HEMATOPOIETIC STEM-CELL DEFICIT OF TRANSPLANTED BONE-MARROW PREVIOUSLY EXPOSED TO CYTOTOXIC AGENTS

High-dose chemotherapy and/or total body irradiation followed by autol ogous bone marrow rescue has improved the survival of patients with a variety of malignancies. Candidates for autologous bone marrow transpl antation (ABMT) often have received prior exposure to cytotoxic agents , some of which may damage primitive stem cells. We have developed an in vivo murine model to evaluate the effects of a number of individual cytotoxic agents on the ability of syngeneic donor marrow to provide long-term hematopoiesis in recipients following high-dose total body i rradiation. Marrow was experimentally obtained by giving donor mice 6 weekly injections of saline, cytosine arabinoside, cyclophosphamide, c isplatin, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), or busulfan, dr ugs known to have differing effects on primitive hematopoietic stem ce lls. After time to allow recovery of marrow and peripheral blood count s, 1x10(7) marrow cells from these mice were transplanted into lethall y irradiated syngeneic recipients. Five to 6 months after marrow trans plantation, the quality of long-term hematopoietic recovery was measur ed by WBC counts, marrow cellularity, CFU-S content, and determination s of stem cell self-renewal. Abnormalities were noted with the use of donor marrow exposed to all cytotoxic agents. Recipients of marrow pre viously exposed to cytosine arabinoside, an agent that spares the most primitive stem cells, were the least affected. Recipients of marrow p reviously exposed to busulfan, an agent known to damage primitive stem cells, were most affected with a decrease in peripheral blood counts, marrow cellularity, stem cell content, self-renewal capacity, and lon g-term survival. A decrease in hematopoietic stem cell self-renewal wa s seen in recipients of marrow previously exposed to cyclophosphamide, cisplatin, and BCNU even when marrow cellularity and CFU-S content we re normal. These data suggest that the capacity of syngeneic donor mar row to provide long-term hematopoiesis in lethally irradiated recipien ts is dependent on its donor marrow primitive stem cell content. Long- term hematopoiesis may be severely compromised in recipients of donor stem cells previously exposed to cytotoxic agents which damage primiti ve stem cells.