The long-term goal of the proposed research is the development of novel and more effective pretransplant conditioning strategies for more successful bone marrow transplantation (BMT) in poor prognosis B-lineage acute lymphoblastic leukemia (ALL). Our research plan involves (a) comparative laboratory studies using in vitro leukemic progenitor cell assays and in vivo severe combined immunodeficiency (SCID) mouse BMT models to examine the potential of novel strategies to overcome radiation resistance in B-lineage ALL and (b) correlative laboratory studies to illuminate the radiobiologic heterogeneity in B-lineage ALL. We propose to examine the efficacy of novel combinative radiochemotherapy regimens against primary blasts from poor prognosis B-lineage ALL patients using in vitro leukemic progenitor cell (LPC) and apoptosis assays as well as in vivo SCID mouse BMT models of human B-lineage ALL. specifically, we will analyze the effects of taxol, topotecan, and etoposide on the in vitro and in vivo anti-leukemic efficacy of gamma-rays. It is our central working HYPOTHESIS that a combination of low-LET radiation and taxol, topotecan, or etoposide will prove more effective against primary B-lineage LPC than radiation alone. In addition, we will continue out correlative laboratory studies to examine the relationship between radiobiologic features of primary B-lineage ALL blasts and their immunobiologic profiles as well as commonly measured disease- or host- related parameters. The knowledge gained from the proposed research may lead to the design of more effective TBI regimens for ALL.
