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• W2154279344 startingPage "2022" @default.
• W2154279344 abstract "Abstract Purpose: AZD1152 is an Aurora B kinase inhibitor currently in clinical trials. As the topoisomerase I poison CPT-11 induces a G2 arrest, a mechanistic understanding of the cell cycle interactions between these agents may prove critical for combination therapy. Methods: 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. Results: 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 G2 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-&gt;AZD, AZD-&gt;CPT, P = 0.008, AUC/d) proved superior to either single agent therapy. However, AZD-&gt;CPT still showed a greater increase in apoptosis and greater suppression of tumor regrowth than CPT-&gt;AZD (P = 0.02, AUC/d). Conclusions: 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." @default.
• W2154279344 created "2016-06-24" @default.
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• W2154279344 date "2009-03-15" @default.
• W2154279344 modified "2023-09-23" @default.
• W2154279344 title "The Topoisomerase I Poison CPT-11 Enhances the Effect of the Aurora B Kinase Inhibitor AZD1152 both <i>In vitro</i> and <i>In vivo</i>" @default.
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• W2154279344 doi "https://doi.org/10.1158/1078-0432.ccr-08-1826" @default.
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