Journal
CANCER GENE THERAPY
Volume 7, Issue 1, Pages 97-106Publisher
STOCKTON PRESS
DOI: 10.1038/sj.cgt.7700102
Keywords
Epstein-Barr virus; CB1954; nitroreductase; lymphoma; suicide gene; gene therapy
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Funding
- NCI NIH HHS [R01 CA 66519] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [R01CA066519] Funding Source: NIH RePORTER
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Epstein-Barr virus (EBV)-based gene delivery vectors that preferentially express toxic genes in EBV-infected cells could be used to target EBV-positive tumors for destruction. We have shown previously that the cytosine deaminase (CD) enzyme, which converts the prodrug 5-fluorocytosine (5-FC) into the toxic compound 5-fluorouracil efficiently kills EBV-positive cells in the presence of 5-FC, with a substantial bystander killing effect in vitro and in vivo. To identify the optimal enzyme/prodrug combination for treating EBV-positive lymphomas, we have compared the effectiveness of the CD/5-FC combination with the nitroreductase (NTR)/CB1954 combination for killing EBV-positive B-cell lines. NTR metabolizes CB1954 Into an alkylating agent that cross-links DNA. When the CD gene or the NTR gene were transfected into two different EBV-positive B-cell lines in vitro, similar to 90% of cells were killed in a prodrug-dependent manner, although the transfection efficiency was (5%, However, severe combined immunodeficient mouse tumors containing either 30% or 100% of NTR-expressing Burkitt lymphoma (Jijoye) cells were growth inhibited, but not cured, by treatment with intraperitoneal CB1954 (20 mg/kg/day) for 10 days. These results suggest that the NTR/CB1954 combination induces efficient bystander killing of EBV-positive B-cell lines in vitro but may not be as effective as the CD/5-FC combination for treating B-cell lymphomas in vivo.
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