Total body irradiation (TBI) in conjunction with high dose cyclophosphamide (CY) followed by allogeneic bone marrow transplantation (BMT) is frequently used to treat childhood and adult acute lymphoblastic leukemia (ALL). Despite such """"""""supralethal"""""""" pre-transplant radio-chemotherapy, recurrent leukemia after BMT is encountered by 25-50% of ALL patients. Our hypothesis is the leukemic progenitor cells in a significant number of ALL patients unlike their normal counterparts, are capable to repair sublethal radiation damage and may also be resistant to CY. Punctum saliens of this proposal will therefore be the elucidation of the radiobiological characteristics of normal as well as leukemic human bone marrow progenitor cells, in particular their capacity to repair sublethal damage. To this end, we will assay the survival of monopotent (CFU-GM, CFU-E, CFLU-MK) and pluripotent (CFU-GEMM) progenitor cells in normal human marrow after various irradiation regimens and compare this data with the survival of ALL progenitor cells subjected to the same regimens. In these studies we will use freshly obtained bone marrow samples from patients with T-or common B-lineage ALL and from healthy volunteer donors. Colony formation in vitro will be used as endpoint to deternime the surviving fraction of normal and leukemic progenitor cells. We strongly believe that the combination of different therapeutic modalities, such as TBI and high dose CY, should not be applied aad libitum but rather be based on a biological rationale if one aims at improving the therapeutic outcome of BMT in ALL. Therefore, we will determine the effects of the primary cytotoxic metabolite of CY (i.e., 4-hydroxy-CY) on radiation damagew to normal and leukemic progenitor cells. We will study the effect of drug treatment on the capacity of irradiated marrow progenitor cells to repair sublethal damage and also the influence of the timing of drug exposure in relation to ionizing radiation. Our proposed studies at the level of normal and leukemic bone marrow progenitor cells will most likely contribute to a more rational and effective use of TBI an CY in BMT for ALL.
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