Accelerated bone marrow recovery from radiation damage in etoposide-pretreated mice

Purpose: Etoposide inhibits the activity of Topoisomerase II, and possesses radiosensitizing effects on cultured cells. We showed that pretreatment of mice with etoposide 1 day before whole-body irradiation (WBI) had a protective effect against radiation-induced bone marrow death. The number of endogeneous colony-forming units (CFU-S) surviving in WBI mice was significantly increased by pretreatment with etoposide. The purpose of the present study is to clarify mechanisms underlying the protective activity of etoposide against radiation-induced bone marrow damage. Methods and Materials: The spleen colony-forming cells (CFU-S) of femoral marrow were assayed by the method of Till and McCulloch. The proliferative state of CFU-S was assessed using the technique of Hodgson. The reduction in exogeneous CFU-S after hydroxyurea injection was used to determine the fraction size of S-phase in CFU-S. Results: Etoposide pretreatment did not modify the cell survival parameters of exogeneous CFU-S when bone marrow cells were assayed immediately after WBI. Recovery of CFU-S in femoral marrow started earlier in mice receiving etoposide pretreatment than in the radiation alone group. Administration of hydroxyurea revealed that the accelerated recovery of CFU-S was due to an increased population of S phase cells, suggesting etoposide pretreatment shortened generation time of CFU-S. Conclusions: The mechanism for the radioprotection appears to be accelerated proliferation of survived bone marrow cells rather than a change in cellular sensitivity to radiation.