ADENOVIRUS REPLICATION COMPETENT ANTICANCER VECTOR

我们已经构建了两种新型的人腺病毒复制型载体，命名为KD 1和KD 3，用于治疗不同的人类癌症。这些载体杀死癌细胞，在细胞间迅速扩散，对非癌细胞的影响最小。与大多数表达外源基因且不能复制的腺病毒载体不同，KD 1和KD 3具有三种治疗原理。首先，它们表达一种蛋白质，介导有效的细胞裂解和病毒从细胞到细胞的传播。其次，它们含有一种突变，可以减少非分裂细胞中的复制。因此，它们只在癌细胞中复制良好。第三，KD 1和KD 3应该刺激炎症和免疫细胞浸润到肿瘤中，这将破坏局部肿瘤以及已经转移的肿瘤。在具体目标1中，我们建议全身注射KD 1和KD 3，并控制病毒，并确定KD 1和KD 3是否导致肿瘤消退。在目的2中，我们将检查KD 1和KD 3补充腺病毒复制缺陷型载体在裸鼠中生长的人肿瘤中传播的能力。在目标3中，我们将在KD 1和KD 3背景下制备组织特异性腺病毒复制能力抗癌载体，然后检查它们破坏裸鼠中生长的组织特异性肿瘤的能力。

We have constructed two novel human adenovirus replication competent vectors, named KD1 and KD3, for use in treating different human cancers. These vectors kill cancer cells, spread rapidly from cell-to-cell, and have minimal effect on non-cancerous cells, Unlike most adenovirus vectors which express a foreign gene and cannot replicate, KD1 and KD3 have three therapeutic principles. First, they express a protein that mediates efficient cell lysis and virus spread from cell-to-cell. Second, they contain a mutation that reduces replication in non-dividing cells. As a result, they only replicate well in cancer cells. Third, KD1 and KD3 should stimulate the infiltration of inflammatory and immune cells into the tumor, which would destroy the local tumor as well as tumors that have metastasized. In Specific Aim 1, we propose to inject KD1 and KD3, and also control viruses, systemically, and determine whether KD1 and KD3 cause regression of tumors. In Aim 2, we will examine KD1 and KD3 for their ability to complement the spread of adenovirus replication- defective vectors in human tumors growing in nude mice. In Aim 3, we will prepare tissue-specific adenovirus replication-competent anti-cancer vectors in a KD1 and KD3 background, then examine their ability to destroy tissue-specific tumors growing in nude mice.