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Tumor-Specific In Vivo Transfection with HSV-1 Thymidine Kinase Gene Using a Sindbis Viral Vector as a Basis for Prodrug Ganciclovir Activation and PET

¹ NYU Cancer Institute, Rita J. and Stanley H. Kaplan Comprehensive Cancer Center, and NYU Gene Therapy Center, NYU School of Medicine, New York, New York; ² Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, New York; ³ Cyclotron and Radiochemistry Facility, Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York; and ⁴ Nuclear Medicine Service, Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York

Correspondence: For correspondence contact: Daniel Meruelo, PhD, Department of Pathology, NYU School of Medicine, 550 First Ave., New York, NY 10016. E-mail: merued01{at}med.nyu.edu

One type of gene therapy of tumors, gene-directed enzyme-prodrug therapy (GDEPT), holds considerable promise, although practical considerations limit its clinical applicability. These include the lack of acceptable noninvasive methods that are adaptable to humans for selective tumor targeting of the therapeutic genetic material. Sindbis virus is an oncolytic, -virus that selectively targets tumors through the 67-kDa laminin receptor (LAMR). In this report we describe a novel approach that permits tumor-selective tumor targeting and quantitative in vivo monitoring using PET of a commonly applied GDEPT, based on herpes simplex virus thymidine kinase type 1 (HSVtk) and ganciclovir (GCV). Methods: Sindbis/tk vectors were harvested from the supernatant of in vitro cultures of a packaging cell produced by electroporation of both replicon RNA (SinRep5/tk) and helper RNA (DH-BB) into baby hamster kidney (BHK) cells. The therapeutic effect of GCV was determined by incubation of transfected tumor cells with increasing concentrations of GCV. BHK tumors growing as xenografts in severe combined immunodeficiency disease (SCID) mice were transfected by parenteral administration of the vector. Imaging was performed using small-animal PET at 2 h after injection of ¹⁸F fluoro-ethyl-arabinosyluridine (¹⁸F-FEAU) and 24 h after the final parenteral injection of Sindbis/tk viral vector. Results: The vector efficiently expresses the HSVtk enzyme in infected tumor cells, both in vitro and in vivo. High levels of HSVtk expression ensure sufficient prodrug GCV conversion and activation for bystander effects that kill the surrounding untransduced tumor cells. Tumor localization of intravenously administered ¹⁸F-FEAU after 2 and 3 parenteral vector treatments of Sindbis/tk demonstrated uptake of 1.7 and 3.1 %ID/g (percentage injected dose per gram), respectively. Conclusion: The vector efficiently targets the HSVtk enzyme gene into Sindbis-infected tumor cells. High levels of HSVtk expression ensure sufficient prodrug GCV conversion and activation for bystander effects that killed many surrounding untransduced tumor cells. In addition, the HSVtk activities in tumors can be noninvasively monitored using PET after systemic Sindbis/tk treatments as a basis for determining the levels and tissue distribution of vector, noninvasively in living animals, and for optimizing in vivo transfection rates of tumor.

Key Words: Sindbis vector • herpes simplex virus thymidine kinase type 1 • gene-directed enzyme-prodrug therapy • PET • in vivo imaging

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