Background

Acute myeloid leukaemia (AML) is characterized by an overproduction of abnormal hematopoietic cells in the bone marrow and peripheral blood. Resistance to therapy is a major obstacle in the treatment of AML and underlies the need to develop new treatments. The Aurora kinases play a critical role in mitosis and have been suggested as targets for cancer therapy due to their overexpression in a variety of tumours.  AZD1152 is a selective Aurora B kinase inhibitor that shows anti-tumour activity in a range of preclinical cancer models^{1, 2}. Cytarabine (Ara-C) is used as a clinical therapy for AML.

Method

In this study, we treated SCID mice bearing subcutaneous human AML tumour (HL60) xenografts with AZD1152 (25mg/kg once daily i.p. for 4 days) or AraC (25mg/kg twice daily i.p. for 2 days) as monotherapies or together  in two overlapping combination schedules [either AZD1152 (Day 1-4) plus AraC (Day 1-2) (SCHEDULE 1) or AZD1152 (Day 1-4) plus AraC (Day 3-4) (SCHEDULE 2)].

Results

As monotherapy, both drugs produced significant tumour growth inhibition (TGI) compared to control animals (Maximum TGI of 31.7% & 48.3% for AraC & AZD1152 respectively, both p<0.05). When dosed in combination, both dosing schedules produced enhanced anti-tumour activity compared to controls (Maximum TGI of 110.9% for SCHEDULE 1 & 76.2% for SCHEDULE 2, both p<0.05). Additionally, the data suggest that the combination SCHEDULE 1 was more effective in inhibiting tumour growth compared to combination SCHEDULE 2. Histological analysis of tumours showed a decrease in mitotic cells and an increase in apoptotic cells in drug treated tumours compared to control tumours.  There was an increased level of apoptosis in SCHEDULE 1 treated group compared to SCHEDULE 2 treated group.

Conclusion

These data indicate a potential strategy of combining AZD1152 and AraC for treatment of AML, and suggest that schedule of drug administration may have a consequence on the overall anti-tumour efficacy.