title: Sequence dependence of MEK inhibitor AZD6244 combined with gemcitabine for the treatment of biliary cancer.
abstract: OBJECTIVE
  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 active in S-phase, and the extracellular signal-regulated kinase (ERK) pathway has a major role driving cell-cycle progression, concurrent use of a MEK inhibitor could potentially antagonize the effect of gemcitabine. We therefore tested the sequence dependence of the combination of gemcitabine and the MEK inhibitor AZD6244 using a series of biliary cancer models.
  
  
  METHODS
  Primary xenografts were established from patients with gallbladder and distal bile duct cancer and grown in severe combined immunodeficient (SCID) mice at the subcutaneous site. Plasma and tumor drug levels and the time course for recovery of ERK signaling and S-phase were measured in tumor-bearing mice treated for 48 hours with AZD6244 and then monitored for 48 hours off treatment. On the basis of these results, two different treatment schedules combining AZD6244 with gemcitabine were tested in four different biliary cancer models.
  
  
  RESULTS
  DNA synthesis was suppressed during treatment with AZD6244, and reentry into S-phase was delayed by approximately 48 hours after treatment. Strong schedule dependence was seen in all four biliary cancer models tested, suggesting that combined treatment with AZD6244 plus gemcitabine would be more active in patients with biliary cancer when gemcitabine is given following a 48-hour interruption in AZD6244 dosing, rather than concurrently.
  
  
  CONCLUSIONS
  The combination of AZD6244 plus gemcitabine is highly schedule dependent, and predicted to be more effective in the clinic using sequential rather than simultaneous dosing protocols.
authors.affiliation: Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Canada.
authors.forename: Junyao
authors.initials: J
authors.lastname: Xu
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Knox
authors.forename: Emin
authors.initials: E
authors.lastname: Ibrahimov
authors.forename: Eric
authors.initials: E
authors.lastname: Chen
authors.forename: Stefano
authors.initials: S
authors.lastname: Serra
authors.forename: Ming
authors.initials: M
authors.lastname: Tsao
authors.forename: Pinjiang
authors.initials: P
authors.lastname: Cao
authors.forename: Douglass
authors.initials: D
authors.lastname: Vines
authors.forename: David E
authors.initials: DE
authors.lastname: Green
authors.forename: Cristiane
authors.initials: C
authors.lastname: Metran-Nascente
authors.forename: Mairead G
authors.initials: MG
authors.lastname: McNamara
authors.forename: David W
authors.initials: DW
authors.lastname: Hedley
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001661:Biliary Tract Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; D003841:Deoxycytidine; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D000093542:Gemcitabine