The topoisomerase i poison CPT-11 enhances the effect of the aurora B kinaseInhibitor AZD1152both in vitro and in Vivo Journal Article

  

Authors:	Nair, J. S.; de Stanchina, E.; Schwartz, G. K.
Article Title:	The topoisomerase i poison CPT-11 enhances the effect of the aurora B kinaseInhibitor AZD1152both in vitro and in Vivo
Abstract:	Purpose: AZD1152 is an Aurora B kinase inhibitor currently in clinical trials. As the topoisomerase I poison CPT-11 induces a G<sub>2</sub> 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<sub>2</sub> 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 super0ior 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. © 2009 American Association for Cancer Research.
Keywords:	controlled study; unclassified drug; human cell; cancer combination chemotherapy; dose response; drug potentiation; nonhuman; antineoplastic agents; ki 67 antigen; cell proliferation; mouse; animals; mice; animal tissue; apoptosis; animal experiment; animal model; 7 ethyl 10 hydroxycamptothecin; camptothecin; in vivo study; in vitro study; tumor xenograft; xenograft model antitumor assays; cell line, tumor; protein p53; irinotecan; drug synergism; cancer inhibition; drug antagonism; enzyme inhibitors; protein-serine-threonine kinases; cell cycle arrest; cell cycle g2 phase; quinazolines; tubulin; protein p21; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; giant cell; polyploidy; drug exposure; 2 [[3 [4 [5 [2 (3 fluoroanilino) 2 oxoethyl] 1h pyrazol 3 ylamino] 7 quinazolinyloxy]propyl](ethyl)amino]ethyl dihydrogen phosphate; 2 [[3 [4 [5 [2 (3 fluoroanilino) 2 oxoethyl] 1h pyrazol 3 ylamino] 7 quinazolinyloxy]propyl](ethyl)amino]ethyl dihydrogen phosphate hydroxyquinazoline pyrazol anilide; dna topoisomerase; prodrug; cell strain hct116; clonogenesis; dna topoisomerases, type i; phosphoric acid esters
Journal Title:	Clinical Cancer Research
Volume:	15
Issue:	6
ISSN:	1078-0432
Publisher:	American Association for Cancer Research
Date Published:	2009-03-15
Start Page:	2022
End Page:	2030
Language:	English
DOI:	10.1158/1078-0432.ccr-08-1826
PUBMED:	19276280
PROVIDER:	scopus
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-63449136392&partnerID=40&md5=5c7593ee64febbd107d54972e11f4188
Notes:	--- - "Cited By (since 1996): 1" - "Export Date: 30 November 2010" - "CODEN: CCREF" - "Source: Scopus"

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