Virus-associated tumor imaging by induction of viral gene expression.
OBJECTIVE
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-beta-D-5-iodouracil-arabinofuranoside (FIAU).


METHODS
Immunoblot, luciferase reporter assay, and in vitro assay with [(14)C]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 [(125)I]FIAU on EBV-associated tumors were done to visualize and confirm, respectively, the EBV(+) tumor-specific effects of bortezomib.


RESULTS
In vitro assays with [(14)C]FIAU and ex vivo biodistribution studies with [(125)I]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 [(125)I]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.
Fu
De-Xue
DX
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
Tanhehco
Yvette C
YC
Chen
Jianmeng
J
Foss
Catherine A
CA
Fox
James J
JJ
Lemas
Victor
V
Chong
Ja-Mun
JM
Ambinder
Richard F
RF
Pomper
Martin G
MG
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives*; D001897:Boronic Acids / Q000627:therapeutic use; D000069286:Bortezomib; D002051:Burkitt Lymphoma / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000821:virology; D003952:Diagnostic Imaging; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005814:Genes, Viral; D004854:Herpesvirus 4, Human / Q000201:enzymology / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging / Q000188:drug therapy; D009858:Oncogenic Viruses / Q000201:enzymology / Q000235:genetics; D011719:Pyrazines / Q000627:therapeutic use; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013937:Thymidine Kinase / Q000235:genetics* / Q000378:metabolism
D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D019275:Radiopharmaceuticals; D001086:Arabinofuranosyluracil; C043457:fialuridine; D000069286:Bortezomib; D013937:Thymidine Kinase