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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Selective inhibition of human papillomavirus-induced cell proliferation by (S)-1-(3-hydroxy-2-(phosphonylmethoxy)propyl)cytosine.
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Selective inhibition of human papillomavirus-induced cell proliferation by (S)-1-(3-hydroxy-2-(phosphonylmethoxy)propyl)cytosine.

机译：（S）-1-（3-羟基-2-（膦酰基甲氧基）丙基）胞嘧啶对人乳头瘤病毒诱导的细胞增殖的选择性抑制。

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摘要

(S)-1-[3-Hydroxy-2-(phosphonylmethoxy)propyl]cytosine (HPMPC) is a nucleoside phosphonate analog which in its active diphosphorylated form is known to inhibit herpesvirus DNA polymerase. In this study, we have demonstrated that, in a dose-dependent manner, this compound irreversibly suppressed proliferation of cells infected with human papillomavirus (HPV), which does not possess a viral DNA polymerase. To elucidate the mechanism of cell growth inhibition, cell cycle indicator-regulator expression, thymidine incorporation, transcript levels of apoptosis factors, and anabolic products of HPMPC following drug treatment were evaluated. HPMPC treatment reduced WAF1 (p21) levels independent of those of p53, while proliferating cell nuclear antigen increased. However, in comparison to controls, HPMPC-treated cells displayed a decrease in thymidine incorporation, indicating an inhibition of host DNA polymerase activity. In normal primary keratinocytes, HPMPC predominantly accumulated in the form of the choline adduct HPMPCp-choline. However, in HPV type 16-transformed keratinocytes, HPMPCpp was the most abundant anabolic product, with little HPMPCp-choline having formed. The data imply that an unrecognized viral factor is modulating the conversion of nucleotides, including HPMPC, to the triphosphorylated form.
机译：（S）-1- [3-羟基-2-（膦酰基甲氧基）丙基]胞嘧啶（HPMPC）是核苷膦酸酯类似物，已知其活性二磷酸化形式抑制疱疹病毒DNA聚合酶。在这项研究中，我们已经证明，该化合物以剂量依赖性方式不可逆转地抑制了感染人乳头瘤病毒（HPV）的细胞的增殖，该病毒不具有病毒DNA聚合酶。为了阐明细胞生长抑制的机制，评估了药物治疗后细胞周期指标调节剂的表达，胸腺嘧啶核苷的掺入，凋亡因子的转录水平和HPMPC的合成代谢产物。 HPMPC处理可降低WAF1（p21）水平，而与p53无关，而增殖细胞核抗原则增加。但是，与对照相比，HPMPC处理的细胞胸腺嘧啶核苷掺入量减少，表明宿主DNA聚合酶活性受到抑制。在正常的原代角质形成细胞中，HPMPC主要以胆碱加合物HPMPCp-胆碱的形式积累。然而，在HPV 16型转化的角质形成细胞中，HPMPCpp是最丰富的合成代谢产物，几乎没有形成HPMPCp-胆碱。数据表明，无法识别的病毒因子正在调节包括HPMPC在内的核苷酸向三磷酸化形式的转化。

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