Complex interactions between the replicating oncolytic effect and the enzyme/prodrug effect of vaccinia-mediated tumor regression.
Replicating viruses for cancer gene therapy have beneficial antitumor effects, however, in the setting of an enzyme/prodrug system, the interactions between these viruses and the activated agents are complex. A replicating vaccinia virus expressing the cytosine deaminase gene (VVCD), which converts the prodrug 5-FC into 5-FU, was characterized in vitro and in vivo for its antitumor effects and pathogenicity. Replicating VVCD (+/-5-FC) at various MOIs was used to infect MC38 murine colon adenocarcinoma cells. At high MOIs (>0.1) virus alone was able to kill the majority (65-90%) of cells by day 5 with no additional benefit from prodrug. At low MOIs only the effect of prodrug is seen. Cell lysates demonstrated 300-fold reduced viral recovery from cells treated with both VVCD and 5-FC compared with controls treated with virus alone. Nude mice bearing subcutaneous MC38 tumors were injected with VVCD (or control) and treated with 5FC or control. Mice injected with VVCD (with or without 5FC treatment) had smaller tumors than the controls, suggesting that replicating vaccinia alone is cytotoxic to tumors in vivo. The addition of 5-FC improved the antitumor response when a low dose of virus was injected into tumors. Also, compared with mice that received virus alone, those that received VVCD and 5FC had significantly prolonged survival from virus-mediated death. In conclusion, the addition of an enzyme/prodrug system to a replicating virus can improve the antitumor response and decrease viral pathogenicity. Gene Therapy (2000) 7, 1217-1223.
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
J A
JA
McCart
M
M
Puhlmann
J
J
Lee
Y
Y
Hu
S K
SK
Libutti
H R
HR
Alexander
D L
DL
Bartlett
D000230:Adenocarcinoma / Q000628:therapy*; D000818:Animals; D003110:Colonic Neoplasms / Q000628:therapy*; D043525:Cytosine Deaminase; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005437:Flucytosine / Q000378:metabolism / Q000627:therapeutic use*; D005472:Fluorouracil / Q000378:metabolism / Q000627:therapeutic use; D015316:Genetic Therapy / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009700:Nucleoside Deaminases / Q000235:genetics*; D011355:Prodrugs / Q000378:metabolism / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D014616:Vaccinia virus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects
D011355:Prodrugs; D005437:Flucytosine; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase; D005472:Fluorouracil