Pulsed Versus Continuous Application of the Prodrug 5-Fluorocytosine to Enhance the Oncolytic Effectiveness of a Measles Vaccine Virus Armed with a Suicide Gene

Abstract

Oncolytic virotherapy with measles vaccine virus (MeV) already has been demonstrated to be safe. However, early clinical results pointed 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 nontoxic prodrug 5-fluorocytosine (5-FC) to the chemotherapeutic drug 5-fluorouracil (5-FU). To preclinically investigate what an optimal prodrug-assisted therapeutic regimen might look like, we added 5-FC at various time points after infection with MeV-SCD and either let the prodrug remain in the tumor cell culture medium continuously for various time periods ("continuous" 5-FC application) or applied it only temporarily for defined shorter periods of time ("pulsed" 5-FC application); we also varied the time point at which 5-FC was added after infection with MeV-SCD. As a result, addition of the prodrug at early times postinfection (e.g., at 3 hr postinfection) was found to be inferior concerning the overall oncolytic effectiveness when compared with addition of 5-FC at later time points (e.g., at 24 hr postinfection). Next, oncolytic effectiveness was found to correlate positively with the overall duration of incubation of MeV-infected tumor cells with 5-FC. Of note, this was true despite our finding that addition of the prodrug could also exert an inhibitory effect on the generation of infectious progeny viral particles, that is, on virus replication. These findings should be helpful for the rational design of further trials (preclinical, clinical) using suicide gene armed virotherapeutics, such as MeV-SCD.

Chemovirotherapy for pancreatic cancer: Gemcitabine plus oncolytic measles vaccine virus

“…Furthermore, new findings concerning tumor biology should be taken into consideration searching for other therapeutic options. In that context, it is very important to analyze different therapeutic regimens (32), and the influence of the immune system on virotherapy-considering both 'negative' aspects as it weakens viral infection and 'positive' aspects as the activation of the immune system leads to anti-tumor immune defense (7,18). In a recently published review the necessity of a very profound investigation and understanding of tumor biology was pointed out as well (33).…”

Combination of the oral histone deacetylase inhibitor resminostat with oncolytic measles vaccine virus as a new option for epi-virotherapeutic treatment of hepatocellular carcinoma

“…We previously have demonstrated that resistance phenomena to MeV-SCD–based oncolysis could be overcome by increasing the MOI of MeV-SCD or by employing the suicide gene function of MeV-encoded SCD, which results in converting the nontoxic antifungal prodrug 5-FC to the well-known cytotoxic drug 5-FU. 11 , 27 , 28 , 34 Nevertheless, increasing the dosage of administered viral vectors in patients is yet limited due to constraints in the respective manufacturing processes and as those oncocytotoxic agents face various biological barriers consisting, e.g. , of the host immune system as well as the tumor microenvironment, it is essential to enhance oncolytic virotherapy (OV) potency by prudent combination strategies.…”

Oncolytic virus delivery: from nano-pharmacodynamics to enhanced oncolytic effect

“… 128 Pulsed application of immunosuppressive drugs is preferred, as seen with the prodrug 5-fluorocytosine and measles vaccine virus. 129 Other immunomodulators such as cobra venom factor may also facilitate infection with HSV. 130 …”