Enhanced killing of ovarian carcinoma using oncolytic measles vaccine virus armed with a yeast cytosine deaminase and uracil phosphoribosyltransferase

Abstract

ObjectiveTo preclinical assess the feasibility of combining oncolytic measles vaccine virus (MeV) with suicide gene therapy for ovarian cancer treatment. MethodsWe genetically engineered a recombinant MeV armed with a yeast-derived bifunctional suicide gene that encodes for cytosine deaminase and uracil phosphoribosyltransferase (MeV-SCD). From this suicide gene, a chimeric protein is produced that converts the non-toxic prodrug 5-fluorocytosine (5-FC) into highly cytotoxic 5-fluorouracil (5-FU) and directly into 5-fluorouridine monophosphate (5-FUMP) thereby bypassing an important mechanism of chemoresistance to 5-FU. ResultsMeV-SCD was demonstrated to infect, replicate in and effectively lyse not only human ovarian cancer cell lines, but also primary tumor cells (albeit at lower efficiencies) that were derived from malignant ascites of ovarian cancer patients. Addition of the prodrug 5-FC significantly enhanced cell killing. Importantly, precision-cut tumor slices of human ovarian cancer patient specimens were efficiently infected with MeV-SCD. The prodrug-converting enzyme SCD was expressed by all infected tumor slices, thereby ensuring provision of the suicide gene arming function in patient-derived materials. ConclusionsWith respect to safety and therapeutic impact, arming of oncolytic measles vaccine virus warrants further clinical investigation for ovarian cancer treatment.