title: Southwest Oncology Group phase II study of ispinesib in androgen-independent prostate cancer previously treated with taxanes.
abstract: OBJECTIVE
  The mitotic spindle has proven to be an effective therapeutic target in antineoplastic efforts. In this study, we sought to assess the efficacy of ispinesib, a mitotic kinesin spindle protein (KSP) inhibitor in androgen-independent prostate cancer progressing after docetaxel.
  
  
  METHODS
  Patients were treated with ispinesib 18 mg/m2 every 21 days and assessed for prostate-specific antigen (PSA) and measurable disease response at regular intervals. Kinesin spindle protein expression in archival tumors, population ispinesib pharmacokinetics, and pharmacodynamic assessments of circulating lymphocytes were included.
  
  
  RESULTS
  The study was terminated after first stage because no responses were seen in the first 21 patients. Median duration of PSA or clinical progression-free survival was 9 weeks. Plasma concentrations of ispinesib were comparable with those observed in previous phase I investigations. Immunohistochemical analysis of archival tumor specimens did not demonstrate significant KSP expression in most of the prostate cancer cases studied. Pharmacodynamic assessments of circulating lymphocytes from patients receiving ispinesib showed an absence of monopolar spindle formation, as would be expected if the drug were having its expected effects.
  
  
  CONCLUSIONS
  Ispinesib was inactive in this study of patients with androgen-independent, and largely docetaxelresistant, prostate cancer. The lack of efficacy might be explained by the low expression of the drug target seen in prostate cancer, whereas not detecting monopolar spindles in circulating lymphocytes with drug treatment likely reflects the lack of dividing cells in peripheral blood.
authors.affiliation: Oregon Health & Science University Cancer Institute, Portland, OR 97239, USA. beert@ohsu.edu
authors.forename: Tomasz M
authors.initials: TM
authors.lastname: Beer
authors.forename: Bryan
authors.initials: B
authors.lastname: Goldman
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Synold
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Ryan
authors.forename: Lakshmi S
authors.initials: LS
authors.lastname: Vasist
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Van Veldhuizen
authors.forename: Shaker R
authors.initials: SR
authors.lastname: Dakhil
authors.forename: Primo N
authors.initials: PN
authors.lastname: Lara
authors.forename: Anibal
authors.initials: A
authors.lastname: Drelichman
authors.forename: Maha H A
authors.initials: MH
authors.lastname: Hussain
authors.forename: E David
authors.initials: ED
authors.lastname: Crawford
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001549:Benzamides / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004341:Drug Evaluation; D019008:Drug Resistance, Neoplasm; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors*; D008297:Male; D008875:Middle Aged; D017430:Prostate-Specific Antigen / Q000032:analysis; D011471:Prostatic Neoplasms / Q000188:drug therapy; D011799:Quinazolines / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D043823:Taxoids / Q000627:therapeutic use
chemical_list: D001549:Benzamides; C470243:KIF11 protein, human; D011799:Quinazolines; D043823:Taxoids; C508757:ispinesib; D017430:Prostate-Specific Antigen; D016547:Kinesins