Smith M R, Abubakr Y, Mohammad R, Xie T, Hamdan M, al-Katib A
Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Cancer Gene Ther. 1995 Sep;2(3):207-12.
The BCL-2 gene product is involved in preventing apoptosis. The t(14,18) chromosomal translocation, which results in a fusion messenger RNA containing the entire coding region of BCL-2 and a portion of the immunoglobulin heavy chain gene, is commonly found in follicular lymphoma and appears to play a role in lymphomagenesis by inhibiting cell death. We tested the hypothesis that downregulation of BCL-2 would decrease accumulation of follicular lymphoma cells by treating the t(14,18)-carrying follicular lymphoma cell line WSU-FSCCL in vitro with antisense oligodeoxyribonucleotides (ODNs) directed against BCL-2. We found dose-dependent, sequence-specific inhibition of cell accumulation by an antisense unmodified ODN directed at codons 2 to 7, which downregulated BCL-2 protein levels. This effect was near maximal at an ODN concentration of 40 micrograms/mL (6.9 mumol/L), with minimal toxicity by control sense, reverse, and mutated antisense ODN at the same concentration. The pre-B leukemia cell line REH showed no sequence-specific growth inhibition by the antisense ODN at these concentrations, and BCL-2 protein levels were not altered. These data suggest that WSU-FSCCL may be useful in a murine model to optimize antisense ODN for potential therapeutic utility.
BCL-2基因产物参与阻止细胞凋亡。t(14,18)染色体易位会产生一种融合信使核糖核酸，其包含BCL-2的整个编码区和免疫球蛋白重链基因的一部分，这种易位常见于滤泡性淋巴瘤中，并且似乎通过抑制细胞死亡在淋巴瘤发生过程中发挥作用。我们通过用针对BCL-2的反义寡脱氧核苷酸（ODN）体外处理携带t(14,18)的滤泡性淋巴瘤细胞系WSU-FSCCL，来检验BCL-2下调会减少滤泡性淋巴瘤细胞积累这一假说。我们发现针对密码子2至7的未修饰反义ODN对细胞积累有剂量依赖性、序列特异性抑制作用，该反义ODN下调了BCL-2蛋白水平。在ODN浓度为40微克/毫升（6.9微摩尔/升）时这种效应接近最大，而相同浓度的对照正义、反向和突变反义ODN毒性最小。前B淋巴细胞白血病细胞系REH在这些浓度下未显示出反义ODN的序列特异性生长抑制，且BCL-2蛋白水平未改变。这些数据表明WSU-FSCCL在小鼠模型中可能有助于优化反义ODN以用于潜在的治疗用途。
