RETROVIRUS-MEDIATED SUICIDE GENE PRODRUG THERAPY TARGETING THYROID-CARCINOMA USING A THYROID-SPECIFIC PROMOTER

To develop gene therapy targeting thyroid carcinoma, the recombinant r etrovirus (LNTGTK) carrying herpes simplex virus thymidine kinase (HSV -TK) gene under the control of thyroglobulin (TG) promoter was constru cted and its efficacy was investigated in 3 thyroid cell lines; a diff erentiated normal rat thyroid cell line (FRTLS), malignant rat thyroid carcinoma cells derived from FRTLS (FRTC) and a human anaplastic thyr oid carcinoma cell line (FRO). TG mRNA was detected by Northern blot a nalysis in FRTLS cells and by RT-PCR in FRTC cells when cultured with 2 U/L TSH and its expression levels were decreased by TSH withdrawal. However, either methods revealed no TG expression in FRO cells. In vit ro cytotoxic assays demonstrated TG expression status-dependent cell k illing by transduction of LNTGTK followed by ganciclovir (GCV) treatme nt. Thus, LNTGTK transduction increased the GCV sensitivity similar to 13,000- and similar to 160-folds in the presence of TSH and similar t o 4- and similar to 27-folds in the absence of TSH in FRTLS and FRTC c ells, respectively. In contrast, there was no difference in the GCV cy totoxicity between parental and transduced FRO cells. Significant grow th inhibition, but not complete eradication, of transduced FRTC cells was observed in in vivo subcutaneous tumor models of nude mice. These results demonstrate that retrovirus-mediated transduction of HSV-TK ge ne under the control of the TG promoter confers the GCV sensitivity se lectively to TG-expressing thyroid cells. This system may therefore be feasible for gene therapy targeting TG-expressing thyroid carcinomas.