Designing and building oncolytic viruses

Maroun, Justin; Muñoz-Alía, Miguel; Ammayappan, Arun; Schulze, Autumn; Peng, Kah-Whye; Russell, Stephen

CD converts 5-flurocytosine (5-FC), an inert small molecule that is administered intravenously, to 5-flurouracil (5-FU), an antimetabolite that irreversibly inhibits thymidylate synthase and is an approved chemotherapeutic agent for a variety of cancers (anal, breast, colorectal, esophageal, stomach, pancreatic and skin) [29] . The argument supporting the CD/5-FC system is that local production of 5-FU in the OV-infected tumor will create a 5-FU concentration gradient that will expose tumor cells to a higher concentration of the drug compared with distant tissues, thereby ameliorating toxicity and enhancing the therapeutic index of the drug. However, 5-FU is freely diffusible so local production of the drug in a CD-positive tumor exposed to high concentrations of 5-FC can lead to systemic toxicity [140] . The dose of 5-FC must therefore be adjusted accordingly. CD has been incorporated into several OVs including adenoviruses, paramyxoviruses and poxviruses, but the one that has advanced ahead of all others in clinical testing is a C-type retrovirus, Toca-511, which is currently being evaluated in a Phase III clinical trial for the treatment of patients with malignant glioma [141] [142] [143] . Besides the TK and CD prodrug convertase systems, there are reports of OVs engineered to express the cyclophosphamide-activating protein CYP2B1, future science group www.futuremedicine.com the CPT11-activating secreted human intestinal carboxylesterase (shiCE) and the fludarabine phosphate activating purine nucleotide phosphorylase [144, 145] .