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Molecular Imaging with ¹²³I-FIAU, ¹⁸F-FUdR, ¹⁸F-FET, and ¹⁸F-FDG for Monitoring Herpes Simplex Virus Type 1 Thymidine Kinase and Ganciclovir Prodrug Activation Gene Therapy of Cancer

¹ Institute of Radiological Science, National Yang-Ming University, Taipei, Taiwan; ² Department of Nuclear Medicine and National PET Cyclotron Center, Veterans General Hospital, Taipei, Taiwan; ³ Department of Nuclear Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan; ⁴ Department of Experimental Diagnostic Imaging, M.D. Anderson Cancer Center, Houston, Texas; and ⁵ Institute of Biomedical Materials, Taipei Medical University, Taipei, Taiwan

Correspondence: For correspondence or reprints contact: Win-Ping Deng, PhD, Institute of Biomedical Materials, Taipei Medical University, 250, Wu-Hsing St., Taipei 110, Taiwan. E-mail: wpdeng{at}ms41.hinet.net

The ability to monitor tumor responses during prodrug activation gene therapy and other anticancer gene therapies is critical for their translation into clinical practice. Previously, we demonstrated the feasibility of noninvasive in vivo imaging with ¹³¹I-5-iodo-2'-fluoro-1-ß-D-arabinofuranosyluracil (¹³¹I-FIAU) for monitoring herpes simplex virus type 1 thymidine kinase (HSV1-tk) cancer gene expression in an experimental animal model. Here we tested the efficacy of SPECT with ¹²³I-FIAU and PET with 5-¹⁸F-fluoro-2'-deoxyuridine (¹⁸F-FUdR), 2-¹⁸F-fluoroethyl-L-tyrosine (¹⁸F-FET), and ¹⁸F-FDG for monitoring tumor responses during prodrug activation gene therapy with HSV1-tk and ganciclovir (GCV). Methods: In the flanks of FVB/N female mice, 4 tumors per animal were established by subcutaneous injection of 1x10⁵ cells of NG4TL4 sarcoma cells, HSV1-tk–transduced NG4TL4-STK cells, or a mixture of these cells in different proportions to model different efficacies of transfection and HSV1-tk gene expression levels in tumors. Ten days later, the animals were treated with GCV (10 mg/kg/d intraperitoneally) for 7 d. -Imaging with ¹²³I-FIAU and PET with ¹⁸F-FUdR, ¹⁸F-FET, and ¹⁸F-FDG were performed before and after initiation of therapy with GCV in the same animal. Results: Before GCV treatment, no significant difference in weight and size was found in tumors that expressed different HSV1-tk levels, suggesting similar in vivo proliferation rates for NG4TL4 and NG4TL4-STK sarcomas. The accumulation of ¹²³I-FIAU at 24 h after injection was directly proportional to the percentage of NG4TL4-STK cells in the tumors. The ¹²³I-FIAU accumulation at 4 and 7 d of GCV therapy decreased significantly compared with pretreatment levels and was proportional to the percentage of HSV1-tk–positive tumor cells. Tumor uptake of ¹⁸F-FUdR in all HSV1-tk–expressing tumors also decreased significantly compared with pretreatment levels and was proportional to the percentage of HSV1-tk–positive tumor cells. The accumulation of ¹⁸F-FET decreased minimally (about 1.5-fold) and ¹⁸F-FDG decreased only 2-fold after 7 d of GCV therapy, and the degree of reduction was proportional to the percentage of HSV1-tk–positive tumor cells. Conclusion: We have shown that -camera imaging with ¹²³I-FIAU was the most reliable method for prediction of tumor response to GCV therapy, which was proportional to the magnitude of HSV1-tk expression in tumor tissue. ¹²³I-FIAU imaging can be used to verify the efficacy of elimination of HSV1-tk–expressing cells by therapy with GCV. PET with ¹⁸F-FUdR reliably visualizes proliferating tumor tissue and is most suitable for the assessment of responses in tumors undergoing HSV1-tk plus GCV prodrug activation gene therapy. PET with ¹⁸F-FDG or ¹⁸F-FET can be used as additional "surrogate" biomarkers of the treatment response, although these radiotracers are less sensitive than ¹⁸F-FUdR for monitoring tumor responses to prodrug activation gene therapy with HSV1-tk and GCV in this sarcoma model.

Key Words: ¹²³I-FIAU • ¹⁸F-FDG • ¹⁸F-FUdR • ¹⁸F-FET • microPET • gene therapy • herpes simplex virus thymidine kinase • ganciclovir • tumor

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