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 vec...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 1994-03, Vol.54 (6), p.1503-1506
Main Authors: MULLEN, C. A, COALE, M. M, LOWE, R, BLAESE, R. M
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Bacterial Proteins - genetics
Bacterial Proteins - immunology
Bacterial Proteins - metabolism
Biological and medical sciences
Chemotherapy
Cytosine Deaminase
Drug Screening Assays, Antitumor
Flucytosine - pharmacology
Gene Expression - drug effects
Gene Expression - genetics
Gene Transfer Techniques
Genetic Vectors - genetics
Immunity, Innate - immunology
Medical sciences
Mice
Mice, Inbred C57BL
Neoplasms, Experimental - enzymology
Neoplasms, Experimental - genetics
Neoplasms, Experimental - immunology
Nucleoside Deaminases - genetics
Nucleoside Deaminases - immunology
Nucleoside Deaminases - metabolism
Pharmacology. Drug treatments
Retroviridae - genetics
Transduction, Genetic - genetics
Tumor Cells, Cultured - drug effects
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Summary: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.
ISSN:0008-5472
1538-7445