Nucleoside Phosphonate Analogs and HPV Positive Cancers

西多福韦(Cdv)是一种广谱抗病毒药物，对大多数双链dna具有活性。 病毒。一些DNA病毒被认为是病毒诱导的重要因素 恶毒。使用抗病毒药物治疗癌症的概念还处于初级阶段，值得探索。这项建议旨在评估新的、高活性的CDV类似物，这些类似物对DNA病毒的活性大大提高，同时降低了肾毒性，肾毒性是西多福韦利用的一个限制因素。我们已经合成并测试了CDV的烷氧基烷基类似物，它们的效力至少是未经修饰的CDV的10倍。我们对人乳头状瘤阳性细胞系Me-180和HeLa的初步实验结果表明，这些药物正在经历细胞凋亡和S期停滞。这种作用在宫颈癌细胞中比在正常的HFF或PHK细胞中要明显得多200-300倍。这可能是由于P53依赖或P53非依赖因素所致。在早期的结构-活性研究中，我们已经发现西多福韦的烷氧乙基酯比烷氧丙基CDV酯对宫颈癌细胞具有更强的抗增殖作用。此外，aikyl链上的一个双键的存在似乎增强了对Me-180和HeLa等宫颈癌细胞的抗增殖活性。OleloxyehyI-CDV的活性是我们评估的第一个化合物HDP-CDV的15到80倍。我们计划继续结构活性工作，评估新化合物的抗增殖作用及其对正常细胞和一组表达高危亚型的HPV DNA+细胞系细胞周期的影响。最活跃和最有选择性的化合物将被挑选出来，在裸鼠身上进行移植肿瘤的测试。其作用机制将通过评估基因和蛋白质的表达以及对细胞周期的影响来探索。我们相信，这种结构-活性和分子分析方法可能会取得成功，并可能广泛适用于HPV癌基因干扰P53和pRb水平和功能的其他类型的癌症。这项提议可能会导致治疗宫颈癌和其他HPV相关癌症的新药物。

Cidofovir (CDV) is a broad spectrum antiviral with activity against most double-stranded DNA viruses. A number of DNA viruses have been implicated as essential factors in viral-induced malignancy. The concept of using antivirals for treating cancers is in its infancy and worth exploring. This proposal seeks to evaluate new, highly active analogs of CDV that are substantially more active against DNA viruses while having reduced nephrotoxicity, a limiting factor in the utilization of cidofovir. We have synthesized and tested alkyoxyalkyl analogs of CDV that were at least 10 fold more potent than unmodified CDV. Our preliminary results in testing such agents against the human papilloma positive cell lines, Me-180 and HeLa, demonstrated that the cells were undergoing apoptosis and S phase arrest. This effect was 200-300 times more prominent in cervical cancer cells than in normal HFF or PHK cells. This may be due to p53 dependent or p53 independent factors. In early structure-activity studies we have identified that alkoxyethyl esters of cidofovir are more more potent antiproliferatives to cervical cancer cells than are alkoxypropyl CDV esters. Furthermore, the presence of one double bond in the aikyl chain seems to enhance the antiproliferative activity against cervical cancer cells such as Me-180 and HeLa. OleyloxyethyI-CDV is 15 to 80 times more active than HDP-CDV, the first compound we evaluated. We plan to continue structure-activity work, assessing antiproliferative effects of the new compounds and their effect on the cell cycle in normal cells and a panel HPV DNA+ cell lines expressing high risk subtypes. The most active and selective compounds will be selected for testing in athymic nude mice implanted with tumors. The mechanism of action will be explored by evaluating gene and protein expression and cell cycle effects. We believe that the structure-activity and molecular analysis approach may yield success and could be broadly applicable to a other types of cancer where HPV oncogenes interfere with the levels and function of p53 and pRb. This proposal could lead to new agents for treatment of cervical cancer and other HPV-associated cancers.