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The Quarterly Journal of Nuclear Medicine 1999 June;43(2):163-9


language: English

Herpes simplex virus thymidine kinase as a marker/reporter gene for PET imaging of gene therapy

Blasberg R. G., Tjuvajev J. G.

From the Department of Neurology Memorial Sloan-Kettering Cancer Center, New York, USA


Imaging trans­gene expres­sion ­with radio­phar­ma­ceu­ti­cals is fea­sible and has ­been dem­on­strat­ed ­with a gam­ma cam­e­ra and by posi­tron emis­sion tomog­ra­phy (PET) in experi­men­tal ani­mals. An impor­tant con­sid­er­a­tion in the devel­op­ment of the imag­ing par­a­digm was the selec­tion of an appro­pri­ate trans­gene and radio­phar­ma­ceu­ti­cal. The ­herpes sim­plex ­virus thy­mi­dine ­kinase ­gene (HSV1-tk) was select­ed as an exam­ple of a “mark­er ­gene”, and radio­lab­eled 5-­iodo-2’-flu­o­ro-2­’deoxy-1-β-D-ara­bi­no-furan­o­syl-ura­cil (­FIAU) was ­shown to be a sub­stan­tial­ly bet­ter “mark­er sub­strate” for the HSV1-TK ­enzyme ­than oth­er nucle­oside ana­logues, includ­ing radio­lab­eled gan­cic­lo­vir and acy­clo­vir. The mag­ni­tude of ­FIAU accu­mu­la­tion in dif­fer­ent HSV1-tk trans­duced ­cell ­lines and in ­tumors ­derived ­from ­these ­cell ­lines, was high­ly cor­re­lat­ed ­with inde­pen­dent meas­ures of HSV1-tk expres­sion; name­ly, to the lev­el of HSV1-tk mRNA in the cor­re­spond­ing ­cell ­lines and to ­their lev­el of sen­si­tiv­ity to the anti­vi­ral ­drug, gan­cic­lo­vir. We ­have dem­on­strat­ed for the ­first ­time ­that high­ly spe­cif­ic non-inva­sive imag­es of HSV1-tk expres­sion in experi­men­tal ani­mal ­tumors can be ­obtained ­using radio­lab­eled ­FIAU and a clin­i­cal gam­ma cam­e­ra or a PET ­system. Given the lev­el of ­FIAU accu­mu­la­tion in the trans­duced ­tumors, it is like­ly ­that a clin­i­cal­ly appli­cable meth­od for imag­ing HSV1-tk ­gene expres­sion can be imple­ment­ed ­using exist­ing clin­i­cal imag­ing tech­niques. Our ­results ­point ­towards the poten­tial for a wid­er appli­ca­tion of HSV1-tk as a “mark­er” ­gene for “indi­rect” imag­ing of oth­er ther­a­peu­tic trans­genes. The use of mul­ti-­gene vec­tor con­structs, ­where imag­ing a “mark­er ­gene” can be ­used to ­assess the lev­el of “ther­a­peu­tic ­gene” expres­sion, ­will be increas­ing­ly devel­oped ­over the ­next ­decade. The abil­ity to ­image the loca­tion (dis­tri­bu­tion) and the lev­el of trans­gene expres­sion ­over ­time ­will pro­vide new and use­ful infor­ma­tion for mon­i­tor­ing clin­i­cal ­gene ther­a­py pro­to­cols in the ­future.

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