Potential risk factors associated with the use of cidofovir to treat benign human papillomavirus-related disease
Potential risk factors associated with the use of cidofovir to treat benign human papillomavirus-related disease
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DOI：
10.3851/imp1421
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发表时间：
2009-01-01
影响因子：
1.2
通讯作者：
Hampson, Ian N.
中科院分区：
文献类型：
--
作者：
Donne, Adam J.;Hampson, Lynne;Hampson, Ian N.
背景：西多福韦目前被用于治疗不同的病毒感染，如良性低风险人乳头瘤病毒（HPV）相关的复发性呼吸道乳头瘤病（RRP）。人们担心这种做法的安全性，因为大鼠研究表明其恶性转化率很高。到目前为止，还没有西多福韦引起人类恶性变化的临床报告。方法：用低危HPV6b或高风险HPV16细胞和载体对照细胞，经端粒酶永生的稳定表达E6蛋白的人角质形成细胞（hTert），分别用低剂量（5 μ g/ml）或高剂量（30 μ g/ml）西多福韦处理2天，并通过克隆生存试验评价效果。在此基础上，对西多福韦处理的低危E6细胞和载体细胞在药物治疗前、治疗中和治疗后进行基因表达芯片分析，并通过real-time PCR对结果进行验证。结果：低危和高危表达e6的细胞在5 μ g/ml西多福韦作用2 d后，较载体对照细胞的长期存活率均有显著提高（hTert T6E6 P=0.0007, hTert T16E6 P=0.00023， hTert载体对照P=0.62）。对低剂量环洛福韦处理的低风险表达e6的细胞进行微阵列和实时PCR分析，揭示了已知与恶性进展相关的基因表达变化，而在药物处理的载体对照细胞中未观察到这种变化。结论：这是首次报道西多福韦可以提高细胞存活率，并诱导基因表达改变，已知这些基因表达改变与低危HPV仅用E6基因转导的细胞的恶性转化有关。我们相信，这些数据提供了对未经许可使用该药物治疗RRP的担忧。
Background: Cidofovir is currently being used off-licence to treat different viral infections, such as benign low-risk human papillomavirus (HPV)-related recurrent respiratory papillomatosis (RRP). There are concerns over the safety of this practice as rat studies demonstrated a high malignant transformation rate. As yet, there are no clinical reports of cidofovir-induced malignant changes in humans.Methods: Telomerase immortalised human keratinocytes (hTert) stably expressing E6 proteins from either low-risk HPV6b or high-risk HPV16 and vector control cells were treated with either low-dose (5 mu g/ml) or higher dose (30 mu g/ml) cidofovir for 2 days and the effects evaluated by clonogenic survival assays. Based on these results, gene expression microarray analysis was performed on cidofovir-treated low-risk E6 and vector cells before, during and after drug treatment, and the results verified by real-time PCR.Results: Both low-risk and high-risk E6-expressing cells show significantly improved long-term survival compared with vector control cells when exposed to 5 mu g/ml cidofovir for 2 days, (hTert T6E6 P=0.0007, hTert T16E6 P=0.00023 and hTert vector control P=0.62). Microarray and real-time PCR analyses of low-dose ciclofovir-treated low-risk E6-expressing cells revealed changes in gene expression that are known to be associated with malignant progression, which were not observed in drug-treated vector control cells.Conclusions: This is the first report that cidofovir can both increase cell survival and induce alterations in gene expression that are known to be associated with malignant transformation in cells transduced only with the E6 gene from low-risk HPV. It is our belief that these data provide cause for concern over the off-license use of this drug to treat RRP.