title: AZD1152, a selective inhibitor of Aurora B kinase, inhibits human tumor xenograft growth by inducing apoptosis.
abstract: OBJECTIVE
  In the current study, we examined the in vivo effects of AZD1152, a novel and specific inhibitor of Aurora kinase activity (with selectivity for Aurora B).
  
  
  METHODS
  The pharmacodynamic effects and efficacy of AZD1152 were determined in a panel of human tumor xenograft models. AZD1152 was dosed via several parenteral (s.c. osmotic mini-pump, i.p., and i.v.) routes.
  
  
  RESULTS
  AZD1152 potently inhibited the growth of human colon, lung, and hematologic tumor xenografts (mean tumor growth inhibition range, 55% to > or =100%; P < 0.05) in immunodeficient mice. Detailed pharmacodynamic analysis in colorectal SW620 tumor-bearing athymic rats treated i.v. with AZD1152 revealed a temporal sequence of phenotypic events in tumors: transient suppression of histone H3 phosphorylation followed by accumulation of 4N DNA in cells (2.4-fold higher compared with controls) and then an increased proportion of polyploid cells (>4N DNA, 2.3-fold higher compared with controls). Histologic analysis showed aberrant cell division that was concurrent with an increase in apoptosis in AZD1152-treated tumors. Bone marrow analyses revealed transient myelosuppression with the drug that was fully reversible following cessation of AZD1152 treatment.
  
  
  CONCLUSIONS
  These data suggest that selective targeting of Aurora B kinase may be a promising therapeutic approach for the treatment of a range of malignancies. In addition to the suppression of histone H3 phosphorylation, determination of tumor cell polyploidy and apoptosis may be useful biomarkers for this class of therapeutic agent. AZD1152 is currently in phase I trials.
authors.affiliation: AstraZeneca Pharmaceuticals, Macclesfield, Cheshire, United Kingdom. robert.wilkinson@astrazeneca.com
authors.forename: Robert W
authors.initials: RW
authors.lastname: Wilkinson
authors.forename: Rajesh
authors.initials: R
authors.lastname: Odedra
authors.forename: Simon P
authors.initials: SP
authors.lastname: Heaton
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Wedge
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Keen
authors.forename: Claire
authors.initials: C
authors.lastname: Crafter
authors.forename: John R
authors.initials: JR
authors.lastname: Foster
authors.forename: Madeleine C
authors.initials: MC
authors.lastname: Brady
authors.forename: Alison
authors.initials: A
authors.lastname: Bigley
authors.forename: Elaine
authors.initials: E
authors.lastname: Brown
authors.forename: Kate F
authors.initials: KF
authors.lastname: Byth
authors.forename: Nigel C
authors.initials: NC
authors.lastname: Barrass
authors.forename: Kirsten E
authors.initials: KE
authors.lastname: Mundt
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Foote
authors.forename: Nicola M
authors.initials: NM
authors.lastname: Heron
authors.forename: Frederic H
authors.initials: FH
authors.lastname: Jung
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Mortlock
authors.forename: F Thomas
authors.initials: FT
authors.lastname: Boyle
authors.forename: Stephen
authors.initials: S
authors.lastname: Green
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D064107:Aurora Kinase B; D064127:Aurora Kinases; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D010755:Organophosphates / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats; D014183:Transplantation, Heterologous
chemical_list: C520647:2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate; D000970:Antineoplastic Agents; D010755:Organophosphates; D011799:Quinazolines; C576921:AURKB protein, human; C576924:Aurkb protein, mouse; C576925:Aurkb protein, rat; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases