Imaging herpes virus thymidine kinase gene transfer and expression by positron emission tomography.
We report a series of studies that assess the feasibility and sensitivity of imaging of herpes virus type one thymidine kinase (HSV1-tk) gene transfer and expression with [124I]-5-iodo-2'-fluoro-1-beta-D-arabinofuranosyluracil ([124I]-FIAU) and positron emission tomography (PET) and the ability of [124I]-FIAU-PET imaging to discriminate different levels of HSV1-tk gene expression. Studies were performed in rats bearing multiple s.c. tumors derived from W256 rat carcinoma and RG2 rat glioma cells. In the first set, we tested the sensitivity of [124I]-FIAU-PET imaging to detect low levels of HSV1-tk gene expression after retroviral-mediated gene transfer. HSV1-tk gene transduction of one of preestablished wild-type W256 tumor in each animal was accomplished by direct intratumoral injection of retroviral vector-producer cells (W256-->W256TK* tumors). Tumors produced from W256 and W256TK+ cells served as the negative and positive control in each animal. Highly specific images of [124I]-FIAU-derived radioactivity were obtained in W256TK* tumors (that were transduced in vivo) and in W256TK+ tumors but not in nontransduced wild-type W256 tumors. The level of "specific" incorporated radioactivity in transduced portions of both W256TK* and W256TK+ tumors was relatively constant between 4 and 50 h. In the second set, we tested whether [124I]-FIAU and PET imaging can measure and discriminate between different levels of HSV1-tk gene expression. Multiple s.c. tumors were produced from wild-type RG2 cells and stably transduced RG2TK cell lines that express different levels of HSV1-tk. A highly significant relationship between the level of [124I]-FIAU accumulation [% injected dose/g and incorporation constant (Ki)] and an independent measure of HSV1-tk expression (sensitivity of the transduced tumor cells to ganciclovir, IC50) was demonstrated, and the slope of this relationship was defined as a sensitivity index. We have demonstrated for the first time that highly specific noninvasive images of HSV1-tk expression in experimental animal tumors can be obtained using radiolabeled 2'-fluoro-nucleoside [124I]-FIAU and a clinical PET system. The ability to image the location (distribution) of gene expression and the level of expression over time provides new and useful information for monitoring clinical gene therapy protocols in the future.
Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
J G
JG
Tjuvajev
N
N
Avril
T
T
Oku
T
T
Sasajima
T
T
Miyagawa
R
R
Joshi
M
M
Safer
B
B
Beattie
G
G
DiResta
F
F
Daghighian
F
F
Augensen
J
J
Koutcher
J
J
Zweit
J
J
Humm
S M
SM
Larson
R
R
Finn
R
R
Blasberg
D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives; D002279:Carcinoma 256, Walker / Q000000981:diagnostic imaging / Q000201:enzymology / Q000473:pathology; D005260:Female; D015774:Ganciclovir / Q000627:therapeutic use*; D018014:Gene Transfer Techniques; D005910:Glioma / Q000000981:diagnostic imaging / Q000201:enzymology / Q000473:pathology; D018259:Herpesvirus 1, Human / Q000201:enzymology / Q000235:genetics*; D007457:Iodine Radioisotopes; D008279:Magnetic Resonance Imaging; D008325:Mammary Neoplasms, Experimental / Q000000981:diagnostic imaging / Q000201:enzymology / Q000473:pathology; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D051381:Rats; D011923:Rats, Nude; D012680:Sensitivity and Specificity; D013937:Thymidine Kinase / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics*; D014055:Tomography, Emission-Computed
D000998:Antiviral Agents; D007457:Iodine Radioisotopes; D001086:Arabinofuranosyluracil; C043457:fialuridine; D013937:Thymidine Kinase; D015774:Ganciclovir