Efficacy of Oncolytic Mutants Targeting pRb and p53 Pathways Is Synergistically Enhanced When Combined with Cytotoxic Drugs in Prostate Cancer Cells and Tumor Xenografts

Abstract Replication-selective oncolytic adenoviruses have proven safety records with promising clinical outcomes. However, strategies to improve efficacy are still required. Here we report greatly improved antitumor efficacy for both attenuated (dl1520) and highly potent (dl922–947) oncolytic mutants in combination with the current standard of care for late-stage hormone-independent prostate cancers, mitoxantrone or docetaxel. In agreement with previous reports, dl922–947 had superior potency compared with dl1520 both as a single agent and in combination with cytotoxic drugs. The dl922–947 mutant caused significant synergistic cell killing in both drug-insensitive and -sensitive prostate cancer cell lines, PC3 and DU145, respectively, when combined with docetaxel or mitoxantrone. The magnitude of the synergistic response was greatest for dl1520 whereas overall efficacy was greatest for dl922–947, and the latter was also more efficacious in vivo in prostate cancer models. In DU145 and PC3 cells increased ...