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Antimicrobial Agents and Chemotherapy, July 2001, p. 2082-2091, Vol. 45, No. 7
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.7.2082-2091.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Induction of Epstein-Barr Virus Kinases To Sensitize Tumor Cells to Nucleoside Analogues

Stacy M. Moore,1 Jennifer S. Cannon,1 Yvette C. Tanhehco,1 Fayez M. Hamzeh,2 and Richard F. Ambinder1,*

Departments of Oncology1 and Medicine,2 Johns Hopkins University School of Medicine, Baltimore, Maryland 21231

Received 27 January 2000/Returned for modification 7 April 2000/Accepted 25 April 2001

The presence of Epstein-Barr virus (EBV) in the tumor cells of some EBV-associated malignancies may facilitate selective killing of these tumor cells. We show that treatment of an EBV+ Burkitt's lymphoma cell line with 5-azacytidine led to a dose-dependent induction of EBV lytic antigen expression, including expression of the viral thymidine kinase (TK) and phosphotransferase (PT). Azacytidine treatment for 24 h modestly sensitized the cell line to all nucleosides tested. To better characterize EBV TK with regard to various nucleoside analogues, we expressed EBV TK in stable cell clones. Two EBV TK-expressing clones were moderately sensitive to high doses of acyclovir and penciclovir (PCV) (62.5 to 500 µM) and to lower doses of ganciclovir (GCV) and bromovinyldeoxyuridine (BVdU) (10 to 100 µM) compared to a control clone and were shown to phosphorylate GCV. Similar experiments in a transient overexpression system showed more killing of cells transfected with the EBV TK expression vector than of cells transfected with the control mutant vector (50 µM GCV for 4 days). A putative PT was also studied in the transient transfection system and appeared similar to the TK in phosphorylating GCV and conferring sensitivity to GCV, but not in BVdU- or PCV-mediated cell killing. Induction of EBV kinases in combination with agents such as GCV merits further evaluation as an alternative strategy to gene therapy for selective killing of EBV-infected cells.

* Corresponding author. Mailing address: 1650 Orleans St., Cancer Research Building, Rm 389, Baltimore, MD 21231. Phone: (410) 955-5617. Fax: (410) 955-0961. E-mail: rambind{at}jhmi.edu.

Antimicrobial Agents and Chemotherapy, July 2001, p. 2082-2091, Vol. 45, No. 7
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.7.2082-2091.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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