Enhancement of Radiation Response in p53-deficient Cancer Cells In vivo using Different Schedules of Radiation and AZD1152, an Aurora B Kinase Inhibitor

Article Outline

• Purpose/Objective(s)
• Materials/Methods
• Results
• Conclusions
• Copyright

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Purpose/Objective(s) 

Overexpression of Aurora kinases has been correlated with cancer susceptibility and poor prognosis in many human cancers. We have recently shown the ability of AZD1152, an Aurora kinase inhibitor with selectivity for Aurora B kinase, to enhance the effect of irradiation. This effect was also observed using siRNA, or by transfection with an inducible kinase-dead Aurora B in p53-deficient cancer cells (Oncogene, in press). The aim of the study reported here was to evaluate the effect the scheduling of AZD1152 administration on radiosensitivity and the effect AZD1152 on fractionated radiation.

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Materials/Methods 

AZD1152 is a highly potent Aurora kinase inhibitor selective for Aurora B kinase. AZD1152 is a phosphate pro-drug that is converted in vivo to the active moiety AZD1152-HQPA. 60Coγ-ray was used for in vivo (nude mice) irradiation.

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Results 

We have previously shown that 4-day administration of AZD1152 35 mg/kg/day increased radiation cell killing in the p53^-/- HCT116 cell line in vivo. In the current study, we administered a single dose of AZD1152 160 mg/kg in vivo following delivery of one 8 Gy fraction of radiation. This single dose of AZD1152 did have an effect on tumor growth inhibition but the effect was not increased when the compound was combined with radiation. We next compared three different schedules of radiation and AZD1152 (4-day dosing of 35 mg/kg/day): neo-adjuvant schedule, AZD1152 on days 1 to 4 then one fraction of 8 Gy radiation on day 5; adjuvant schedule, one fraction of 8 Gy radiation on day 1 and then AZD1152 on days 2-5; concomitant schedule, AZD1152 on days 1-4 combined with one fraction of 8 Gy radiation on day 1. Significantly greater tumor growth delays were observed when AZD1152 was combined with radiation compared with administration of radiation or AZD1152 alone in all three schedules. We have shown that AZD1152 enhanced the in vivo cell killing effect not only when combined with single dose (8 Gy) irradiation, but also when combined with fractionated radiation (2.5 Gy for 4 days concomitantly delivered with 4 days of AZD1152 35 mg/kg/day). Finally, we show that AZD1152 can lead to mitotic catastrophe in cancer cells in vitro and in vivo by inducing micronuclei and multinucleation.

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Conclusions 

This study demonstrates that different schedules of administration of AZD1152 and radiation can enhance radiation-induced cell death in p53-deficient cancer cells in vivo. These preclinical data support further clinical exploration of scheduling of chemo-radiotherapy and fractionated radiotherapy as frequently used in clinical practice.