The nitroreductase/CB1954 combination in Epstein-Barr virus-positive B-cell lines: induction of bystander killing in vitro and in vivo.
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.
Westphal
E M
EM
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill 27599-7295, USA.
Ge
J
J
Catchpole
J R
JR
Ford
M
M
Kenney
S C
SC
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001388:Aziridines / Q000008:administration & dosage / Q000494:pharmacology*; D001402:B-Lymphocytes; D002144:Callithrix; D043525:Cytosine Deaminase; D004195:Disease Models, Animal; D015316:Genetic Therapy; D004854:Herpesvirus 4, Human / Q000235:genetics*; D006801:Humans; D008223:Lymphoma / Q000235:genetics / Q000628:therapy*; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009601:Nitroreductases / Q000008:administration & dosage / Q000235:genetics* / Q000378:metabolism; D009700:Nucleoside Deaminases / Q000235:genetics* / Q000378:metabolism; D010957:Plasmids / Q000235:genetics; D011355:Prodrugs / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001388:Aziridines; D011355:Prodrugs; C100099:tretazicar; D009601:Nitroreductases; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase