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


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 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).


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.
Nair
Jayasree S
JS
Laboratory of New Drug Development, Department of Medicine, MSKCC, New York, New York, USA.
de Stanchina
Elisa
E
Schwartz
Gary K
GK
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D064107:Aurora Kinase B; D064127:Aurora Kinases; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D010755:Organophosphates / Q000494:pharmacology*; D011123:Polyploidy; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000494:pharmacology*; D059004:Topoisomerase I Inhibitors; D023041:Xenograft Model Antitumor Assays
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; D004791:Enzyme Inhibitors; D010755:Organophosphates; D011799:Quinazolines; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; C576921:AURKB protein, human; C576924:Aurkb protein, mouse; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D002166:Camptothecin