Introduction: A major issue with current cancer treatment is myelosuppression, which is the harmful depletion of the haematopoietic system that occurs as a result of chemotherapy. We have previously identified that treatment with AC220 (quizartinib), a second-generation FLT3 inhibitor, induces a transient quiescence in early haematopoietic progenitor cells in a murine model. We investigated this phenomenon further to determine whether AC220-induced quiescence could protect wild-type (WT) progenitors from chemotherapy-induced death. Furthermore, we investigated the selectivity of this protective effect for WT against leukaemic bone marrow in chimeric mouse models.
Methods: B6 mice were dosed via oral gavage with AC220, or vehicle, to determine quiescence (via flow cytometric Ki67 expression and cell cycle analysis) and the resultant sensitivity to the chemotherapeutic agent 5-FU. AC220-resistant leukaemic bone marrow was mixed with WT bone marrow and transplanted into irradiated recipient B6.SJL.45.1 mice. These chimeric mice were treated with multiple rounds of AC220, or vehicle, plus 5-FU.
Results: B6 mice dosed with AC220 display a transient induction of quiescence in their haematopoietic progenitor cell compartment. This AC220-induced quiescence proved sufficient to induce protection from the cytotoxic actions of 5-FU such that pre-treatment with AC220 (2-18hr prior to 5-FU) led to a 10-fold increase in the number of haematopoietic multipotent progenitor cells surviving 2 days post injection. Furthermore, AC220-primed B6 mice displayed significantly higher survival and improved peripheral blood parameters after serial 5-FU treatment. Leukaemic chimeric mice treated with AC220-primed 5-FU demonstrated improvements in survival.
Conclusion: A priming dose of AC220 before 5-FU provides a simple and effective means to protect bone marrow progenitors from chemotherapy-induced death. This experimental protocol has the potential to drastically improve the quality of life of cancer patients and reduce costs associated with chemotherapy-induced myelosuppression.