Suicide gene-armed measles vaccine virus for the treatment of AML

Virotherapy comprises a novel therapeutic approach to selectively eliminate cancer cells. Preclinical, as well as clinical data have demonstrated the efficacy of tumor-selective (oncolytic) viruses in hematological malignancies. In this study, we infected AML cell lines and primary AML cells from patients with measles vaccine virus either expressing GFP or armed with super cytosine deaminase, which converts the prodrug, 5-fluorocytosine, into the chemotherapeutic compound, 5-fluorouracil. Target cell density of the measles entry receptor, CD46, infection rates of targeted leukemic cells, tumor cell viability, and apoptotic rates were determined. We found that measles vaccine virus infected the leukemic blasts and profoundly diminished the number and viability of leukemic cells via the induction of apoptosis. The conversion of 5-fluorocytosine to 5-fluorouracil exerted a potent additive tumoricidal effect. This was also observed in cases when leukemic cells displayed only moderate susceptibility to the oncolytic virus and hence direct oncolysis. Taken together, in this study, we provide a first characterization of the combinatorial use of measles vaccine virus and 5-fluorouracil for treatment of AML. Our approach to site-specifically produce the active drug and combine this agent with the direct lytic effect of virotherapy may overcome present limitations and constitutes a feasible method with which to introduce 5-fluorouracil in the treatment of AML.