrug J1 can be activated by aminopeptidase N, leading to a possible target directed release of melphalan.
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The alkylating prodrug J1 can be activated by aminopeptidase N, leading to a possible target directed release of melphalan.

机译：烷基化前药J1可以被氨肽酶N激活，导致可能的目标定向释放马法兰。

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The alkylating prodrug of melphalan, J1 (melphalanyl-L-p-fluorophenylalanyl ethyl ester) is currently in early clinical trials. Preclinical studies have shown that J1-mediated cytotoxicity is dependent on hydrolytic activity of tumor cells. In this report we have analyzed potential peptidases and esterases of importance for release of free melphalan from J1. Exposure of tumor cell lines to J1 resulted in a significant increased level of free intracellular melphalan, at least tenfold at C(max), compared to exposure to melphalan at the same molar concentration. This efficient intracellular delivery could be inhibited in both magnitude and in time by bestatin, a broad spectrum inhibitor of the aminopeptidases, including the metalloproteinase aminopeptidase N (APN, EC 3.4.11.2.), and ebelactone A, an esterase inhibitor. These effects resulted, as expected, in decreased cytotoxic effects of J1. A specific role of APN in hydrolyzing J1 releasing free melphalan was demonstrated in vitro with pure APN enzyme. By using plasmid-based overexpression of APN or down regulation of endogenous APN with siRNA in different tumor cell lines we here confirm the involvement of APN in J1-mediated cytotoxic and apoptotic signaling. In conclusion, this study demonstrates a role of APN in the activation of the melphalan prodrug J1 and subsequently, its cytotoxicity. Given that APN is shown to be overexpressed in several solid tumors our data suggest that J1 may be activated in a tumor selective manner.
机译：美法仑J1的烷基化前药（美法兰基-L-对氟苯丙氨酰基乙基酯）目前处于早期临床试验中。临床前研究表明，J1介导的细胞毒性取决于肿瘤细胞的水解活性。在本报告中，我们分析了潜在的肽酶和酯酶对从J1释放游离马法兰的重要性。与暴露于相同摩尔浓度的马法兰相比，暴露于J1的肿瘤细胞系导致游离细胞内马法兰的水平显着增加，在C（max）时至少增加十倍。这种有效的细胞内递送可在其大小和时间上受到Bestatin（一种氨基肽酶的广谱抑制剂，包括金属蛋白酶氨基肽酶N（APN，EC 3.4.11.2））和ebelactone A（一种酯酶抑制剂）的抑制。如所预期的，这些作用导致J1的细胞毒性作用降低。在体外用纯APN酶证明了APN在水解J1释放游离马法兰中的特定作用。通过在不同肿瘤细胞系中使用基于质粒的APN过度表达或内源性APN与siRNA的下调，我们在这里证实APN参与J1介导的细胞毒性和凋亡信号转导。总之，这项研究证明了APN在美法仑前药J1的激活及其随后的细胞毒性中的作用。考虑到APN在几种实体瘤中均过表达，我们的数据表明J1可能以肿瘤选择性方式被激活。

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