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.