Marrow sensitization to 5-fluorouracil using the ligands for Flt-3 and c-Kit

In vivo administration of c-kit ligand (KL) expands early hemopoietic proge nitors and stem cells and sensitizes clonogenic progenitors to 5-Fu-mediate d cell death. Studies were performed to determine whether the in vivo admin istration of Flk-2/Fit-3 ligand (FL) is also capable of sensitizing progeni tors to 5-FU, Mice were treated with FL (100 mu g/kg every 12 hours for a t otal of 3 doses), KL (50 mu g/kg, same schedule) or both, either alone or i n combination with 5-FU (a single 125 mg/kg injection 3 hours before the la st dose of cytokine), Femurs and spleens were harvested 48 hours following the last dose of cytokine, and the total numbers of mononuclear cells and c olony forming unit cells (CFU-C) per femur and spleen were determined, Stat istically significant increases in the number of CFU-C per femur were obser ved in response to FL, KL and FL+KL, In the spleen, statistically significa nt increases in CFU-C were observed only with the FL+KL combination. 5-FU a lone produced marked reductions in CFU-C both in the femur and in the splee n. In the femur, Ei-FU-mediated reductions in CFU-C were enhanced 3- to 30- fold in the presence of concomitant KL, FL or KL+FL administration. Surpris ingly, the combination of KL;FL was no more effective in sensitizing marrow CFU-C to 5-FU than was KZ,alone, suggesting that CFU-C that are capable of surviving the KL/5-FU combination cannot be driven into cell cycle by FL. The effects of concomitant cytokine/5-FU administration in the spleen contr asted sharply with those observed in the femur, as FL, KL and FL+KL all fai led to enhance 5-FU-mediated reductions in CFU-C, The ability of FL+KL to s timulate CFU-C expansion in the spleen combined with the inability of this cytokine combination to augment 5-FU-mediated progenitor toxicity in the sp leen supports the contention that cytokine-mobilized progenitors are not in cycle, FL's capacity to specifically sensitize marrow to the effects of cy totoxic drugs may have applications in bone marrow transplant conditioning regimens. (C) 1999 International Society for Experimental Hematology, Publi shed by Elsevier Science Inc.