Busulfan

Busulfan inhibits the cobblestone area-forming cell frequency but fails to cause a significant increase in apoptosis in hematopoietic stem cell alike cells and progenitors. Busulfan inhibits the hematopoietic function of HSC alike cells and progenitors via an apoptosis-independent mechanism. Busulfan induces bone marrow hematopoietic cell senescence associated with an increased expression of p16^Ink4a and p19^Arf in a time-dependent manner. ^[1] Busulfan, an alkylating agent that causes DNA damage by cross-linking DNAs and DNA and proteins, induces senescence in normal human diploid WI38 fibroblasts through the extracellular signal-regulated kinase (Erk) and p38 mitogen-activated protein kinase (p38 MAPK) cascade independent of the p53-DNA damage pathway. Busulfan induces a transient reduction in GSH but a continuous increase in ROS production. ^[2] Busulfan-induced hypophosphorylation of Rb prevents apoptosis of spermatogonial stem cells by inhibiting PCNA expression in testicular cells. ^[3]

Busulfan-treated mice exhibit a marked increase in apoptosis and a decrease in testis weight. Busulfan is administered at the rate of 40 mg/kg body weight to induce a maximal number of apoptotic cells while minimizing the number of necrotic cells. ^[3] Busulfan conditioning and irradiation results in comparable sensitivity of HSC detection as evaluated by limiting dilution analysis in NOD/SCID mice. ^[4] Busulfan-transplanted mice has slow and incomplete lymphoid engraftment. Busulfan (20 mg/kg to 100 mg/kg) provides dose-dependent congenic lymphoid reconstitution in mice. ^[5]