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In vivo and microarray analysis of rexinoid-responsive anaplastic thyroid carcinoma.
Clin Cancer Res 2008; 14(2):589-96CC

Abstract

PURPOSE

Anaplastic thyroid carcinoma is rare, yet lethal despite aggressive therapy. Molecular targeting may be beneficial using the rexinoid LGD1069, a retinoid X receptor-selective agonist, as a novel treatment. In this report, we describe the efficacy of LGD1069 in anaplastic thyroid carcinoma in vitro and assess the in vivo treatment effects on a responsive cancer. Additionally, we explore potential mediators of the rexinoid effect on a responsive anaplastic thyroid cancer using comparative microarray analysis.

EXPERIMENTAL DESIGN

Anaplastic thyroid cancer cell lines DRO, ARO, and FRO were treated with LGD1069 in vitro. Responsive DRO xenograft tumors were treated with control chow or chow containing a low dose (30 mg/kg/d) or a high dose (100 mg/kg/d) of LGD1069. Comparative microarray analysis of DRO cells treated with LGD1069 compared with volume-equivalent control was assessed after 24 h of treatment to evaluate early gene expression changes.

RESULTS

DRO xenograft tumor growth was inhibited by LGD1069 treatment in a dose-dependent manner. Comparative microarray analysis showed that 80 genes had a significant increase in expression and 29 genes had a decrease in expression after 24 h of treatment with LGD1069. Expression of angiopoietin-like 4 (ANGPTL4) mRNA was increased 6.5-fold. A trend towards an increase in ANGPTL4 mRNA (not statistically significant) was seen in treated tumors in vivo and this correlated with decreased tumor vascularity and increased necrosis.

CONCLUSIONS

LGD1069 therapy decreases proliferation in an anaplastic thyroid cancer cell line that expresses retinoid X receptor-gamma, and this effect is confirmed with decreased tumor size in vivo in a nude mouse model. ANGPTL4 is increased in DRO in response to LGD1069 and may be a potential mediator of the effects of rexinoid treatment.

Authors+Show Affiliations

Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado at Denver and Health Sciences Center, Aurora, CO 80045, USA. joshua.klopper@uchsc.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18223235

Citation

Klopper, Joshua P., et al. "In Vivo and Microarray Analysis of Rexinoid-responsive Anaplastic Thyroid Carcinoma." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, vol. 14, no. 2, 2008, pp. 589-96.
Klopper JP, Berenz A, Hays WR, et al. In vivo and microarray analysis of rexinoid-responsive anaplastic thyroid carcinoma. Clin Cancer Res. 2008;14(2):589-96.
Klopper, J. P., Berenz, A., Hays, W. R., Sharma, V., Pugazhenthi, U., Janssen, J., ... Haugen, B. R. (2008). In vivo and microarray analysis of rexinoid-responsive anaplastic thyroid carcinoma. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 14(2), pp. 589-96. doi:10.1158/1078-0432.CCR-07-0269.
Klopper JP, et al. In Vivo and Microarray Analysis of Rexinoid-responsive Anaplastic Thyroid Carcinoma. Clin Cancer Res. 2008 Jan 15;14(2):589-96. PubMed PMID: 18223235.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In vivo and microarray analysis of rexinoid-responsive anaplastic thyroid carcinoma. AU - Klopper,Joshua P, AU - Berenz,Andrew, AU - Hays,William R, AU - Sharma,Vibha, AU - Pugazhenthi,Umarani, AU - Janssen,Jennifer, AU - Singh,Meenakshi, AU - Bissonnette,Reid P, AU - Haugen,Bryan R, PY - 2008/1/29/pubmed PY - 2008/3/28/medline PY - 2008/1/29/entrez SP - 589 EP - 96 JF - Clinical cancer research : an official journal of the American Association for Cancer Research JO - Clin. Cancer Res. VL - 14 IS - 2 N2 - PURPOSE: Anaplastic thyroid carcinoma is rare, yet lethal despite aggressive therapy. Molecular targeting may be beneficial using the rexinoid LGD1069, a retinoid X receptor-selective agonist, as a novel treatment. In this report, we describe the efficacy of LGD1069 in anaplastic thyroid carcinoma in vitro and assess the in vivo treatment effects on a responsive cancer. Additionally, we explore potential mediators of the rexinoid effect on a responsive anaplastic thyroid cancer using comparative microarray analysis. EXPERIMENTAL DESIGN: Anaplastic thyroid cancer cell lines DRO, ARO, and FRO were treated with LGD1069 in vitro. Responsive DRO xenograft tumors were treated with control chow or chow containing a low dose (30 mg/kg/d) or a high dose (100 mg/kg/d) of LGD1069. Comparative microarray analysis of DRO cells treated with LGD1069 compared with volume-equivalent control was assessed after 24 h of treatment to evaluate early gene expression changes. RESULTS: DRO xenograft tumor growth was inhibited by LGD1069 treatment in a dose-dependent manner. Comparative microarray analysis showed that 80 genes had a significant increase in expression and 29 genes had a decrease in expression after 24 h of treatment with LGD1069. Expression of angiopoietin-like 4 (ANGPTL4) mRNA was increased 6.5-fold. A trend towards an increase in ANGPTL4 mRNA (not statistically significant) was seen in treated tumors in vivo and this correlated with decreased tumor vascularity and increased necrosis. CONCLUSIONS: LGD1069 therapy decreases proliferation in an anaplastic thyroid cancer cell line that expresses retinoid X receptor-gamma, and this effect is confirmed with decreased tumor size in vivo in a nude mouse model. ANGPTL4 is increased in DRO in response to LGD1069 and may be a potential mediator of the effects of rexinoid treatment. SN - 1078-0432 UR - https://www.unboundmedicine.com/medline/citation/18223235/In_vivo_and_microarray_analysis_of_rexinoid_responsive_anaplastic_thyroid_carcinoma_ L2 - http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=18223235 DB - PRIME DP - Unbound Medicine ER -