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J Nucl Med. 2008; 49 (Supplement 1):333P
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Oncology-Basic Science: Therapy, Metrics & Intervention

Therapy, Metrics & Intervention Posters

Development of HSV1-tk mutants with altered activity towards acycloguanosine analogs

Yury Likar1, Konstantin Dobrenkov1, Malgorzata Olszewska1, Jelena Vider1, Larissa Shenker1, Juan Zurita1, Shangde Cai1, Hedvig Hricak1 and Vladimir Ponomarev1

1 Radiology, MSKCC, New York, New York

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Objectives: Herpes simplex virus type-1 thymidine kinase (HSV1-tk) is widely used as a suicide gene in combination with ganciclovir (GCV) and a PET reporter gene with an appropriate reporter probe. Purpose: To develop a new HSV1-tk mutant with compromised acycloguanosine activity for PET imaging in patients treated with acycloguanosine antiviral drugs.

Methods: We assessed HSV1-tk and its mutants HSV1-sr39tk, HSV1-R176Qtk, HSV1-R176Qsr39tk using in vitro 2-hour radiotracer uptake assay with 3H-FEAU and 3H-PCV, ganciclovir (GCV) and bromovinyl-2’-deoxyuridine (BVdU) sensitivity assays and PET imaging with 18F- FEAU and 18F- FHBG in mice followed by tissue sampling.

Results: In vitro 3H-FEAU accumulation was observed in all transduced cells. Wild-type-HSV1-tk, HSV1-sr39tk and HSV1-R176Q-sr39tk cells showed similar levels of 3H-FEAU uptake, while HSV1-R176Q-tk cells showed decreased 3H-FEAU uptake. In vitro 3H-PCV accumulation was significantly reduced in HSV1-R176Q-tk and HSV1-R176Q-sr39tk cells compared with wild-type-HSV1-tk and HSV1-sr39tk. HSV1-R176Q-tk and HSV1-R176Q-sr39tk cells showed lower sensitivity to GCV and BVdU compared with wild-type-HSV1-tk and HSV1-sr39tk cells. In vivo 18F-FEAU accumulation was observed in all transduced xenografts. However, 18F-FHBG accumulation was significantly reduced in HSV1-R176Q-tk and HSV1-R176Q-sr39tk xenografts compared with wild-type-HSV1-tk tumors.

Conclusions: We developed a new mutant of HSV1-tk, HSV1-R176Q-sr39tk, with significantly reduced acycloguanosine activity. This reporter gene can be used for PET imaging with pyrimidine-based radiotracers (18F-FEAU). Studies on further improvement of pyrimidine-specificity of HSV1-tk are underway.





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Right arrow Articles by Likar, Y.
Right arrow Articles by Ponomarev, V.