Jin L, Neff T, Blau C A
Department of Medicine, University of Washington, Seattle 98195, USA.
Exp Hematol. 1999 Mar;27(3):520-5. doi: 10.1016/s0301-472x(98)00039-3.
In vivo administration of c-kit ligand (KL) expands early hemopoietic progenitors and stem cells and sensitizes clonogenic progenitors to 5-FU-mediated cell death. Studies were performed to determine whether the in vivo administration of Flk-2/Flt-3 ligand (FL) is also capable of sensitizing progenitors to 5-FU. Mice were treated with FL (100 micrograms/kg every 12 hours for a total of 3 doses), KL (50 micrograms/kg, same schedule) or both, either alone or in combination with 5-FU (a single 125 mg/kg injection 3 hours before the last dose of cytokine). Femurs and spleens were harvested 48 hours following the last dose of cytokine, and the total numbers of mononuclear cells and colony forming unit cells (CFU-C) per femur and spleen were determined. Statistically significant increases in the number of CFU-C per femur were observed in response to FL, KL and FL + KL. In the spleen, statistically significant increases in CFU-C were observed only with the FL + KL combination. 5-FU alone produced marked reductions in CFU-C both in the femur and in the spleen. In the femur, 5-FU-mediated reductions in CFU-C were enhanced 3- to 30-fold in the presence of concomitant KL, FL or KL + FL administration. Surprisingly, the combination of KL + FL was no more effective in sensitizing marrow CFU-C to 5-FU than was KL 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 contrasted sharply with those observed in the femur, as FL, KL and FL + KL all failed to enhance 5-FU-mediated reductions in CFU-C. The ability of FL + KL to stimulate CFU-C expansion in the spleen combined with the inability of this cytokine combination to augment 5-FU-mediated progenitor toxicity in the spleen supports the contention that cytokine-mobilized progenitors are not in cycle. FL's capacity to specifically sensitize marrow to the effects of cytotoxic drugs may have applications in bone marrow transplant conditioning regimens.
体内给予c-kit配体（KL）可扩增早期造血祖细胞和干细胞，并使克隆性祖细胞对5-氟尿嘧啶（5-FU）介导的细胞死亡敏感。本研究旨在确定体内给予Flk-2/Flt-3配体（FL）是否也能使祖细胞对5-FU敏感。给小鼠分别单独或联合5-FU（在最后一剂细胞因子前3小时单次注射125 mg/kg）给予FL（每12小时100微克/千克，共3剂）、KL（50微克/千克，相同给药方案）或两者。在最后一剂细胞因子后48小时采集股骨和脾脏，测定每根股骨和脾脏的单核细胞总数和集落形成单位细胞（CFU-C）数。观察到给予FL、KL和FL+KL后，每根股骨的CFU-C数量有统计学意义的增加。在脾脏中，仅FL+KL组合使CFU-C有统计学意义的增加。单独使用5-FU可使股骨和脾脏中的CFU-C显著减少。在股骨中，同时给予KL、FL或KL+FL时，5-FU介导的CFU-C减少增强了3至30倍。令人惊讶的是，KL+FL组合在使骨髓CFU-C对5-FU敏感方面并不比单独使用KL更有效，这表明能够在KL/5-FU组合中存活的CFU-C不能被FL驱动进入细胞周期。细胞因子与5-FU联合给药在脾脏中的作用与在股骨中观察到的作用形成鲜明对比，因为FL、KL和FL+KL均未能增强5-FU介导的CFU-C减少。FL+KL刺激脾脏中CFU-C扩增但不能增强该细胞因子组合对脾脏中5-FU介导的祖细胞毒性的能力，支持了细胞因子动员的祖细胞不在细胞周期中的观点。FL特异性使骨髓对细胞毒性药物作用敏感的能力可能在骨髓移植预处理方案中有应用价值。
