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Exploration of novel therapies for thyroid cancer: adenoviral gene therapy and 17-allylamino-17-demethoxygeldanamycin

Marsee, Derek K

Abstract Details

2004, Doctor of Philosophy, Ohio State University, Molecular, Cellular, and Developmental Biology.
Thyroid cancer is the most common endocrine malignancy, and new therapies are needed for tumors unresponsive to current treatment. Adenoviral gene therapy represents a novel form of cancer therapy. The expression of receptors that mediate adenoviral infection was examined along with adenoviral infectivity in thyroid cell lines. Loss of coxsackie-adenovirus receptor (CAR) expression resulted in poor adenoviral transduction, but was not predictive of infectivity. Surface expression of CAR in a thyroid tumor array demonstrated variable expression, with low levels in Hurthle cell and anaplastic carcinomas. High levels of surface CAR were detected in papillary, follicular, and insular carcinomas, suggesting that adenoviral gene therapy may be useful for patients with these forms of thyroid cancer. Despite the possibilities of gene therapy, however, problems exist with vector delivery and tissue targeting. The inclusion of an imaging gene is one strategy to monitor vector delivery and therapeutic gene expression. The Na + /I - symporter (NIS) is a membrane glycoprotein that facilitates the uptake of iodine into thyroid follicular cells. Pulmonary metastatic tumors were established by intravenous injection of MatLyLu cells expressing exogenous NIS into nude mice. Using single-photon emission computed tomography (SPECT) with pinhole collimation, tumor development was repetitively and non-invasively monitored. By combining dual isotope imaging, it was determined that tumors 3 mm in diameter could be detected using this technology. These studies demonstrate the utility of SPECT for monitoring imaging genes in small animal models of gene therapy. RET/PTC gene rearrangements are commonly observed in papillary thyroid carcinomas. Using co-immunoprecipitation studies combined with mass spectrometry, hsp90 and the cochaperone p50cdc37 are identified as novel PTC1-associated factors. Inhibition of hsp90 function with 17-allylamino-17-demethoxygeldanamycin (17-AAG) increased radioiodine accumulation, mediated by NIS. Radioiodine accumulation in PTC1-expressing PC-Cl3 cells, was higher than parental PC-Cl3 cells following 17-AAG treatment. An important mechanism of increased radioiodine accumulation by 17-AAG appeared to be decreased iodine efflux, which was more pronounced in PTC1-expressing than parental PC-Cl3 cells. Treatment with 17-AAG did not increase the amount of NIS protein or its localization at the plasma membrane. These results suggest that use of 17-AAG may be a useful chemotherapeutic agent for thyroid carcinomas.
Sissy Jhiang (Advisor)
118 p.

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Citations

  • Marsee, D. K. (2004). Exploration of novel therapies for thyroid cancer: adenoviral gene therapy and 17-allylamino-17-demethoxygeldanamycin [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1087497053

    APA Style (7th edition)

  • Marsee, Derek. Exploration of novel therapies for thyroid cancer: adenoviral gene therapy and 17-allylamino-17-demethoxygeldanamycin. 2004. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1087497053.

    MLA Style (8th edition)

  • Marsee, Derek. "Exploration of novel therapies for thyroid cancer: adenoviral gene therapy and 17-allylamino-17-demethoxygeldanamycin." Doctoral dissertation, Ohio State University, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=osu1087497053

    Chicago Manual of Style (17th edition)