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“Pulsed” versus “continuous” application of the prodrug 5-FC for enhancing oncolytic effectiveness of a measles vaccine virus armed with a suicide gene
Oncolytic virotherapy with measles vaccine virus (MeV) has already been demonstrated to be safe (Galanis et al., 2010). However, when monitoring the expression of the MeV encoded reporter gene CEA it was found (i) that only few tumor cells were infected by MeV and (ii) that subsequently to initial tumor colonization no substantial production of progeny MeV particles took place in the respective cancer patients (Russell, Peng & Bell, 2012). These early clinical results point out the necessity for an enhancement of oncolytic effectiveness of MeV-based virotherapeutics.
In our work, we are developing an armed measles vaccine virus (MeV-SCD) encoding a suicide fusion gene of yeast cytosine deaminase/uracil phosphoribosyltransferase, converting the non-toxic prodrug 5-FC to the chemotherapeutic drug 5-FU (Berchtold et al., 2013).
To preclinically investigate how an optimal prodrug-assisted therapeutic regimen could look like, we added 5-FC at different time points after infection with MeV-SCD and either let the prodrug stay in the culture medium continuously for different time periods (“continuous” 5-FC application) or applied it only temporarily for defined shorter time periods (“pulsed” 5-FC application); we also varied the time point at which 5-FC was added after infection with MeV-SCD.
As a result, an early and continuous addition of 5-FC was found to be superior in terms of oncolytic effectiveness to any later or shorter application; of note, this was despite our finding that addition of the prodrug could also have an inhibitory effect on virus replication. In the clinical perspective, a 5-FC-induced “chemotherapeutic” break up of tumor cells might also help to foster viral spreading throughout targeted tumor masses.
Taken together, these findings are helpful for the rational design of further preclinical and clinical trials using suicide gene armed virotherapeutics, such as MeV-SCD.