Experimental therapy of allogeneic solid tumors induced in athymic mice with suicide gene-transducing replication-competent foamy virus vectors.
A replication competent foamy virus derived retroviral vector expressing suicide genes has been constructed and characterized in vitro. Here we used vectors expressing the purine nucleoside phosphorylase (FOV-7/pnp), the nitroreductase (FOV-7/ntr), or the thymidine kinase (FOV-7/tk) suicide gene in an in vivo athymic (nude) mice/human glioblastoma tumor model. Gliomas were induced by subcutanous injection of U87 tumor cells. The virus vector was injected when the tumor became visible. Mice with vector virus-injected tumors were treated with the respective prodrug. The treatment resulted in significant inhibition of tumor growth. Surprisingly, in mice with vector virus-injected tumors without prodrug treatment a similar suppression of tumor growth was observed. In 65% (pnp vector), 75% (ntr vector) and 37% (tk vector) of these mice the tumors stopped growing or vanished and the animals remained tumor free for the 25 weeks of the experiment, whereas all mice of the control groups had to be killed because of the tumor growth. In control experiments, the suppression of tumor growth could also be observed when wild-type foamy virus was injected instead of the suicide gene-transducing vectors. Similar results were obtained using the nude mice/G59 human glioblastoma tumor model. In conclusion, the experiments demonstrate an oncolytic activity of foamy virus replication in a nude-mice glioblastoma xenograft tumor model. The analysis of vector virus DNA by PCR revealed that the vector persisted in different organs of the animals irrespective of the use of a prodrug or the elimination of a tumor.
Heinkelein
Martin
M
1Institut für Virologie und Immunbiologie, Universität Würzburg, Versbacher Strasse 7, 97078 Würzburg, Germany.
Hoffmann
Ursula
U
Lücke
Markus
M
Imrich
Horst
H
Müller
Justus G
JG
Meixensberger
Jürgen
J
Westphahl
Martin
M
Kretschmer
Axel
A
Rethwilm
Axel
A
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006224:Cricetinae; D004279:DNA, Viral / Q000235:genetics; D041722:Genes, Transgenic, Suicide / Q000235:genetics*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D016092:Spumavirus / Q000235:genetics*; D015996:Survival Rate; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
D004279:DNA, Viral