Sequence Dependence of MEK Inhibitor AZD6244 Combined with Gemcitabine for the Treatment of Biliary Cancer

摘要: Purpose: MEK inhibition has clinical activity against biliary cancers and might therefore be successfully combined with gemcitabine, one of the most active chemotherapy agents for these cancers. As gemcitabine is in S-phase, extracellular signal-regulated kinase (ERK) pathway a major role driving cell-cycle progression, concurrent use inhibitor could potentially antagonize effect gemcitabine. We tested sequence dependence combination AZD6244 using series cancer models. Experimental Design: Primary xenografts were established from patients gallbladder distal bile duct grown severe immunodeficient (SCID) mice at subcutaneous site. Plasma tumor drug levels time course recovery ERK signaling S-phase measured tumor-bearing treated 48 hours then monitored off treatment. On basis results, two different treatment schedules combining four Results: DNA synthesis was suppressed during AZD6244, reentry into delayed by approximately after Strong schedule seen all models tested, suggesting that plus would more when given following 48-hour interruption dosing, rather than concurrently. Conclusions: The highly dependent, predicted to effective clinic sequential simultaneous dosing protocols. Clin Cancer Res; 19(1); 118–27. ©2012 AACR .