Preventing chemotherapy-induced myelosuppression by repurposing the FLT3 inhibitor quizartinib.
Samuel J TaylorJohanna M DuyvestynSamantha A DaggerEmma J DishingtonCatherine A RinaldiOliver M DoveyGeorge S VassiliouCarolyn S GroveWallace Y LangdonPublished in: Science translational medicine (2018)
We describe an approach to inhibit chemotherapy-induced myelosuppression. We found that short-term exposure of mice to the FLT3 inhibitor quizartinib induced the transient quiescence of multipotent progenitors (MPPs). This property of quizartinib conferred marked protection to MPPs in mice receiving fluorouracil or gemcitabine. The protection resulted in the rapid recovery of bone marrow and blood cellularity, thus preventing otherwise lethal myelosuppression. A treatment strategy involving quizartinib priming that protected wild-type bone marrow progenitors, but not leukemic cells, from fluorouracil provided a more effective treatment than conventional induction therapy in mouse models of acute myeloid leukemia. This strategy has the potential to be extended for use in other cancers where FLT3 inhibition does not adversely affect the effectiveness of chemotherapy. Thus, the addition of quizartinib to cancer treatment regimens could markedly improve cancer patient survival and quality of life.
Keyphrases
- acute myeloid leukemia
- chemotherapy induced
- bone marrow
- wild type
- mesenchymal stem cells
- allogeneic hematopoietic stem cell transplantation
- tyrosine kinase
- randomized controlled trial
- systematic review
- squamous cell carcinoma
- mouse model
- case report
- stem cells
- high fat diet induced
- papillary thyroid
- metabolic syndrome
- drug induced
- endothelial cells
- subarachnoid hemorrhage
- human health