Epstein-Barr virus-driven gene therapy for EBV-related lymphomas.
Genetic alterations in malignant tissues are potential targets for gene-based cancer therapies. Alternatively, aberrant expression of certain specific genes associated with malignant transformation may be envisioned to enhance the expression of chemosensitizing drugs. Epstein-Barr virus (EBV)-related B-cell lymphomas are fatal complications of immunosuppression due to AIDS, organ transplantation or congenital immune abnormalities. The malignant cells latently infected with EBV typically express the transcription factor EBNA2 as one of nine latent viral genes. We tested whether an EBNA2-responsive EBV promoter may selectively target EBV-related lymphoma cells by virus-regulated expression of a suicide gene. Using the BamC promoter driving a hygromycin-thymidine kinase fusion gene or controls, we demonstrated that sensitivity to ganciclovir was selectively enhanced in cells expressing EBNA2. Further, there was complete macroscopic regression of established B-cell lymphomas in mice with severe combined immunodeficiency disease (SCID mice) treated with a single course of ganciclovir. These data provide in vitro and in vivo support for a model of exploiting the molecular basis of tumor development to enhance the specificity of gene therapy.
Franken
M
M
Division of Hematology/Oncology, Harvard Medical School, Boston, Massachusetts, USA.
Estabrooks
A
A
Cavacini
L
L
Sherburne
B
B
Wang
F
F
Scadden
D T
DT
D000818:Animals; D000963:Antimetabolites / Q000627:therapeutic use*; D002051:Burkitt Lymphoma / Q000628:therapy*; D002934:Cinnamates; D019309:Epstein-Barr Virus Nuclear Antigens / Q000235:genetics; D015774:Ganciclovir / Q000627:therapeutic use*; D015316:Genetic Therapy / Q000379:methods*; D004854:Herpesvirus 4, Human / Q000235:genetics*; D006801:Humans; D006921:Hygromycin B / Q000031:analogs & derivatives; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011993:Recombinant Fusion Proteins; D018139:Simplexvirus / Q000201:enzymology; D013937:Thymidine Kinase / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D014407:Tumor Cells, Cultured
D000963:Antimetabolites; D002934:Cinnamates; D019309:Epstein-Barr Virus Nuclear Antigens; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D006921:Hygromycin B; C026273:hygromycin A; D013937:Thymidine Kinase; D015774:Ganciclovir