RESUMEN
BACKGROUND: Presently, few options are available for refractory colorectal cancer (CRC). O6-methyl-guanine-DNA-methyltransferase (MGMT) promoter methylation is a frequent and early event in CRC tumourigenesis. This epigenetic silencing is a predictor of response to the alkylating drug temozolomide in glioblastoma. Preclinical evidences and some case reports showed temozolomide activity in CRC with MGMT silencing, but the available data from clinical trials are inconsistent. METHODS: This was a multicentre, phase 2 trial, planned according to a two-stage Simon's optimal design to investigate activity and safety of temozolomide in refractory CRC harbouring MGMT promoter methylation. The primary end point was overall response rate (ORR). Patients who failed two or more prior treatments received temozolomide at a dose of 150-200 mg m-2 per day on days 1-5 every 28 days. RESULTS: From July 2012 to June 2016, 225 patients were screened, 80 showed MGMT promoter methylation and 41 were enrolled. Overall response rate was 10% and disease control rate was 32%. Median progression-free survival and overall survival were 1.9 and 5.1 months, respectively. CONCLUSIONS: Temozolomide showed a modest activity in this heavily pretreated population and the study did not meet its primary end point. The role of temozolomide in CRC remains still controversial and further research is warranted.
Asunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Dacarbazina/análogos & derivados , Proteínas Supresoras de Tumor/genética , Anciano , Anciano de 80 o más Años , Anemia/inducido químicamente , Antineoplásicos Alquilantes/efectos adversos , Neoplasias Colorrectales/patología , Metilación de ADN , Dacarbazina/efectos adversos , Dacarbazina/uso terapéutico , Supervivencia sin Enfermedad , Femenino , GTP Fosfohidrolasas/genética , Humanos , Proteínas de la Membrana/genética , Persona de Mediana Edad , Mutación , Náusea/inducido químicamente , Metástasis de la Neoplasia , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Retratamiento , Tasa de Supervivencia , Temozolomida , Trombocitopenia/inducido químicamente , Resultado del Tratamiento , Vómitos/inducido químicamenteRESUMEN
The study of cAMP signaling has received a renewed impulse since the recognition that a key aspect of this pathway is the tight spatial control of signal propagation. The study of the mechanism that regulates cAMP signaling in space and time has prompted the development of new methodological approaches to detect cAMP in intact cells. Over the last decades, techniques to assess cAMP concentration with high spatial and temporal resolution in living cells have been elaborated that are based on fluorescent molecules and the phenomenon of fluorescence resonance energy transfer (FRET). A FRET-based indicator of cAMP concentration is typically a protein, including two fluorophores that are linked to a cAMP-binding domain. Binding of cAMP causes a change in the protein conformation and, as a consequence, in the distance between the fluorophores, thus altering the energy transfer between them. Several FRET indicators have been developed, differing in their affinity for cAMP, kinetic features and intracellular targeting. Such indicators enable the measurement of cAMP fluctuations as they happen in the complex intracellular environment and are proving to be effective tools to dissect compartmentalized cAMP signaling.
