DTS-108, a novel peptidic prodrug of SN38:: In vivo efficacy and toxicokinetic studies
DTS-108, a novel peptidic prodrug of SN38:: In vivo efficacy and toxicokinetic studies
复制标题
DOI：
10.1158/1078-0432.ccr-07-4580
复制
发表时间：
2008-04-01
影响因子：
11.5
通讯作者：
Kearsey, Jonathan
中科院分区：
文献类型：
--
作者：
Meyer-Losic, Florence;Nicolazzi, Celine;Kearsey, Jonathan
目的：伊立替康是一种主要通过肝脏羧酸酯酶作用转化为活性细胞毒分子SN38的前药。伊立替康的疗效受到肝脏激活的限制，这种肝脏激活会导致低转化率、高患者间变异性和剂量限制性胃肠道毒性。本研究的目的是评估一种新型的SN38前药（DTS-108），与伊立替康相比，它可以绕过肝脏激活，从而降低胃肠道毒性和患者间变异性。实验设计：SN38通过酯酶可切割连接体与阳离子肽（Vectocell）偶联。临床前开发计划包括在许多不同的模型和物种中进行毒性和疗效评估。结果：该偶联物（DTS-108）具有高可溶性，体外人血浆半衰期为400分钟。对狗的研究表明，DTS-108释放的游离SN38水平明显高于伊立替康，而不会引起胃肠道毒性。此外，与伊立替康相比，DTS-108给药后无活性SN38-葡萄糖醛酸代谢物与活性SN38代谢物的比值显著降低，这与肝脏代谢降低一致。体内疗效研究表明，与伊立替康相比，DTS-108具有更高的活性。在所有模型中均观察到明显的剂量依赖性抗肿瘤疗效，DTS-108与其他临床相关治疗剂联合使用具有协同作用。结论：DTS-108能够比伊立替康提供更高水平的SN38，而没有伊立替康的相关毒性，从而增加了DTS-108在临床前模型中的治疗窗口。这些令人鼓舞的数据值得进一步的临床前和临床研究。
Purpose: Irinotecan is a prodrug converted to the active cytotoxic molecule SN38 predominantly by the action of liver carboxylesterases. The efficacy of irinotecan is limited by this hepatic activation that results in a low conversion rate, high interpatient variability, and dose-limiting gastrointestinal toxicity. The purpose of this study was to evaluate a novel pepticlic prodrug of SN38 (DTS-108) developed to bypass this hepatic activation and thus reduce the gastrointestinal toxicity and interpatient variability compared with irinotecan.Experimental Design: SN38 was conjugated to a cationic peptide (Vectocell) via an esterase cleavable linker.The preclinical development plan consisted of toxicity and efficacy evaluation in a number of different models and species.Results: The conjugate (DTS-108) is highly soluble, with a human plasma half-life of 400 minutes in vitro. Studies in the dog showed that DTS-108 liberates significantly higher levels of free SN38 than irinotecan without causing gastrointestinal toxicity. In addition, the ratio of the inactive SN38-glucuronicle metabolite compared with the active SN38 metabolite is significantly lower following DTS-108 administration, compared with irinotecan, which is consistent with reduced hepatic metabolism. In vivo efficacy studies showed that DTS-108 has improved activity compared with irinotecan. A significant dose-dependent antitumoral efficacy was observed in all models tested and DTS-108 showed synergistic effects in combination with other clinically relevant therapeutic agents.Conclusions: DTS-108 is able to deliver significantly higher levels of SN38 than irinotecan, without the associated toxicity of irinotecan, resulting in an increased therapeutic window for DTS-108 in preclinical models. These encouraging data merit further preclinical and clinical investigation.