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AZD1152, a Selective Inhibitor of Aurora B Kinase, Inhibits Human Tumor Xenograft Growth by Inducing Apoptosis

Robert W. Wilkinson¹, Rajesh Odedra¹, Simon P. Heaton¹, Stephen R. Wedge¹, Nicholas J. Keen², Claire Crafter¹, John R. Foster¹, Madeleine C. Brady¹, Alison Bigley¹, Elaine Brown¹, Kate F. Byth², Nigel C. Barrass¹, Kirsten E. Mundt¹, Kevin M. Foote¹, Nicola M. Heron¹, Frederic H. Jung³, Andrew A. Mortlock¹, F. Thomas Boyle^1, and Stephen Green¹

Authors' Affiliations: ¹ AstraZeneca Pharmaceuticals, Macclesfield, Cheshire, United Kingdom; ² Cancer and Infection Discovery, AstraZeneca Pharmaceuticals LP, Waltham, Massachusetts; and ³ AstraZeneca, Centre de Recherches, Reims, France

Requests for reprints: Robert W. Wilkinson, AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom. Phone: 44-1625-516661; E-mail: robert.wilkinson{at}astrazeneca.com.

Purpose: 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).

Experimental Design: 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 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.

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