Schwartz G N, Liu Y Q, Tisdale J, Walshe K, Fowler D, Gress R, Bergan R C
Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Antisense Nucleic Acid Drug Dev. 1998 Aug;8(4):329-39. doi: 10.1089/oli.1.1998.8.329.
p210bcr-abl-Related tyrosine kinase activity has been shown to cause chronic myelogenous leukemia (CML), a disease of bone marrow stem cells. Having previously demonstrated that the aptameric oligonucleotide, ODN-1, could inhibit p210bcr-abl kinase activity, the current study sought to determine if ODN-1 could selectively inhibit the growth of CML cells relative to that of normal bone marrow. ODN-1, when introduced by electroporation into peripheral blood mononuclear cells (PBMC) from patients with CML, decreased the number of committed progenitors (CML CFU-GM) by an average of 67%+/-19% (mean+/-SEM, range 28-98%). Treatment of CML PBMC with ODN-1 was also shown to decrease the number of more primitive cobblestone area-forming cells (CAFC) by 35%-87%. In contrast, there was little suppressive effect by the combination of electroporation and ODN-1 on either CFU-GM or CAFC numbers from normal donor bone marrow. These studies suggest that inhibition of p210bcr-abl protein-tyrosine kinase (PTK) activity by ODN-1 is associated with some degree of selective growth inhibition of p210bcr-abl-transformed cells. p210bcr-abl kinase inhibitory agents may be useful for the ex vivo purging of bone marrow or peripheral blood progenitor/stem cells in the setting of autologous transplantation for CML.
p210bcr - abl相关的酪氨酸激酶活性已被证明可导致慢性粒细胞白血病（CML），这是一种骨髓干细胞疾病。先前已证明适体寡核苷酸ODN - 1可抑制p210bcr - abl激酶活性，当前研究旨在确定ODN - 1相对于正常骨髓是否能选择性抑制CML细胞的生长。当通过电穿孔将ODN - 1引入CML患者的外周血单个核细胞（PBMC）时，定向祖细胞（CML CFU - GM）数量平均减少67%±19%（平均值±标准误，范围28 - 98%）。用ODN - 1处理CML PBMC还显示可使更原始的鹅卵石区域形成细胞（CAFC）数量减少35% - 87%。相比之下，电穿孔与ODN - 1的组合对正常供体骨髓的CFU - GM或CAFC数量几乎没有抑制作用。这些研究表明，ODN - 1对p210bcr - abl蛋白酪氨酸激酶（PTK）活性的抑制与p210bcr - abl转化细胞的一定程度的选择性生长抑制相关。p210bcr - abl激酶抑制剂可能有助于在CML自体移植过程中对骨髓或外周血祖细胞/干细胞进行体外净化。
