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（由申请人提供）：正在测试几种抗逆转录病毒药物作为预防艾滋病毒性传播的外用杀微生物剂，因为有效的艾滋病毒预防需要健康个体经常使用外用抗逆转录病毒药物，因此这种使用必须是安全的。最近在 MTN-007 试验中进行的 1% 替诺福韦凝胶体内综合评估中，我们发现它对直肠基因表达具有深远影响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，特别是线粒体功能的明显损害和致癌性的前景。有可能禁止使用替诺福韦以及同一 DNA 链终止剂类别的其他药物作为局部杀菌剂，因此必须立即广泛扩展这些发现，以便证实替诺福韦对粘膜的副作用，以确定性交时使用是否比日常使用更安全，并比较其在体内对直肠和阴道粘膜的影响。在本提案的目标 1 中，我们将使用系统生物学方法解决这些问题。使用直肠和阴道组织标本测试 1% 替诺福韦凝胶、MTN-014 和 MTN-017 的试验除了我们的数据间接表明替诺福韦可能会增加肿瘤过程外。大量数据表明，DNA 链终止剂药物（如替诺福韦和叠氮胸苷）具有剂量依赖性致癌性和致突变性，因为这种作用的潜在严重性以及在粘膜中达到的高浓度活性药物。局部应用后的组织（比口服给药高>2 个对数），我们在目标 2 中建议直接研究局部替诺福韦的粘膜致癌性，并确定是否像达匹韦林这样的非 DNA 链终止剂可能是更安全的替代品，我们提出了创新方法，旨在克服传统啮齿动物致癌性模型的局限性，纳入人类原代粘膜上皮细胞，并包括对人乳头状瘤病毒 (HPV) 作为辅助因子的评估。这些研究将有助于确定替诺福韦等药物与达匹韦林等非 DNA 链终止剂相比作为局部预防剂的相对适用性，并提供相关信息。用于评估候选杀微生物剂药物粘膜安全性的新工具，包括致癌性的可能性。如果我们的研究证实 DNA 链终止剂药物对于粘膜应用风险太大，我们希望能发现像达匹韦林这样的药物是有效的。和更安全的替代品。