THE EFFECT OF SEQUENCE AND TIME-INTERVAL BETWEEN CYCLOPHOSPHAMIDE AND TOTAL-BODY IRRADIATION ON LUNG AND BONE-MARROW DAMAGE FOLLOWING BONE-MARROW TRANSPLANTATION IN MICE

The compromise between bone marrow killing effect and toxicity (mainly on the lungs) of the conditioning protocol used prior to bone marrow transplantation (BMT) determine to a great extent the final outcome. In search of an optimal balance between minimum lung damage and maximum bone marrow cell kill, we have tested the effect of varying the sequence and time interval between cyclophosphamide (CTX) and total body irradiation (TBI). CTX was administered almost concomitantly with TBI (i.e., 15 min before TBI) or 1-7 days before or after TBI. Lung damage was assessed by the lethality (LD) of the mice between day 28 and day 180 after treatment, bone marrow damage by the LD of the mice between day 7 and day 28 after treatment and by the spleen colony assay. Mice chosen for lung damage testing were rescued from death due to bone marrow ablation by transplantation with syngeneic marrow cells. CTX potentiated radiation damage in both bone marrow and lungs. The effect on the bone marrow was greater when CTX was given after TBI than when given before TBI and this effect was significantly more than additive when the interval between the two agents was 3 days. Lung toxicity, on the other hand, was greater when CTX was given before TBI than when given after TBI. A therapeutic gain factor (TGF) was estimated by dividing the dose enhancement ratio (DEF) of bone marrow damage over the DEF of lung damage at all the time intervals studied. The results were consistently higher when CTX was given after TBI than when given before. The highest TGF values were with the two agents separated by more than 3 days, independent of sequence. The clinical implication of this observation may be that BMT requires a conditioning regimen where CTX is applied after, and not before, TBI and that the two agents should be separated by more than 3 days. This hypothesis needs thorough clinical testing.