title: Vincristine activates c-Jun N-terminal kinase in chronic lymphocytic leukaemia in vivo.
abstract: OBJECTIVE
  The authors' aim was to conduct a proof-of-principle study to test whether c-Jun N-terminal kinase (JNK) phosphorylation and Noxa induction occur in peripheral blood chronic lymphocytic leukaemia (CLL) cells in patients receiving a vincristine infusion.
  
  
  METHODS
  Patients with CLL received 2 mg vincristine by a 5-min intravenous infusion. Blood samples were collected at baseline and up to 6 h after the vincristine infusion, and assayed for JNK activation, Noxa induction and vincristine plasma concentrations.
  
  
  RESULTS
  Ex vivo treated peripheral CLL cells activated JNK in response to 10-100 nM vincristine in 6 h. Noxa protein expression, while variable, was also observed over this time frame. In CLL patients, vincristine infusion led to rapid (<1 h) JNK phosphorylation in peripheral blood CLL cells which was sustained for at least 4-6 h after the vincristine infusion. Noxa protein expression was not observed in response to vincristine infusion.
  
  
  CONCLUSIONS
  This study confirmed that vincristine can activate JNK but not induce Noxa in CLL cells in vivo. The results suggest that novel JNK-dependent drug combinations with vincristine warrant further investigation.
authors.affiliation: Department of Medicine.|Norris Cotton Cancer Center; Geisel School of Medicine at Dartmouth, One Medical Center Drive, Lebanon, NH, 03756, USA.
authors.forename: Darcy J P
authors.initials: DJ
authors.lastname: Bates
authors.affiliation: Department of Medicine.|Department of Pharmacology and Toxicology.|Norris Cotton Cancer Center; Geisel School of Medicine at Dartmouth, One Medical Center Drive, Lebanon, NH, 03756, USA.
authors.forename: Lionel D
authors.initials: LD
authors.lastname: Lewis
authors.affiliation: Department of Pharmacology and Toxicology.|Norris Cotton Cancer Center; Geisel School of Medicine at Dartmouth, One Medical Center Drive, Lebanon, NH, 03756, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Eastman
authors.affiliation: Department of Medicine.|Norris Cotton Cancer Center; Geisel School of Medicine at Dartmouth, One Medical Center Drive, Lebanon, NH, 03756, USA.
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Danilov
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D048031:JNK Mitogen-Activated Protein Kinases / Q000097:blood / Q000378:metabolism*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000201:enzymology*; D008214:Lymphocytes / Q000187:drug effects / Q000201:enzymology; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014750:Vincristine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D014750:Vincristine; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Noxa; apoptosis; c-Jun N-terminal kinase; chronic lymphocytic leukaemia; vincristine