Oncolytic adenoviruses for treatment of ovarian cancer

摘要: Virotherapy, the use of oncolytic properties viruses for eradication tumor cells, is an attractive strategy treating cancers resistant to traditional modalities. Adenoviruses can be genetically modified selectively replicate in and destroy cells through exploitation molecular differences between normal cancer cells. The lytic life cycle adenoviruses results oncolysis infected spreading virus progeny surrounding local amplification input dose. Normal are spared due lack replication. Nevertheless, despite excellent preclinical data proven safety humans with these agents, several obstacles remain. potency might limited poor transduction target Most adenoviral gene therapy strategies based on serotype 5 (Ad5), which binds coxsackie-adenovirus receptor (CAR). However, expression CAR frequently low many types advanced cancers. Lack circumvented by substituting knob domain Ad5 fiber 3 (Ad3) knob. This allows binding entry Ad3 receptor, expressed at high levels most Clinical trials early-generation have indicated that complete elimination solid masses rarely occurs. A powerful approach improving efficacy virotherapy utilization combination conventional therapies such as chemotherapeutic agents. We evaluated Ad5/3-Δ24, a receptor-targeted adenovirus, gemcitabine or epirubicin against ovarian cancer. agents showed synergistic cell killing vitro compared single treatments. Our also indicate reduces initial rate Ad5/3-Δ24 replication without affecting total amount produced. In orthotopic murine model peritoneally disseminated cancer, combining either resulted greater therapeutic benefit than agent alone, 60% mice were cured. dose sequencing critical versus toxicity, some treated succumbed treatment-related liver damage. Another useful increasing arm transgenes genes encoding prodrug-converting enzymes. constructed Ad5/3-Δ24-TK-GFP, infectivity-enhanced adenovirus thymidine kinase (TK) – green fluorescent protein (GFP) fusion protein. novel replicated efficiently correlated increased GFP expression. Delivery prodrug ganciclovir (GCV) immediately after infection abrogated viral replication, utility switch mechanism. Oncolytic