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


METHODS
A cohort study design was used.


METHODS
The study setting was laboratory bench-top experiments.


METHODS
In vitro TG-expressing and nonexpressing thyroid cell culture lines, nonthyroid tumor cell lines, as well as preclinical thyroid tumor-bearing mice were studied.


METHODS
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 10(9) plaque-forming units AdhTGEP, AdLacZ (control virus), or PBS to 50- to 75-mm(3) tumors. XTC cells showed intense immunohistochemical staining, whereas FTC-133 and all other control cell lines showed minimal staining for viral infection with AdhTGEP.


METHODS
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 mm(3)) compared with AdLacZ-treated XTC (228 +/- 45 mm(3); P < 0.01), PBS-treated XTC (372 +/- 70 mm(3); P < 0.001), or AdhTGEP-treated FTC-133 tumors (598 +/- 168 mm(3)).


CONCLUSIONS
Replication-selective virus-mediated oncolysis is a potential therapy for recurrent, well-differentiated, TG-secreting thyroid cancer that is unresponsive to standard treatment.
Kesmodel
Susan
S
Division of Endocrine and Oncologic Surgery, HUP, 4 Silverstein Building, 3400 Spruce Street, Philadelphia, Pennsylvania 19104, USA.
Prabakaran
Indira
I
Canter
Robert
R
Menon
Chandrakala
C
Molnar-Kimber
Kathy
K
Fraker
Douglas
D
D000256:Adenoviridae / Q000235:genetics / Q000502:physiology*; D001483:Base Sequence; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015331:Cohort Studies; D017931:DNA Primers; D004742:Enhancer Elements, Genetic; D015316:Genetic Therapy; D006801:Humans; D011401:Promoter Regions, Genetic; D013954:Thyroglobulin / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000473:pathology / Q000628:therapy*; D014162:Transfection; D014779:Virus Replication
D017931:DNA Primers; D013954:Thyroglobulin