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

Autor: Guido Bocci, A. Paradiso, Anita Mangia, Sinto Sebastian, Ae Quatrale, Letizia Porcelli, M. Del Tacca, Gm Simone, Donatella Del Bufalo, Patrizia Chiarappa, P Sini, Anna Fioravanti, Amalia Azzariti
Rok vydání: 2011
Předmět:
Male
Cancer Research
Pancreatic disease
Organoplatinum Compounds
Colorectal cancer
pancreatic cancer
Apoptosis
AZD1152
Aurora B kinase
pancreas cancer
Deoxycytidine
Mice
Aurora Kinases
Antineoplastic Combined Chemotherapy Protocols
Aurora Kinase B
Cell Cycle
gemcitabine
Organophosphates
Spindle checkpoint
colon cancer
Oncology
Colonic Neoplasms
embryonic structures
biological phenomena
cell phenomena
and immunity
medicine.medical_specialty
Aurora inhibitor
Mice
Nude
Antineoplastic Agents
Protein Serine-Threonine Kinases
Biology
Cell Line
Tumor
Pancreatic cancer
Internal medicine
medicine
Animals
Humans
Cell Proliferation
oxaliplatin
Cancer
medicine.disease
Xenograft Model Antitumor Assays
Pancreatic Neoplasms
Endocrinology
Quinazolines
Cancer research
Drug Screening Assays
Antitumor
Translational Therapeutics
Zdroj: British Journal of Cancer
ISSN: 1532-1827
0007-0920
DOI: 10.1038/bjc.2011.21
Popis: 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.
Databáze: OpenAIRE
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