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Virus-Associated Tumor Imaging by Induction of Viral Gene Expression

Authors' Affiliations: ¹ Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, and ² Department of Radiology, Johns Hopkins Medical Institutions, Baltimore, Maryland

Requests for reprints: Martin G. Pomper, Department of Radiology, Johns Hopkins Medical Institutions, 1550 Orleans Street, 492 CRB II, Baltimore, MD 21231. Phone: 410-955-2789; Fax: 443-817-0990; E-mail: mpomper{at}jhmi.edu.

Purpose: EBV and other herpesviruses are associated with a variety of malignancies. The EBV thymidine kinase (TK) is either not expressed or is expressed at very low levels in EBV-associated tumors. However, EBV-TK expression can be induced in vitro with several chemotherapeutic agents that promote viral lytic induction. The goal of this study is to image EBV-associated tumors by induction of viral TK expression with radiolabeled 2'-fluoro-2'-deoxy-ß-D-5-iodouracil-arabinofuranoside (FIAU).

Experimental Design: Immunoblot, luciferase reporter assay, and in vitro assay with [¹⁴C]FIAU were used to show the effects of bortezomib on the induction of lytic gene expression of EBV-associated tumor cells. In vivo imaging and ex vivo biodistribution studies with [¹²⁵I]FIAU on EBV-associated tumors were done to visualize and confirm, respectively, the EBV(+) tumor–specific effects of bortezomib.

Results: In vitro assays with [¹⁴C]FIAU and ex vivo biodistribution studies with [¹²⁵I]FIAU showed that uptake and retention of radiolabeled FIAU was specific for cells that express EBV-TK. Planar gamma imaging of EBV(+) Burkitt's lymphoma xenografts in severe combined immunodeficient mice showed [¹²⁵I]FIAU localization within tumors following treatment with bortezomib.

Conclusions: These results indicate the feasibility of imaging chemotherapy-mediated viral lytic induction by radiopharmaceutical-based techniques such as single photon emission computed tomography and positron emission tomography.

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