Systems and carcinogenic impact assessment of topical microbicides on human mucosa

局部杀菌剂对人体粘膜的系统和致癌影响评估

基本信息

批准号：
8922415
负责人：
Florian Hladik
金额：
$ 69.05万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8922415
关键词：
AIDS prevention Address Adverse effects Anti-Inflammatory Agents Anti-Retroviral Agents Anti-inflammatory Apoptosis Biological Assay Biopsy Cell Density Cell Differentiation process Cell Survival Cells Cervical Cervix Uteri Clinical Cross-Over Trials DNA Data Diphosphates Dose Drug Formulations Effectiveness Epithelial Cells Fluorescence Force of Gravity Frequencies Gel Gene Expression Gene Expression Profile Genital system Gilead brand of tenofovir disoproxil fumarate HIV HIV Infections Homeostasis Human Human Papillomavirus Human papilloma virus infection Human papillomavirus 16 Immune Immunodeficient Mouse Impairment Incidence Individual Inflammation Inflammation Mediators Inflammatory Interleukin-10 Intestinal Neoplasms Irritants Lead Leukocytes Licensure Local Microbicides Longitudinal Studies Malignant Neoplasms Malignant neoplasm of cervix uteri Mitochondria Modeling Mucous Membrane Mus Mutation Neoplastic Processes Nonoxynol 9 Oral Patients Pharmaceutical Preparations Phase Phase III Clinical Trials Placebos Prevention Prevention strategy Proliferating Prophylactic treatment Proteins Proteome Publishing Rectum Regulatory Pathway Relative (related person)Resistance Reverse Transcriptase Inhibitors Risk Rodent Route Safety Schedule Specimen Stimulus Suggestion System Systems Biology T-Lymphocyte TMC120-R147681 Tenofovir Testing Thymidine Time Tissues Topical application Toxic effect Transgenic Mice Vagina Vagina Carcinoma Vaginal Ring Woman Xenograft procedure Zidovudine arm carcinogenesis carcinogenicity cervicovaginal chemokine design digital ds-DNA efficacy trial follow-up in vitro Assay in vivo innovation microbicide mouse model neoplastic cell novel novel strategies nucleoside analog phase 1 study prevent protective efficacy public health relevance rectal repaired screening sexual HIV transmission tool tumor

项目摘要

DESCRIPTION (provided by applicant): Several antiretroviral drugs are being tested as topical microbicides for the prevention of sexual HIV transmission. Because effective HIV prophylaxis would entail frequent use of topical antiretroviral drugs by healthy individuals, such use would need to be safe. However, in a recent comprehensive assessment of 1% tenofovir gel in vivo, conducted in the MTN-007 trial, we uncovered that it had profound effects on gene expression in the rectal mucosa, suggesting important changes in gut immune and self-repair homeostasis. When we followed up on these results using human primary vaginal epithelial cells, we found very similar changes. These changes, in particular pronounced impairment of mitochondrial function and the prospect of carcinogenicity, have the potential to contraindicate the use of tenofovir, and potentially of other drugs of the same DNA chain terminator class, as a topical microbicide. It is therefore imperative to extensively and immediately expand on these findings in order to corroborate tenofovir's side effects on the mucosa, to determine whether pericoital use is safer than daily use, and to compare its effects on the rectal and vaginal mucosa in vivo. In Aim 1 of this proposal we will address these issues using systems biology approaches in two trials testing 1% tenofovir gel, MTN-014 and MTN-017, using rectal and vaginal tissue specimens. Besides indirect suggestions in our data that tenofovir could increase neoplastic processes in the mucosa, a large body of data has demonstrated that DNA chain terminator drugs, like tenofovir and azidothymidine, are carcinogenic and mutagenic in a dose-dependent manner. Because of the potential gravity of this effect and the high concentrations of active drug achieved in mucosal tissues after topical application (>2 logs higher than achieved by oral dosing), we propose in Aim 2 to directly investigate the mucosal carcinogenicity of topical tenofovir and to determine whether non-DNA chain terminators like dapivirine might be safer alternatives. We propose innovative approaches designed to overcome the limitations of traditional rodent carcinogenicity models, incorporate human primary mucosal epithelial cells, and include an assessment of human papilloma virus (HPV) as a co-factor in tenofovir-induced carcinogenesis. These studies will help determine the relative suitability of drugs like tenofovir as topical prevention agents in comparison to non-DNA chain terminators like dapivirine, and provide novel tools for the assessment of the mucosal safety profile of candidate microbicide drugs, including the likelihood of carcinogenicity. Should our study confirm that DNA chain terminator drugs are too risky for mucosal application, it is hoped that we will find drugs like dapivirine to be effective and safer alternatives.

描述（由适用提供）：几种抗逆转录病毒药物正在作为局部杀菌剂测试，以预防性HIV传播。由于有效的HIV预防会经常使用健康个体的局部抗逆转录病毒药物，因此需要安全。但是，在MTN-007试验中进行的1％替诺福韦凝胶的最新全面评估中，我们发现它对直肠粘膜中的基因表达产生了深远的影响，这表明肠道免疫和自我重复稳态的重要变化。当我们使用人类原代阴道上皮细胞跟踪这些结果时，我们发现了非常相似的变化。这些变化特别是明显的线粒体功能损害和致癌性的前景，有可能禁忌使用替诺福韦的使用，并且有可能作为局部DNA链终结剂类的其他药物作为局部菌糖。因此，必须广泛并立即对这些发现进行扩展，以证实替诺福韦对粘膜的副作用，以确定上腹的使用是否比日常使用更安全，并比较其对直肠和阴道粘膜在体内的影响。在该提案的目标1中，我们将使用直肠和阴道组织标本在两项试验中使用系统生物学方法来解决这些问题。除了我们数据中的间接建议外，替诺福韦可能会增加粘膜中的肿瘤过程外，大量数据表明，替代性的剂量依赖性的DNA链终结药物（如Tenofovir和Azidothymidine）具有致癌性和诱变性。由于这种作用的潜在重力和局部应用后在粘膜组织中获得的高浓度的活性药物（> 2的对数高于口服给药），我们提出AIM 2的建议直接研究局部替诺福韦的粘膜致癌性，并确定像dapivirine这样的非DNA链终结剂是否可以安全地替代。我们提出了旨在克服传统啮齿动物致癌模型的局限性的创新方法，并结合了人类原发性粘膜上皮细胞，并包括评估人类乳头状瘤病毒（HPV）作为替诺福韦诱导的致癌作用中的共同因素。与非DNA链终结剂（如Dapivirine）相比，这些研究将有助于确定像Tenofovir一样作为局部预防药物的药物的相对适合性，并为评估候选菌心药物的粘膜安全性（包括癌性的可能性）提供了新的工具。如果我们的研究证实DNA链终结药对粘膜的施用太冒险了，希望我们能发现像Dapivirine这样的药物是有效且更安全的替代方法。