Zídek Zdenĕk, Kmonícková Eva, Holý Antonín
Institute of Experimental Medicine, Academy of Sciences, Vídenská 1083, Prague, Czech Republic.
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2005 Dec;149(2):315-9. doi: 10.5507/bp.2005.049.
Biological effectiveness of antiviral acyclic nucleoside phosphonate adefo vir, 9-[2-(phosphonomethoxy)ethy]ade nine (PMEA) and its more lipophilic (bis)pivaloyloxymethyl ester prodrug adefovir dipivoxil (bis-POM-PMEA) were compared under in vitro conditions in mammalian cell systems. Proliferation of murine splenocytes was inhibited in a concentration-dependent manner, the bis-POM-PMEA being more effective than PMEA. In contrast to PMEA, bis-POM-PMEA inhibited production of nitric oxide (NO) in macrophages activated with interferon-gamma (IFN-gamma) and lipopolysaccharide (LPS). Viability of both splenocytes and macrophages remained uninfluenced by PMEA, whereas pronounced cytocidal effects were exhibited by bis-POM-PMEA. The IC(50)s reached the values of 15 microM and 30 microM in cultures of macrophages and splenocytes, respectively (assayed at the interval of 24 hrs). The effects could partly be mimicked by formaldehyde, a decomposition product of the pivoxil moiety of bis-POM-PMEA. The other possible product, pivalic acid, was ineffective in this respect. The present data are consistent with the view that pivoxil prodrug of PMEA, bis-POM-PMEA possesses enhanced but also broader spectrum of biological effects than the parent compound.
在体外条件下，于哺乳动物细胞系统中比较了抗病毒的无环核苷膦酸阿德福韦、9-[2-(膦酰甲氧基)乙基]腺嘌呤（PMEA）及其亲脂性更强的（双）新戊酰氧甲基酯前药阿德福韦酯（双-POM-PMEA）的生物学活性。小鼠脾细胞的增殖受到浓度依赖性抑制，双-POM-PMEA比PMEA更有效。与PMEA不同，双-POM-PMEA抑制了经γ干扰素（IFN-γ）和脂多糖（LPS）激活的巨噬细胞中一氧化氮（NO）的产生。PMEA对脾细胞和巨噬细胞的活力均无影响，而双-POM-PMEA则表现出明显的杀细胞作用。在巨噬细胞和脾细胞培养物中，IC50分别达到15μM和30μM（在24小时间隔内测定）。甲醛（双-POM-PMEA新戊酰基部分的分解产物）可部分模拟这些作用。另一种可能的产物新戊酸在这方面无效。目前的数据与以下观点一致，即PMEA的新戊酰基前药双-POM-PMEA比母体化合物具有更强且更广泛的生物学效应谱。
