Virus-mediated oncolysis of thyroid cancer by a replication-selective adenovirus driven by a thyroglobulin promoter-enhancer region

Abstract

Context: Currently, there is no effective treatment for iodine-resistant thyroid cancers. Objective: As a new approach to treatment, the efficacy of replication-selective, human thyroglobulin (TG) enhancer and promoterdriven, adenovirus (AdhTGEP)-mediated oncolysis was investigated using two well-differentiated thyroid cancer cell lines, XTC (TG positive) and FTC-133 (TG negative), and other control tumor and nontumor cell lines (all TG negative). Design: A cohort study design was used. Setting: The study setting was laboratory bench-top experiments. Subjects/Participants: In vitro TG-expressing and nonexpressing thyroid cell culture lines, nonthyroid tumor cell lines, as well as preclinical thyroid tumor-bearing mice were studied. Intervention: Adenoviral infection of cell lines was determined by immunohistochemistry, selective replication by one-step growth assays, and cytotoxicity by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulphophenyl) -2H-tetrozolium (MTS) assay. In vivo tumor growth inhibition was determined by a single intratumoral injection of 1 × 109 plaque-forming units AdhTGEP, AdLacZ (control virus), or PBS to 50- to 75-mm3 tumors. XTC cells showed intense immunohistochemical staining, whereas FTC-133 and all other control cell lines showed minimal staining for viral infection with AdhTGEP. Main Outcome Measures: Cell survival and tumor growth inhibition after adenoviral infection were the main outcome measures. Results: One-step growth assays showed at least a more than 60-fold titer of AdhTGEP in XTC than in FTC-133 cells. Cytotoxicity assays showed approximately 68% cell kill in XTC and minimal cell kill in FTC-133 and all other control cell lines at a multiplicity of infection of 250. There was significant in vivo growth inhibition of AdhTGEPtreated XTC tumors (67 ± 49 mm3) compared with AdLacZ-treated XTC (228 ± 45mm3; P < 0.01), PBS-treated XTC (372 ± 70mm3; P < 0.001), or AdhTGEP-treated FTC-133 tumors (598 ± 168 mm3). Conclusion: Replication-selective virus-mediated oncolysis is a potential therapy for recurrent, well-differentiated, TG-secreting thyroid cancer that is unresponsive to standard treatment. Copyright © 2005 by The Endocrine Society.