The Combination of Carboxylesterase-Expressing Oncolytic Vaccinia Virus and Irinotecan

• Main Author: Becker, Michelle Caitlin
• Language: en
• Published: 2013
• Subjects: Cancer; Oncolytic virus; Vaccinia virus; Carboxylesterase; Irinotecan; CPT-11; Gene-directed enzyme prodrug therapy; Vascular endothelial growth factor; Angiogenesis; Virus delivery; Virus spread; Plaque purification; Virus aggregation; Virus filtration
• Online Access: http://hdl.handle.net/10393/23653

This project combines oncolytic Vaccinia virus (VV) with irinotecan (CPT-11) for the treatment of cancer. VV can infect, replicate in and destroy cancer cells, yet leave healthy cells relatively unaffected. CPT-11 is a chemotherapeutic of which ~5% is converted to the more active chemotherapeutic SN-38 by endogenous carboxylesterase (CE) enzymes. SN-38 is a topoisomerase I inhibitor that induces DNA double strand breaks, leading to growth arrest and apoptosis. Consequently, VV has been engineered to express a more effective isoform of the CE enzyme. The virus’ tumour tropism should restrict enhanced conversion of CPT-11 to the tumour. Neither CPT-11 nor SN-38 interfered with VV replication or spread. Engineered recombinants expressed CE enzyme which, when combined with CPT-11, produced DNA double strand breaks and cancer cell death. In vitro, the combination of CE-virus and CPT-11 killed more K-562 cancer cells than its non-CE counterpart and CPT-11.