Radioprotective agents stimulating hematopoietic stem cell reconstitution: A translational approach

Abstract

Toxicity associated with myelosuppression is an important dose-limiting factor when using radiation or chemotherapy. Certain growth factors, such as Thrombopoietin (TPO) can protect stem cells from radiation and accelerate recovery of hematopoietic stem cells (HSC). TPO is an important hematopoietic growth factor that stimulates megakaryocytopoieses and thrombopoiesis, but also has a direct radioprotective effect on HSCs. The development of neutralizing antibodies against TPO in healthy blood donors and patients has hampered clinical applications of TPO. However, it was found that by using a modified TPO administration schedule, the appearance of neutralizing antibodies could be completely prevented without loss of efficacy. The modified administration schedule even allowed for multiple rounds of treatment with TPO without induction of neutralizing antibodies. In addition, several new radioprotective agents are currently developed, including TPOmimetics, agents that either resemble TPO itself or activate and bind to the TPO-receptor. Granulocyte colony stimulating factor (G-CSF) has been used in the clinics to accelerate recovery of white blood cells after cytoreductive therapy and for mobilization of HSCs to the peripheral blood. Although combination therapy with G-CSF and Flt3-ligand results in an increased mobilization of progenitor cells to the peripheral blood, it was found that transplantation of these cells in irradiated monkeys did not result in accelerated recovery, but rather resulted in a loss of 1 log of repopulating stem cells. 5-Androstenediol (5-AED) is an androgenic steroid with immune modulating and radioprotective characteristics. In mouse and non-human primate models, it was shown that 5-AED treatment accelerated recovery of peripheral blood cells and bone marrow through direct effects of 5-AED on repopulating HSCs.