| Abstract | Aurora kinases are potential targets for cancer therapy. Previous studies have validated Aurora kinase A as a therapeutic target in multiple myeloma (MM), and have demonstrated in vitro anti-myeloma effects of small molecule Aurora kinase inhibitors that inhibit both Aurora A and B. This study demonstrated that Aurora B kinase was strongly expressed in myeloma cell lines and primary plasma cells. The selective Aurora B inhibitor AZD1152-induced apoptotic death in myeloma cell lines at nanomolar concentrations, with a cell cycle phenotype consistent with that reported previously for Aurora B inhibition. In some cases, AZD1152 in combination with dexamethasone showed increased anti-myeloma activity compared with the use of either agent alone. AZD1152 was active against sorted CD138(+) BM plasma cells from myeloma patients but also, as expected, was toxic to CD138(-) marrow cells from the same patients. In a murine myeloma xenograft model, AZD1152-inhibited tumour growth at well-tolerated doses and induced cell death in established tumours, with associated mild, transient leucopenia. AZD1152 shows promise in these preclinical studies as a novel treatment for MM. |
| Authors | Robert P Evans, Claudia Naber, Tara Steffler, Tamara Checkland, Christopher A Maxwell, Jonathan J Keats, Andrew R Belch, Linda M Pilarski, Raymond Lai, Tony Reiman
(Affiliation: Department of Oncology, University of Alberta/Cross Cancer Institute, Edmonton, AB, Canada.)
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| Journal | British journal of haematology
(Br J Haematol)
Vol. 140
Issue 3
Pg. 295-302
(Feb 2008)
ISSN: 1365-2141 England |
| PMID | 18076711
(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
- Phosphoric Acid Esters
- Quinazolines
- RNA, Messenger
- Syndecan-1
- aurora kinase
- Protein-Serine-Threonine Kinases
|
| Topics |
- Animals
- Antineoplastic Agents
(therapeutic use)
- Apoptosis
- Cell Line, Tumor
- Flow Cytometry
- Humans
- Immunophenotyping
- Mice
- Mice, SCID
- Multiple Myeloma
(drug therapy, enzymology, pathology)
- Phosphoric Acid Esters
(therapeutic use)
- Plasma Cells
(enzymology, immunology)
- Protein-Serine-Threonine Kinases
(analysis, antagonists & inhibitors, genetics)
- Quinazolines
(therapeutic use)
- RNA, Messenger
(analysis)
- Reverse Transcriptase Polymerase Chain Reaction
- Syndecan-1
(analysis)
- Xenograft Model Antitumor Assays
|
