The Topoisomerase I Poison CPT-11 Enhances the Effect of the Aurora B Kinase Inhibitor AZD1152 both In vitro and In vivo

被引:33
|
作者
Nair, Jayasree S. [1 ]
de Stanchina, Elisa [2 ]
Schwartz, Gary K. [1 ]
机构
[1] Mem Sloan Kettering Canc Ctr, Lab New Drug Dev, Dept Med, New York, NY 10021 USA
[2] Mem Sloan Kettering Canc Ctr, Dept Mol Pharmacol & Chem, New York, NY 10021 USA
关键词
CHROMOSOMAL PASSENGER PROTEIN; CELL-DIVISION; APOPTOSIS; EXPRESSION; ARREST; GROWTH; CYCLE;
D O I
10.1158/1078-0432.CCR-08-1826
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: 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 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-> 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.
引用
收藏
页码:2022 / 2030
页数:9
相关论文
共 50 条
  • [31] The specific Aurora kinase inhibitor AZD1152 significantly affects the growth of human leukaemic cells in an in vivo AML model.
    Pearce, Daniel
    Odedra, Rajesh
    Wilkinson, Robert
    Bonnet, Dominique
    BLOOD, 2006, 108 (11) : 52A - 52A
  • [32] Enhancement of radiation response in p53 deficient cancer cells by the Aurora-B kinase inhibitor AZD1152
    Tao, Yungan
    Zhang, Ping
    Frascogna, Valerie
    Castedo, Maria
    Bourhis, Jean
    Kroemer, Guido
    Deutsch, Eric
    MOLECULAR CANCER THERAPEUTICS, 2007, 6 (12) : 3418S - 3419S
  • [33] Enhancement of radiation response in p53-deficient cancer cells by the Aurora-B kinase inhibitor AZD1152
    Y Tao
    P Zhang
    F Girdler
    V Frascogna
    M Castedo
    J Bourhis
    G Kroemer
    E Deutsch
    Oncogene, 2008, 27 : 3244 - 3255
  • [34] Enhancement of radiation response in p53-deficient cancer cells by the Aurora-B kinase inhibitor AZD1152
    Tao, Y.
    Zhang, P.
    Girdler, F.
    Frascogna, V.
    Castedo, M.
    Bourhis, J.
    Kroemer, G.
    Deutsch, E.
    ONCOGENE, 2008, 27 (23) : 3244 - 3255
  • [35] ENHANCEMENT OF RADIATION RESPONSE IN P53-DEFICIENT CANCER CELLS IN VIVO USING DIFFERENT SCHEDULES OF RADIATION AND AZD1152, AN AURORA B KINASE INHIBITOR
    Tao, Y.
    Leteur, C.
    Frascogna, V.
    Zhang, P.
    Opolon, P.
    Mundt, K.
    Kroemer, G.
    Bourhis, J.
    Deutsch, E.
    RADIOTHERAPY AND ONCOLOGY, 2008, 88 : S42 - S42
  • [36] Detection of surrogate markers of apoptosis in the peripheral blood of a preclinical tumour model treated with a selective inhibitor of Aurora B kinase (AZD1152)
    Wilkinson, R. W.
    Odedra, R.
    Heaton, S. P.
    Crafter, C.
    Growcott, J.
    Mundt, K.
    Cummings, J.
    Ward, T. H.
    Hegarty, C.
    Dive, C.
    EJC SUPPLEMENTS, 2006, 4 (12): : 144 - 144
  • [37] Enhancement of radiation response in p53-deficient cancer cells in vivo using different schedules of radiation and AZD1152, an Aurora B kinase inhibitor
    Tao, Y.
    Leteur, C.
    Frascogna, V.
    Zhang, P.
    Opolon, P.
    Mundt, K. E.
    Kroerner, G.
    Bourhis, J.
    Deutsch, E.
    INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS, 2008, 72 (01): : S713 - S713
  • [38] AZD1152, an Aurora Kinase B Inhibitor, Sensitizes Prostate Cancer Cells Through Mitotic Arrest and Reduced DNA Damage Repair
    Mitchell, L. R.
    Kopsombut, P.
    Li, J.
    Kim, K.
    Sun, Y.
    Lu, B.
    INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS, 2009, 75 (03): : S569 - S569
  • [39] A Phase I study to assess the safety, pharmacokinetics and efficacy of barasertib (AZD1152), an Aurora B kinase inhibitor, in Japanese patients with advanced acute myeloid leukemia
    Tsuboi, Kosuke
    Yokozawa, Toshiya
    Sakura, Toru
    Watanabe, Takashi
    Fujisawa, Shin
    Yamauchi, Takahiro
    Uike, Naokuni
    Ando, Kiyoshi
    Kihara, Rika
    Tobinai, Kensei
    Asou, Hiroya
    Hotta, Tomomitsu
    Miyawaki, Shuichi
    LEUKEMIA RESEARCH, 2011, 35 (10) : 1384 - 1389
  • [40] AZD1152, highly potent Aurora kinase inhibitor, with selectivity for Aurora kinase B, induces pharmacodynamic effects and significant growth inhibition in human tumor xenograft models.
    Wilkinson, RW
    Odedra, R
    Heaton, SP
    Keen, N
    Wedge, SR
    Brown, E
    Crafter, C
    Foote, KM
    Mortlock, AA
    Jung, FH
    Heron, NM
    Brady, MC
    Khatri, L
    Foster, JJ
    Green, S
    CLINICAL CANCER RESEARCH, 2005, 11 (24) : 9085S - 9085S