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Clin Cancer Res. 2009 Mar 15;15(6):2022-30. doi: 10.1158/1078-0432.CCR-08-1826. Epub 2009 Mar 10.

The topoisomerase I poison CPT-11 enhances the effect of the aurora B kinase inhibitor AZD1152 both in vitro and in vivo.

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  • 1Laboratory of New Drug Development, Department of Medicine, MSKCC, New York, New York, USA.



AZD1152 is an Aurora B kinase inhibitor currently in clinical trials. As the topoisomerase I poison CPT-11 induces a G(2) arrest, a mechanistic understanding of the cell cycle interactions between these agents may prove critical for combination therapy.


AZD1152 was tested in vitro and in vivo with SN-38 and CPT-11 against HCT-116 cells. Inhibition of clonogenicity, induction of apoptosis, effects on polyploidy, and tumor growth were examined.


AZD1152 alone induced polyploidy of HCT-116 cells at low nanomolar concentrations. The induction of apoptosis required prolonged exposure (48 hours) and higher concentrations of drug. When SN-38 was given before or concomitantly with AZD1152, SN-38 blocked the AZD1152 effect by arresting cells in G(2) and inhibiting cells from undergoing polyploidy. With the reverse combination (AZD1152 followed by SN-38), there was a significant induction of polyploidy and apoptosis, even with shorter exposure (24 hours) of AZD1152. In vivo, AZD1152 alone suppressed HCT-116 xenograft tumor growth in a dose-dependent manner with target inhibition of phosphoH3, induction of multinucleated giant cells, but without induction of apoptosis. In combination, both sequences in vivo (CPT->AZD, AZD->CPT, P = 0.008, AUC/d) proved superior to either single agent therapy. However, AZD->CPT still showed a greater increase in apoptosis and greater suppression of tumor regrowth than CPT->AZD (P = 0.02, AUC/d).


The results from these studies indicate a promising therapeutic strategy for combining AZD1152 with CPT-11, and suggest that the sequence of drug administration is pivotal when an Aurora B kinase inhibitor is administered with a topoisomerase I poison.

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