Aurora B kinase inhibitor AZD1152: determinants of action and ability to enhance chemotherapeutics effectiveness in pancreatic and colon cancer

被引：60

作者：

Azzariti, A. ^{[1
]}

Bocci, G. ^{[2
]}

Porcelli, L. ^{[1
]}

Fioravanti, A. ^{[2
]}

Sini, P. ^{[3
]}

Simone, G. M. ^{[1
]}

Quatrale, A. E. ^{[1
]}

Chiarappa, P. ^{[1
]}

Mangia, A. ^{[1
]}

Sebastian, S. ^{[1
]}

Del Bufalo, D. ^{[4
]}

Del Tacca, M. ^{[5
]}

Paradiso, A. ^{[1
]}

机构：

[1] Natl Canc Inst, Clin Expt Oncol Lab, I-70126 Bari, Italy

[2] Univ Pisa, Scuola Med, Dept Internal Med, Div Pharmacol & Chemotherapy, I-56126 Pisa, Italy

[3] AstraZeneca, Canc & Infect Res Area, Macclesfield, Cheshire, England

[4] Regina Elena Inst Canc Res, Expt Chemotherapy Lab, I-00158 Rome, Italy

[5] Azienda Osped Univ Pisana, Clin Pharmacol Ctr Drug Expt, I-56126 Pisa, Italy

来源：

BRITISH JOURNAL OF CANCER | 2011年 / 104卷 / 05期

关键词：

AZD1152; gemcitabine; oxaliplatin; colon cancer; pancreatic cancer; CELLS IN-VITRO; SELECTIVE INHIBITOR; GROWTH ARREST; GEMCITABINE; EXPRESSION; PROTEIN; CHEMOSENSITIVITY; COMBINATION; SUPPRESSION; CHECKPOINT;

D O I：

10.1038/bjc.2011.21

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

BACKGROUND: AZD1152, the prodrug for AZD1152-hydroxyquinazoline pyrazol anilide (HQPA), is a selective inhibitor of Aurora B kinase activity. Preclinical evaluation of AZD1152 has been reported in several human cancer models. The potentiality of this compound in combination therapy warrants further investigation in solid tumours. EXPERIMENTAL DESIGN: This study explored the effects of AZD1152-HQPA in colon and pancreatic tumour cells. The antitumour properties of AZD1152, either as single agent or in combination with chemotherapeutics, were evaluated in each study model. The efficacy and the toxicity of AZD1152 alone and in combination with gemcitabine were validated in pancreatic tumour xenograft model. RESULTS: AZD1152-HQPA treatment resulted in a dramatic increase of chromosome number, modification of cell cycle and induction of apoptosis. The most effective combination was that with chemotherapeutics given soon after AZD1152 in both tumour cell types. The effectiveness of the sequential schedule of AZD1152 with gemcitabine was confirmed in nude mice bearing MiaPaCa-2 tumours, showing inhibition of tumour volumes and delaying of tumour growth after the interruption of the treatments. CONCLUSION: Here we show that AZD1152-HQPA enhances oxaliplatin and gemcitabine effectiveness in colon and pancreatic cancer, respectively. First, we provide advances into administration schedules and dosing regimens for the combination treatment in in vivo pancreatic tumour. British Journal of Cancer (2011) 104, 769-780. doi:10.1038/bjc.2011.21 www.bjcancer.com Published online 8 February 2011 (C) 2011 Cancer Research UK

引用

页码：769 / 780

页数：12

共 48 条

[1] The selective Aurora B kinase inhibitor AZD1152 as a novel treatment for hepatocellular carcinoma [J].