Effect of split dose TBI on hematopoietic stem-cell survival in combined radiation-drug exposures

Studies were carried out to determine if a priming dose of total body irradiation (TBI) given before the first drug exposure in chemo-radiation protocols similar to those used in marrow transplantation would reduce the survival of hematopoietic stem cells. The cytotoxic drugs employed were cyclophosphamide (CY) and piperazinedione (PIP), both of which are currently used in the clinic for ablation of the host marrow prior to transplantation therapy for leukemia. The effects were evaluated in a normal and a leukemic mouse model using the endogenous colony-former technique. Splitting the TBI to give part of the total dose before the first dose of drug was found to enhance stem cell kill in some instances, but not in others. The optimum proportion of TBI given as the first dose did not appear to exceed 100 rads. When a higher proportion of the total TBI was given as the initial dose there was an indication of a protective effect on the stem cells with the PIP-TBI protocols, but similar protection was not observed with the CY-TBI protocols. When CY and PIP were combined together in the same protocol it was found that a simple inversion of the order of these two drugs could result in a six-fold difference in the extent of stem cell ablation achieved, indicating that with multiple drug protocols the drug sequencing itself could be equally important as the manner in which the radiation is given.