Recently, in an effort to reduce leukemia recurrence following marrow transplantation, several clinical groups have begun applying fractionated-total-body-irradiation (FTBI) in their preparatory marrow ablation protocols. However, the effectiveness of this approach is a matter of controversy. The clinical data are conflicting, and the data from radiobiological models suggest that certain of the approaches to fractionation may in fact be less effective than the previously used single-dose TBI. The original (and most effective) single-dose TBI marrow ablation protocols were patterned after mouse models in which their ability could be directly tested by CFU-S assays. However, most of the current FTBI protocols have been derived empirically in the clinic without testing in a model, and there is reason to believe from radiobiological considerations that some of these may not be sound in their design. On the other hand, it is also the case that when cytotoxic drugs are combined with TBI the effect on hematopoietic stem cell survival may not be predictable on the basis of radiation considerations alone. It is therefore possible that certain FTBI protocols in which drug-radiation interactions occur may offer a therapeutic gain in marrow ablation over single-dose TBI protocols. Which types of combinations might offer such a gain also are not wholely predictable on the basis of empirical considerations. However, their potential effectiveness as a class can be straight-forwardly evaluated in a mouse model where stem cell survival can be directly measured by CFU-S techniques. Using such a model, involving normal mice and three different murine leukemia strains, we propose to evaluate by means of CFU-S assays--which will be followed by transplantation studies--the effectiveness of FTBI applied in three fashions: Before drugs; After drugs; and Interspersed with drugs. The data obtained with the leukemic models will be compared against their normal controls both in terms of CFU-S response, and in terms of overall differences in hematopoietic cell kinetics between the normal and leukemic tissues which could affect their manner of response. The results obtained with the FTBI will be compared to similar regimens where the total of the TBI is applied as a single-dose to determine if, and under what conditions, FTBI plus drugs may result in a therapeutic gain for marrow ablation over single-dose TBI plus drugs.
