The nitroreductase/CB1954 combination in Epstein-Barr virus-positive B-cell lines: induction of bystander killing in vitro and in vivo.

Abstract

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, approximately 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.

• Authors: E M Westphal, J Ge, J R Catchpole, M Ford, S C Kenney
• Journal: Cancer gene therapy (Cancer Gene Ther) Vol. 7 Issue 1 Pg. 97-106 (Jan 2000) ISSN: 0929-1903 [Print] England
• PMID: 10678362 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Aziridines
• Prodrugs
• tretazicar
• Nitroreductases
• Nucleoside Deaminases
• Cytosine Deaminase

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Aziridines (administration & dosage, pharmacology)
• B-Lymphocytes
• Callithrix
• Cytosine Deaminase
• Disease Models, Animal
• Genetic Therapy
• Herpesvirus 4, Human (genetics)
• Humans
• Lymphoma (genetics, therapy)
• Mice
• Mice, SCID
• Neoplasm Transplantation
• Nitroreductases (administration & dosage, genetics, metabolism)
• Nucleoside Deaminases (genetics, metabolism)
• Plasmids (genetics)
• Prodrugs (therapeutic use)
• Tumor Cells, Cultured