Tumors expressing the cytosine deaminase suicide gene can be eliminated in vivo with 5-fluorocytosine and induce protective immunity to wild type tumor.
Successful expression of the cytosine deaminase (CD) suicide gene in vivo is demonstrated in three weakly immunogenic murine tumor models: the 102 and 205 fibrosarcomas and the 38 adenocarcinoma. Normal mammalian cells do not contain cytosine deaminase, but tumor cells transduced with retroviral vectors containing the CD gene metabolize the relatively nontoxic prodrug 5-fluorocytosine to the highly toxic 5-fluorouracil. In vitro cells expressing the CD gene are killed by 5-fluorocytosine while unmodified cells are not. When injected into syngeneic mice, CD+ tumors can also be eliminated in vivo by systemic treatment with 5-fluorocytosine without significant toxicity to the host. Animals whose CD+ tumors were eliminated with prodrug treatment resist subsequent rechallenge with unmodified wild type tumor. This posttreatment immunity appears to be tumor specific. Applications of the CD system in gene therapy models are discussed.
Mullen
C A
CA
Metabolism Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892.
Coale
M M
MM
Lowe
R
R
Blaese
R M
RM
D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D043525:Cytosine Deaminase; D004354:Drug Screening Assays, Antitumor; D005437:Flucytosine / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics; D007113:Immunity, Innate / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics* / Q000276:immunology*; D009700:Nucleoside Deaminases / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D014161:Transduction, Genetic / Q000235:genetics; D014407:Tumor Cells, Cultured / Q000187:drug effects
D001426:Bacterial Proteins; D005437:Flucytosine; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase