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Virus-Mediated Oncolysis of Thyroid Cancer by a Replication-Selective Adenovirus Driven by a Thyroglobulin Promoter-Enhancer Region

Division of Endocrine and Oncologic Surgery, Department of Surgery (S.K., I.P., R.C., C.M., D.F.), and Department of Pathology (K.M.-K.), University of Pennsylvania, Philadelphia, Pennsylvania 19104

Address all correspondence and requests for reprints to: Dr. Douglas Fraker, Division of Endocrine and Oncologic Surgery, HUP, 4 Silverstein Building, 3400 Spruce Street, Philadelphia, Pennsylvania 19104. E-mail: frakerd{at}uphs.upenn.edu.

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 promoter-driven, 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 x 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 AdhTGEP-treated XTC tumors (67 ± 49 mm³) compared with AdLacZ-treated XTC (228 ± 45 mm³; P < 0.01), PBS-treated XTC (372 ± 70 mm³; 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.

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