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There is a pressing need to develop new treatments for breast cancer. Oncolytic, conditionally-replicating adenoviruses (CRADs) represent one such approach. Our objective to develop new CRADs containing mutant DNA polymerases with a high functional dNTP requirement; we hypothesize that these vectors will replicate selectively in tumor cells. We have now shown that the thermostable Pfu DNA polymerase can be used as a surrogate for the adenovirus DNA polymerase, and we have used this approach to identify new amino acid residues that affect dNTP binding and utilization (residues Y690, M689 and G688 in adenovirus polymerase). We have also shown that mutations which drastically alter the dNTP binding efficiency of the adenovirus DNA polymerase give rise to replication-defective viruses, when substituted into the backbone of an intact adenovirus vector. In contrast, some mutations with more modest effects on dNTP binding efficiency (e.g., the I664V mutation) are compatible with virus replication and permit the recovery of infectious virus. In year two, we will develop and test additional CRADs with mutant DNA polymerases, and we will then examine their ability to selectively replicate in, and lyse, breast cancer cells.