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.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Deoxycytidine/analogs & derivatives , Organophosphates/therapeutic use , Pancreatic Neoplasms/drug therapy , Protein Serine-Threonine Kinases/antagonists & inhibitors , Quinazolines/therapeutic use , Animals , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Aurora Kinase B , Aurora Kinases , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Colonic Neoplasms , Deoxycytidine/administration & dosage , Drug Screening Assays, Antitumor , Humans , Male , Mice , Mice, Nude , Organophosphates/adverse effects , Organoplatinum Compounds/administration & dosage , Oxaliplatin , Quinazolines/adverse effects , Xenograft Model Antitumor Assays , GemcitabineABSTRACT
The generation of panels of somatic cell hybrids specific for chimpanzee, gorilla, orangutan, and olive baboon is reported. The chromosome content of each hybrid clone was characterized using reverse painting on human normal metaphases and by the use of appropriate sequence tag sites (STSs), one for each chromosome arm. These resources can be advantageously exploited in the characterization of chromosome architecture of different primate species, with special reference to the discrimination of inter- and intra-chromosomal arrangement of segmental duplications.
