Smith M R, Xie T, Zhou Z Z, Joshi I
Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Clin Cancer Res. 2001 Feb;7(2):400-6.
In t(14;18)-positive lymphoma cells, bcl-2 is expressed from a fusion mRNA transcript containing the full coding sequence of bcl-2 and 3' immunoglobulin sequences. We reported previously that antisense oligodeoxyribonucleotides directed at the bcl-2 translational start site, as well as those targeted to immunoglobulin sequences 3' of the translocation breakpoint, down-regulate bcl-2 and inhibit growth of the t(14;18)-positive lymphoma line WSU-FSCCL in vitro. We have developed a scid mouse model with this human cell line and demonstrate that antisense oligodeoxyribonucleotides targeted to immunoglobulin c(mu) sequences down-regulate bcl-2 protein expression and induce apoptosis of WSU-FSCCL cells in vivo. This leads to prolonged survival of the mice. Targeting non-oncogenic sequences outside of the breakpoints of fusion transcripts may be a clinically useful therapeutic strategy.
在t(14;18)阳性淋巴瘤细胞中，bcl-2由一种融合mRNA转录本表达，该转录本包含bcl-2的完整编码序列和3'免疫球蛋白序列。我们之前报道过，针对bcl-2翻译起始位点的反义寡脱氧核苷酸，以及针对易位断点3'端免疫球蛋白序列的反义寡脱氧核苷酸，可下调bcl-2并在体外抑制t(14;18)阳性淋巴瘤细胞系WSU-FSCCL的生长。我们用这种人类细胞系建立了一种严重联合免疫缺陷(scid)小鼠模型，并证明针对免疫球蛋白c(μ)序列的反义寡脱氧核苷酸可下调bcl-2蛋白表达并在体内诱导WSU-FSCCL细胞凋亡。这导致小鼠存活期延长。靶向融合转录本断点以外的非致癌序列可能是一种临床上有用的治疗策略。
