Inhibition of the growth of papillary thyroid carcinoma cells by CI-1040.
Arch Otolaryngol Head Neck Surg
; 135(4): 347-54, 2009 Apr.
Article
en En
| MEDLINE
| ID: mdl-19380355
ABSTRACT
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 OUTCOMEMEASURES:
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 0.052microM for PTC cells with a BRAF mutation and 1.1microM 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.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Benzamidas
/
Neoplasias de la Tiroides
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Carcinoma Papilar
/
Proliferación Celular
/
Inhibidores Enzimáticos
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Arch Otolaryngol Head Neck Surg
Asunto de la revista:
OTORRINOLARINGOLOGIA
Año:
2009
Tipo del documento:
Article
País de afiliación:
Estados Unidos