RESUMEN
PURPOSE: Irinotecan (CPT11) treatment significantly improves the survival of colorectal cancer patients and is routinely used for the treatment of these patients, alone or in combination with other agents. However, only 20% to 30% of patients show an objective response to irinotecan, and there is great need for new molecular markers capable of identifying the subset of patients who are unlikely to respond. EXPERIMENTAL DESIGN: Here we used microarray analysis of a panel of 30 colorectal cancer cell lines and immunohistochemistry to identify and validate a new biomarker of response to irinotecan. RESULTS: A good correlation was observed between irinotecan sensitivity and the expression of aprataxin (APTX), a histidine triad domain superfamily protein involved in DNA repair. Moreover, using an isogenic in vitro system deficient in APTX, we show that aprataxin directly regulates the cellular sensitivity to camptothecin, suggesting that it could be used to predict patient response to irinotecan. We constructed a tissue microarray containing duplicate tumor samples from 135 patients that received irinotecan for the treatment of advanced colorectal cancer. Immunohistochemical assessment of the tumor levels of aprataxin showed a significant association with treatment response and patient survival. Patients with low aprataxin had longer progression-free (9.2 versus 5.5 months; P = 0.03) and overall survival (36.7 versus 19.0 months; P = 0.008) than patients with high tumor aprataxin. No associations were found between coding APTX variants and aprataxin levels or camptothecin sensitivity. CONCLUSIONS: These results show that aprataxin tumor levels can be used to identify patients with low probability of response to irinotecan-based therapy who are ideal candidates to receive treatment with alternative agents in an attempt to improve patient survival.
Asunto(s)
Antineoplásicos Fitogénicos/uso terapéutico , Camptotecina/análogos & derivados , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteínas Nucleares/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Western Blotting , Camptotecina/uso terapéutico , Proliferación Celular , Neoplasias Colorrectales/patología , Proteínas de Unión al ADN/genética , Progresión de la Enfermedad , Femenino , Perfilación de la Expresión Génica , Humanos , Técnicas para Inmunoenzimas , Irinotecán , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Proteínas Nucleares/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Polimorfismo Genético , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tasa de Supervivencia , Análisis de Matrices Tisulares , Inhibidores de Topoisomerasa I , Resultado del Tratamiento , Células Tumorales CultivadasRESUMEN
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