Modification of radiation-induced damage to bone marrow stem cells by dose rate, dose fractionation, and prior exposure to cytoxan as judged by the survival of CFU s: Application to bone marrow transplantation (BMT)

Abstract

The relative importance of the effects of dose rate, dose fractionation, and prior exposure to Cytoxan on the recovery of cells in the bone marrow, following conditioning for BMT, remains controversial. Traditionally, bone marrow stem cells and leukemic cells have been considered as having a limited ability to repair radiation-induced damage following total body irradiation (TBI) compared to cells of the lung (the dose-limiting tissue for TBI). We examined the survival response of the bone marrow stem cells of mice (CFU s) at three TBI dose rates (0.47, 0.25 and 0.08 Gy/min). The radiation response of CFU s (compilation D 0 = 0.75 Gy) was independent of dose rate. One TBI dose fractionation was chosen: two fractions per day, separated by 6 hours, for 3 days. The radiation survival curve of CFU s showed a compilation D 0 of 1.09 Gy, compared to 0.75 Gy for the one-fraction case. The recovery of CFU s following 2 days of Cytoxan demonstrated an “overshoot,” whereas recovery of CFU s was incomplete, even by day 23, following the initiation of the complete conditioning regimen of Cytoxan plus TBI. These data demonstrate no significant effect of dose rate, at least in the range 0.08 to 0.48 Gy/min, on the survival of CFU s following either single or six fractionated TBI doses. However, the statistically significant difference in the D 0 of CFU s in going from one to six fractions has direct application to bone marrow transplantation techniques. Moreover, Cytoxan, at least at 200 mg/kg for 2 days, prior to TBI, appears to have only a marginal modifying effect on the eventual recovery of CFU s.