REPAIR CAPACITY OF MOUSE LUNG AFTER TOTAL-BODY IRRADIATION ALONE OR COMBINED WITH CYCLOPHOSPHAMIDE

Purpose. Cyclophosphamide (CTX) combined with fractionated total body irradiation (TBI) is frequently used in the conditioning of patients p rior to bone marrow transplantation (BMT). This study was performed to investigate the effect of CTX on the repair capacity of lung tissue a fter TBI in a mouse model for BMT, Materials and methods. TBI was give n as a single fraction, 3 fractions in 3 days (Fx 3) or 9 fractions in 3 days (Fx 9) either alone or 24 h after a single dose of CTX. The si ngle fraction TBI was given at either high dose rate (HDR) of 0.71 Gy/ min or low dose rate (LDR) of 0.08 Gy/min. All mice were transplanted 4-6 h after the last TBI fi action. Lung damage was assessed using ven tilation rate (VR) and lethality between 28 and 180 days. The repair c apacity of lung tissue was estimated using the direct analysis method with the probability of reaching the end point described by a logistic formulation of the linear quadratic model. Results. The VR data confi rmed the high repair capacity of lung tissue with an alpha/beta ratio of 4.4 Gy though with a wide 95% confidence interval (CI = 0.03-10.5). Giving CTX before fractionated TBI markedly reduced the doses needed to cause response in 50% of the animals. The sparing effect of using f ractionated TBI was still evident in the combined CTX-TBI schedules. T he estimated alpha/beta ratio was 1.6 Gy (CI = 0.01-4.7) which is with in the range of values reported after thoracic radiation only. On the other hand, the sparing effect seen in going from single fraction HDR to LDR was completely abolished when CTX was given 24 h before TBI. Th e same pattern was repeated when lethality between 28-180 days was use d. Yet, the use of lethality to estimate lung damage in a TBI model, m arkedly underestimated the repair capacity. Conclusions. These results confirm the high repair capacity of lung tissue after TBI and emphasi ze the value of using a specific end point in testing lung damage afte r TBI. It also shows that there can be a negative effect of CTX on the repair capacity of lung damage which is more pronounced when CTX is f ollowed (24 h later) by single fraction TBI at LDR than by a fractiona ted TBI course over a few days.