title: Phase I and pharmacological study of cytarabine and tanespimycin in relapsed and refractory acute leukemia.
abstract: BACKGROUND
  In preclinical studies the heat shock protein 90 (Hsp90) inhibitor tanespimycin induced down-regulation of checkpoint kinase 1 (Chk1) and other client proteins as well as increased sensitivity of acute leukemia cells to cytarabine. We report here the results of a phase I and pharmacological study of the cytarabine + tanespimycin combination in adults with recurrent or refractory acute leukemia.
  
  
  METHODS
  Patients received cytarabine 400 mg/m(2)/day continuously for 5 days and tanespimycin infusions at escalating doses on days 3 and 6. Marrow mononuclear cells harvested before therapy, immediately prior to tanespimycin, and 24 hours later were examined by immunoblotting for Hsp70 and multiple Hsp90 clients.
  
  
  RESULTS
  Twenty-six patients were treated at five dose levels. The maximum tolerated dose was cytarabine 400 mg/m(2)/day for 5 days along with tanespimycin 300 mg/m(2) on days 3 and 6. Treatment-related adverse events included disseminated intravascular coagulation (grades 3 and 5), acute respiratory distress syndrome (grade 4), and myocardial infarction associated with prolonged exposure to tanespimycin and its active metabolite 17-aminogeldanamycin. Among 21 evaluable patients, there were two complete and four partial remissions. Elevations of Hsp70, a marker used to assess Hsp90 inhibition in other studies, were observed in more than 80% of samples harvested 24 hours after tanespimycin, but down-regulation of Chk1 and other Hsp90 client proteins was modest.
  
  
  CONCLUSIONS
  Because exposure to potentially effective concentrations occurs only for a brief time in vivo, at clinically tolerable doses tanespimycin has little effect on resistance-mediating client proteins in relapsed leukemia and exhibits limited activity in combination with cytarabine. (Clinicaltrials.gov identifier: NCT00098423).
authors.affiliation: Division of Hematology, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. kaufmann.scott@mayo.edu
authors.forename: Scott H
authors.initials: SH
authors.lastname: Kaufmann
authors.forename: Judith E
authors.initials: JE
authors.lastname: Karp
authors.forename: Mark R
authors.initials: MR
authors.lastname: Litzow
authors.forename: Ruben A
authors.initials: RA
authors.lastname: Mesa
authors.forename: William
authors.initials: W
authors.lastname: Hogan
authors.forename: David P
authors.initials: DP
authors.lastname: Steensma
authors.forename: Karen S
authors.initials: KS
authors.lastname: Flatten
authors.forename: David A
authors.initials: DA
authors.lastname: Loegering
authors.forename: Paula A
authors.initials: PA
authors.lastname: Schneider
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Peterson
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Maurer
authors.forename: B Douglas
authors.initials: BD
authors.lastname: Smith
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Greer
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Chen
authors.forename: Joel M
authors.initials: JM
authors.lastname: Reid
authors.forename: S Percy
authors.initials: SP
authors.lastname: Ivy
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Ames
authors.forename: Alex A
authors.initials: AA
authors.lastname: Adjei
authors.forename: Charles
authors.initials: C
authors.lastname: Erlichman
authors.forename: Larry M
authors.initials: LM
authors.lastname: Karnitz
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects*; D016227:Benzoquinones / Q000008:administration & dosage / Q000009:adverse effects; D000071877:Checkpoint Kinase 1; D003561:Cytarabine / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000008:administration & dosage / Q000009:adverse effects; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011494:Protein Kinases / Q000378:metabolism; D012008:Recurrence; D013997:Time Factors
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D003561:Cytarabine; C112765:tanespimycin; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1