Back to Search
Start Over
Optimizing Therapeutic Effect of Aurora B Inhibition in Acute Myeloid Leukemia with AZD2811 Nanoparticles
- Source :
- Molecular Cancer Therapeutics. 16:1031-1040
- Publication Year :
- 2017
- Publisher :
- American Association for Cancer Research (AACR), 2017.
-
Abstract
- Barasertib (AZD1152), a highly potent and selective aurora kinase B inhibitor, gave promising clinical activity in elderly acute myeloid leukemia (AML) patients. However, clinical utility was limited by the requirement for a 7-day infusion. Here we assessed the potential of a nanoparticle formulation of the selective Aurora kinase B inhibitor AZD2811 (formerly known as AZD1152-hQPA) in preclinical models of AML. When administered to HL-60 tumor xenografts at a single dose between 25 and 98.7 mg/kg, AZD2811 nanoparticle treatment delivered profound inhibition of tumor growth, exceeding the activity of AZD1152. The improved antitumor activity was associated with increased phospho-histone H3 inhibition, polyploidy, and tumor cell apoptosis. Moreover, AZD2811 nanoparticles increased antitumor activity when combined with cytosine arabinoside. By modifying dose of AZD2811 nanoparticle, therapeutic benefit in a range of preclinical models was further optimized. At high-dose, antitumor activity was seen in a range of models including the MOLM-13 disseminated model. At these higher doses, a transient reduction in bone marrow cellularity was observed demonstrating the potential for the formulation to target residual disease in the bone marrow, a key consideration when treating AML. Collectively, these data establish that AZD2811 nanoparticles have activity in preclinical models of AML. Targeting Aurora B kinase with AZD2811 nanoparticles is a novel approach to deliver a cell-cycle inhibitor in AML, and have potential to improve on the clinical activity seen with cell-cycle agents in this disease. Mol Cancer Ther; 16(6); 1031–40. ©2017 AACR.
- Subjects :
- 0301 basic medicine
Cancer Research
Myeloid
Aurora B kinase
Antineoplastic Agents
Apoptosis
HL-60 Cells
Pharmacology
Polyploidy
Mice
03 medical and health sciences
0302 clinical medicine
Bone Marrow
Cell Line, Tumor
medicine
Animals
Aurora Kinase B
Humans
Protein Kinase Inhibitors
Dose-Response Relationship, Drug
business.industry
Cytarabine
Myeloid leukemia
Cancer
medicine.disease
Xenograft Model Antitumor Assays
Organophosphates
Rats
Tumor Burden
Disease Models, Animal
Leukemia, Myeloid, Acute
Leukemia
030104 developmental biology
medicine.anatomical_structure
Oncology
Cell culture
030220 oncology & carcinogenesis
Quinazolines
Nanoparticles
Drug Therapy, Combination
Female
Bone marrow
business
Subjects
Details
- ISSN :
- 15388514 and 15357163
- Volume :
- 16
- Database :
- OpenAIRE
- Journal :
- Molecular Cancer Therapeutics
- Accession number :
- edsair.doi.dedup.....fb1fb84513231106f68c3f235cbfc599