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

Abstract

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. 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.

• Authors: A Azzariti, G Bocci, L Porcelli, A Fioravanti, P Sini, G M Simone, A E Quatrale, P Chiarappa, A Mangia, S Sebastian, D Del Bufalo, M Del Tacca, A Paradiso
• Journal: British journal of cancer (Br J Cancer) Vol. 104 Issue 5 Pg. 769-80 (Mar 01 2011) ISSN: 1532-1827 [Electronic] England
• PMID: 21304529 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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
• Antineoplastic Agents
• Organophosphates
• Organoplatinum Compounds
• Quinazolines
• Oxaliplatin
• Deoxycytidine
• AURKB protein, human
• Aurkb protein, mouse
• Aurora Kinase B
• Aurora Kinases
• Protein Serine-Threonine Kinases
• Gemcitabine

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Apoptosis (drug effects)
• Aurora Kinase B
• Aurora Kinases
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Colonic Neoplasms
• Deoxycytidine (administration & dosage, analogs & derivatives)
• Drug Screening Assays, Antitumor
• Humans
• Male
• Mice
• Mice, Nude
• Organophosphates (adverse effects, therapeutic use)
• Organoplatinum Compounds (administration & dosage)
• Oxaliplatin
• Pancreatic Neoplasms (drug therapy)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Quinazolines (adverse effects, therapeutic use)
• Xenograft Model Antitumor Assays
• Gemcitabine