Nucleoside Phosphonate Analogs and HPV Positive Cancers

核苷磷酸盐类似物和 HPV 阳性癌症

• 批准号: 7082203
• 负责人: Karl Y Hostetler
• 金额: $ 28.23万
• 依托单位: VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7082203
• 关键词: DNA virus; antineoplastics; apoptosis; athymic mouse; cell cycle; cell proliferation; chemical structure; chemical synthesis; cidofovir; drug screening /evaluation; gene expression; human papillomavirus; laboratory mouse; lead; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; neoplastic cell; nucleoside analog; oncogenic virus; pharmacokinetics; phosphonate

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.

西多福韦 (CDV) 是一种广谱抗病毒药物，对大多数双链 DNA 均具有活性 病毒。许多 DNA 病毒已被认为是病毒诱导的 恶性肿瘤。使用抗病毒药物治疗癌症的概念尚处于起步阶段，值得探索。该提案旨在评估新的、高活性的 CDV 类似物，这些类似物对 DNA 病毒的活性显着提高，同时降低肾毒性（西多福韦利用的限制因素）。我们合成并测试了 CDV 的烷氧基烷基类似物，其效力比未修饰的 CDV 至少高 10 倍。我们针对人乳头状瘤阳性细胞系 Me-180 和 HeLa 测试此类药物的初步结果表明，这些细胞正在经历凋亡和 S 期停滞。这种效应在宫颈癌细胞中比在正常 HFF 或 PHK 细胞中显着 200-300 倍。这可能是由于 p53 依赖性或 p53 独立因素造成的。在早期的结构-活性研究中，我们发现西多福韦烷氧基乙基酯比烷氧基丙基 CDV 酯对宫颈癌细胞具有更强的抗增殖作用。此外，烷基链中存在一个双键似乎增强了对宫颈癌细胞（如 Me-180 和 HeLa）的抗增殖活性。 OleyloxyethylI-CDV 的活性比我们评估的第一个化合物 HDP-CDV 高 15 至 80 倍。我们计划继续进行结构活性研究，评估新化合物的抗增殖作用及其对正常细胞和表达高风险亚型的 HPV DNA+ 细胞系的细胞周期的影响。将选择最具活性和选择性的化合物在植入肿瘤的无胸腺裸鼠中进行测试。将通过评估基因和蛋白质表达以及细胞周期效应来探索作用机制。我们相信，结构-活性和分子分析方法可能会取得成功，并且可以广泛适用于 HPV 癌基因干扰 p53 和 pRb 的水平和功能的其他类型的癌症。该提案可能会催生治疗宫颈癌和其他 HPV 相关癌症的新药。