RELATIONSHIPS BETWEEN ABLATION OF DISTINCT HEMATOPOIETIC-CELL SUBSETSAND THE DEVELOPMENT OF DONOR BONE-MARROW ENGRAFTMENT FOLLOWING RECIPIENT PRETREATMENT WITH DIFFERENT ALKYLATING DRUGS

A number of different alkylating chemotherapeutic agents - busulphan, dimethylbusulphan (DMB), isopropylmethane sulphonate (IMS), melphalan, cyclophosphamide (CY) and bischloroethylnitrosourea (BCNU)- were inve stigated for their cytotoxic effects on different haemopoietic cell po pulations in host mice and for their ability to induce short-and long- term engraftment of transplanted bone marrow. At 24 h after drug treat ment the femoral content of transient and permanent repopulating stem cell subsets was assessed, respectively, from the frequency of early- (day 5-15) and late- (day 25-35) developing cobblestone area-forming c ells (CAFCs), growing in vitro in long-term bone marrow cultures (LTBM Cs). At this time a fixed complement of 10(7) congenically marked dono r bone marrow cells (B6-Gpi-1(a) ---> B6-Gpi-1(b)) was infused in the drug-treated mice and erythroid engraftment was followed over 36 weeks . Diverse effects on early- and late-developing CAFC frequencies were found for the different drugs; these were generally related to the pat tern of donor bone marrow engraftment in treated recipients. Melphalan was more toxic to early-developing than to late-developing CAFC subse ts, and the transplant only offered an early wave of blood chimerism f ollowed by return of host cells. CY and BCNU had minimal to moderate e ffects on CAFC content and engraftment with no apparent preference for any particular haemopoietic cell subset. IMS also had a relatively lo w toxic effect on host marrow CAFC frequencies but appeared exceptiona l in its ability to allow for more donor-type engraftment. The dimetha ne sulphonate compounds busulphan and DMB were especially potent at de pleting late CAFC subsets and ensured high and lasting levels of donor bone marrow engraftment. These studies support the value of CAFC meas urements for predicting the fate and growth of transplanted bone marro w cells in recipients pretreated with a variety of cytotoxic agents.