权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Hamster Model for Oncolytic Adenovirus Vectors

溶瘤腺病毒载体的仓鼠模型

基本信息

批准号：
7804580
负责人：
WILLIAM SM WOLD
金额：
$ 25.34万
依托单位：
SAINT LOUIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-06-16 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7804580
关键词：
Adenovirus Death Protein Adenovirus Infections Adenovirus Protein Adenovirus Vector Adenoviruses Affect Animal Model Animals Antibodies Architecture Biodistribution Biological Assay C57BL/6 Mouse Cancer Model Cancer cell line Cause of Death Cell Culture Techniques Cell Line Cells Clinical Trials Clone Cells Code Cytolysis Dose Drug Kinetics DsRed Firefly Luciferases Genes Growth Hamster Cell Line Hamsters Human Human Adenoviruses Immune response Immune system Immunity Immunocompetent Immunohistochemistry In Vitro Indirect Immunofluorescence Infection Injection of therapeutic agent Laboratories Life Cycle Stages Liver Lung Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Mesocricetus auratus Microscopy Modeling Monitor Mus Names Neoplasm Metastasis Normal Cell Normal tissue morphology Nude Mice Oncogenes Oncolytic Organ Pathogenesis Production Property Proprotein Convertase 1 Proteins Radiation Renal carcinoma Research Research Personnel Resistance Reverse Transcriptase Polymerase Chain Reaction Rodent Role SCID Mice Safety Series Therapeutic Time Toxic effect Virion Virus Xenograft procedure base cancer cell cancer therapy chemotherapeutic agent chemotherapy cytokine defective adenoviral vector design enhanced green fluorescent protein gene therapy in vivo interest intravenous administration killings leiomyosarcoma molecular imaging mouse model neoplastic cell novel overexpression promoter radiation effect safety study subcutaneous tumor tumor growth vector

项目摘要

DESCRIPTION (provided by applicant): Adenovirus vectors have been evaluated for their efficacy in treating cancer. As cancer is the second leading cause of death in the U.S. and current therapeutics are not always sufficient, new cancer therapies are desired. Replication-competent oncolytic adenovirus vectors have been designed to kill cancer cells as part of the virus life cycle. Our laboratory has developed a series of unique oncolytic adenovirus vectors based on the overexpression of an adenovirus-coded protein named ADP. ADP promotes virus release from the cell late in infection and aids in the cell-to-cell spread of adenovirus. Our hypothesis is that high level of expression of ADP will increase the ability of the vector to spread from cell-to-cell in the tumor and thereby destroy the tumor. Our vectors are efficacious in destroying human cancer cells in cell culture and suppressing the growth of tumors in immunodeficient (nude) mice. The human xenograft-nude mouse model is commonly used to evaluate oncolytic adenovirus vectors because the dogma holds that human adenoviruses do not replicate in animals. A more realistic animal model that is permissive or at least semi-permissive for human adenovirus replication and that has an intact immune system would be of great value to the field of oncolytic adenovirus cancer gene therapy. We have identified the Syrian hamster as an animal model for oncolytic adenovirus vectors with promising results. We found that adenovirus is able to infect, replicate, and spread from cell-to-cell in cancer cell lines of this animal. Adenovirus replicates in the lungs, liver, and other organs. Our oncolytic adenovirus vector suppresses the growth of three different hamster tumors and replicates within these tumors. The toxicity and pharmacokinetic biodistribution of our vector as well as wild-type adenovirus and replication-defective adenovirus controls have been determined following intravenous administration of these viruses. We propose to further develop this animal model for oncolytic adenovirus cancer gene therapy. In Specific Aim 1 we will investigate the interaction between the host, vector, and tumor cells. We will examine vector replication and spreading in tumors, identify factors such as tumor architecture, vector resistance, or immunity that limit the efficacy of vectors, and study the role of the immune system in suppressing tumor growth. In Specific Aim 2 we will determine the effect of radiation and chemotherapy on the efficacy of Ad vectors, both in cell culture and in the animal model. In Specific Aim 3 we will investigate the efficacy of replication-selective vectors in this model and attempt to develop orthotopic lung metastasis and pancreatic cancer models in the hamster. These studies should help advance our vectors and possibly oncolytic adenovirus vectors from other research groups toward clinical trials. Although not proposed specifically in this application, these studies should also provide novel information on adenovirus pathogenesis.

描述（由申请人提供）：腺病毒载体已被评估其治疗癌症的功效。由于癌症是美国第二大死亡原因，而目前的治疗方法并不总是足够的，因此需要新的癌症治疗方法。作为病毒生命周期的一部分，具有复制能力的溶瘤腺病毒载体被设计用于杀死癌细胞。我们的实验室基于腺病毒编码蛋白ADP的过表达，开发了一系列独特的溶瘤腺病毒载体。ADP在感染后期促进病毒从细胞中释放，并有助于腺病毒的细胞间传播。我们的假设是，ADP的高水平表达将增加载体在肿瘤细胞间传播的能力，从而破坏肿瘤。我们的载体在细胞培养中有效地破坏人类癌细胞，并抑制免疫缺陷（裸）小鼠肿瘤的生长。人类异种移植裸鼠模型通常用于评估溶瘤腺病毒载体，因为教条认为人类腺病毒不会在动物中复制。一个允许或至少半允许人类腺病毒复制且具有完整免疫系统的更现实的动物模型将对溶瘤腺病毒癌基因治疗领域具有重要价值。我们已经确定了叙利亚仓鼠作为溶瘤腺病毒载体的动物模型，并取得了有希望的结果。我们发现腺病毒在这种动物的癌细胞系中能够感染、复制和在细胞间传播。腺病毒在肺、肝和其他器官中复制。我们的溶瘤腺病毒载体抑制三种不同的仓鼠肿瘤的生长，并在这些肿瘤中复制。在静脉注射这些病毒后，我们的载体以及野生型腺病毒和复制缺陷腺病毒对照的毒性和药代动力学生物分布已经确定。我们建议进一步开发该动物模型用于溶瘤腺病毒癌的基因治疗。在特异性目的1中，我们将研究宿主、载体和肿瘤细胞之间的相互作用。我们将研究载体在肿瘤中的复制和传播，确定诸如肿瘤结构，载体抗性或免疫等限制载体功效的因素，并研究免疫系统在抑制肿瘤生长中的作用。在特异性目标2中，我们将在细胞培养和动物模型中确定放射和化疗对Ad载体疗效的影响。在Specific Aim 3中，我们将研究复制选择载体在该模型中的有效性，并尝试在仓鼠中建立原位肺转移和胰腺癌模型。这些研究应该有助于将我们的载体和其他研究组的溶瘤腺病毒载体推向临床试验。虽然没有特别提出在这方面的应用，但这些研究也应该提供关于腺病毒发病机制的新信息。