Animal Model for Adenovirus Oncolytic Vectors

描述（由申请人提供）：还评价了腺病毒载体在治疗癌症中的功效。由于癌症是美国的第二大死亡原因，并且目前的治疗方法并不总是足够的，因此需要新的癌症疗法。具有复制能力的溶瘤腺病毒载体已被设计成杀死癌细胞作为其生命周期的一部分。本实验室基于ADP蛋白的过表达，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，并有助于腺病毒的传播。我们的载体可有效破坏细胞培养中的人类癌细胞，并抑制免疫缺陷（裸）小鼠中的肿瘤生长。人异种移植物-裸鼠模型通常用于评价溶瘤腺病毒载体，因为教条认为人腺病毒不在动物中复制。允许或至少半允许hum（腺病毒复制）并且具有完整免疫系统的更现实的动物模型对于溶瘤腺病毒癌症基因治疗领域具有重要价值。我们已经确定了一种腺病毒的动物模型，结果令人鼓舞。我们发现，腺病毒能够感染，复制，并在这种动物的癌细胞系中从细胞扩散到细胞，这些特征在用腺病毒载体治疗癌症中是至关重要的。我们拟探讨此动物模型用于溶瘤腺病毒肿瘤基因治疗。具体目标1的目的是进一步研究腺病毒感染该动物癌细胞系的体外特征，例如腺病毒蛋白表达的时程。 此外，我们将对感染ADP突变体的细胞进行细胞活力测定，以评估ADP是否在这些动物细胞中发挥作用。具体目标2将解决腺病毒癌症基因治疗的动物模型的发展。我们将用载体注射皮下肿瘤，并通过大体病理学、免疫组织化学和组织病理学评估这些载体的有效性和安全性。

DESCRIPTION (provided by applicant): Adenovirus vectors have also 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 their life cycle. Our laboratory has developed a series of unique oncolytic adenovirus vectors based on the overexpression of a protein named ADP. ADP promotes virus release from the cell late in infection and aids in the spread of adenovirus. 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 hum,an 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 an animal model for adenovirus 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, features that are critical in the treatment of cancer with adenovirus vectors. We propose to explore this animal model for oncolytic adenovirus cancer gene therapy. The goal of Specific Aim 1 is to further investigate the in vitro characteristics of adenovirus infection of cancer cell lines from this animal such as the timecourse of expression of adenovirus proteins. In addition, we will conduct cell viability assays for cells infected with ADP mutants to evaluate whether ADP functions in these animal cells. Specific Aim 2 will address the development of the animal model for adenovirus cancer gene therapy. We will inject subcutaneous tumors with vectors and evaluate the efficacy and safety of these vectors by gross pathology, immunohistochemistry, and histopathology.