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

Susan Kesmodel, Indira Prabakaran, Robert J Canter, Chandrakala Menon, Kathy Molnar-Kimber, Douglas Fraker

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)3440-3448
Number of pages9
JournalJournal of Clinical Endocrinology and Metabolism
Volume90
Issue number6
DOIs
StatePublished - Jun 2005
Externally publishedYes

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Thyroglobulin
Viruses
Thyroid Neoplasms
Genetic Promoter Regions
Adenoviridae
Tumors
Cells
Cell Line
Growth
Assays
Neoplasms
Tumor Cell Line
Thyroid Gland
Cytotoxicity
Infection
Outcome Assessment (Health Care)
Staining and Labeling
Bearings (structural)
Virus Diseases
Virus Replication

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

Cite this

Virus-mediated oncolysis of thyroid cancer by a replication-selective adenovirus driven by a thyroglobulin promoter-enhancer region. / Kesmodel, Susan; Prabakaran, Indira; Canter, Robert J; Menon, Chandrakala; Molnar-Kimber, Kathy; Fraker, Douglas.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 90, No. 6, 06.2005, p. 3440-3448.

Research output: Contribution to journalArticle

Kesmodel, Susan ; Prabakaran, Indira ; Canter, Robert J ; Menon, Chandrakala ; Molnar-Kimber, Kathy ; Fraker, Douglas. / Virus-mediated oncolysis of thyroid cancer by a replication-selective adenovirus driven by a thyroglobulin promoter-enhancer region. In: Journal of Clinical Endocrinology and Metabolism. 2005 ; Vol. 90, No. 6. pp. 3440-3448.
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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.",
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AU - Menon, Chandrakala

AU - Molnar-Kimber, Kathy

AU - Fraker, Douglas

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N2 - 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.

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