TY - JOUR
T1 - Inhibition of the growth of papillary thyroid carcinoma cells by CI-1040
AU - Henderson, Ying C.
AU - Ahn, Soon Hyun
AU - Clayman, Gary L.
PY - 2009/4
Y1 - 2009/4
N2 - Background: Papillary thyroid carcinoma (PTC), the most common type of thyroid malignancy, usually possesses mutations, either RET/PTC rearrangement or BRAF mutation. Both mutations can activate the mitogen- activated protein kinase kinase/extracellular signal- related kinase signaling transduction pathway, which results in activation of transcription factors that regulate cellular proliferation, differentiation, and apoptosis. Objective: To test the effects of CI-1040 (PD184352), a specific MEK1/2 inhibitor, on PTC cells carrying either an RET/PTC1 rearrangement or a BRAF mutation. Design: The effects of CI-1040 on PTC cells were evaluated in vitro and in vivo. Main Outcome Measures: The effects of CI-1040 on PTC cells were evaluated in vitro using a cell proliferation assay, cell cycle analysis, and immunoblotting. The antitumor effects of CI-1040 in vivo were evaluated in an orthotopic mouse model. Results: The concentrations of CI-1040 needed to inhibit 50% cell growth were 0.052μM for PTC cells with a BRAF mutation and 1.1μM for PTC cells with the RET/PTC1 rearrangement. After 3 weeks of oral administration of CI-1040 (300 mg/kg/d) to mice with orthotopic tumor implants of PTC cells, the mean tumor volume of implants bearing the RET/PTC1 rearrangement (n = 5) was reduced 47.5% compared with untreated mice (from 701.9 to 368.5 mm 3), and the mean volume of implants with a BRAF mutation (n = 8) was reduced 31.3% (from 297.3 to 204.2 mm 3). Conclusions: CI-1040 inhibits PTC cell growth in vitro and in vivo. Because RET/PTC rearrangements are unique to thyroid carcinomas and a high percentage of PTCs possess either mutation, these findings support the clinical evaluation of CI-1040 for patients with PTC.
AB - Background: Papillary thyroid carcinoma (PTC), the most common type of thyroid malignancy, usually possesses mutations, either RET/PTC rearrangement or BRAF mutation. Both mutations can activate the mitogen- activated protein kinase kinase/extracellular signal- related kinase signaling transduction pathway, which results in activation of transcription factors that regulate cellular proliferation, differentiation, and apoptosis. Objective: To test the effects of CI-1040 (PD184352), a specific MEK1/2 inhibitor, on PTC cells carrying either an RET/PTC1 rearrangement or a BRAF mutation. Design: The effects of CI-1040 on PTC cells were evaluated in vitro and in vivo. Main Outcome Measures: The effects of CI-1040 on PTC cells were evaluated in vitro using a cell proliferation assay, cell cycle analysis, and immunoblotting. The antitumor effects of CI-1040 in vivo were evaluated in an orthotopic mouse model. Results: The concentrations of CI-1040 needed to inhibit 50% cell growth were 0.052μM for PTC cells with a BRAF mutation and 1.1μM for PTC cells with the RET/PTC1 rearrangement. After 3 weeks of oral administration of CI-1040 (300 mg/kg/d) to mice with orthotopic tumor implants of PTC cells, the mean tumor volume of implants bearing the RET/PTC1 rearrangement (n = 5) was reduced 47.5% compared with untreated mice (from 701.9 to 368.5 mm 3), and the mean volume of implants with a BRAF mutation (n = 8) was reduced 31.3% (from 297.3 to 204.2 mm 3). Conclusions: CI-1040 inhibits PTC cell growth in vitro and in vivo. Because RET/PTC rearrangements are unique to thyroid carcinomas and a high percentage of PTCs possess either mutation, these findings support the clinical evaluation of CI-1040 for patients with PTC.
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U2 - 10.1001/archoto.2009.17
DO - 10.1001/archoto.2009.17
M3 - Article
C2 - 19380355
AN - SCOPUS:66149149478
SN - 0886-4470
VL - 135
SP - 347
EP - 354
JO - Archives of Otolaryngology - Head and Neck Surgery
JF - Archives of Otolaryngology - Head and Neck Surgery
IS - 4
ER -