Pepper C, Thomas A, Hoy T, Cotter F, Bentley P
Department of Haematology, Llandough Hospital, Penarth, South Glamorgan, London.
Br J Haematol. 1999 Dec;107(3):611-5. doi: 10.1046/j.1365-2141.1999.01726.x.
Although advances have been made in the development of more effective treatment modalities, B-cell chronic lymphocytic leukaemia (B-CLL) remains incurable due to the development of drug resistance. Defective programmed cell death mechanisms rather than dysregulation of cell cycle appears to predominate in B-CLL and it is likely that a failure to initiate apoptosis contributes to chemoresistance. Most B-CLL cells contain high levels of the anti-apoptotic protein Bcl-2 and high Bcl-2/Bax ratios have been associated with in vitro resistance to cytotoxic agents. In this study we evaluated the cellular responses to a Bcl-2 antisense oligonucleotide in terms of Bcl-2 mRNA and protein expression and the induction of apoptosis. The antisense molecule induced a specific reduction in Bcl-2 mRNA and protein expression over the 48 h culture period and was associated with increased apoptosis. The study indicates that Bcl-2 protein is central to the mediation of resistance to apoptosis in B-CLL. Therefore Bcl-2 antisense oligonucleotides might be useful in the treatment of B-CLL.
尽管在开发更有效的治疗方式方面已取得进展，但由于耐药性的产生，B细胞慢性淋巴细胞白血病（B-CLL）仍然无法治愈。在B-CLL中，程序性细胞死亡机制缺陷而非细胞周期失调似乎占主导地位，未能启动细胞凋亡可能导致化疗耐药。大多数B-CLL细胞含有高水平的抗凋亡蛋白Bcl-2，高Bcl-2/Bax比率与体外对细胞毒性药物的耐药性有关。在本研究中，我们从Bcl-2 mRNA和蛋白表达以及细胞凋亡诱导方面评估了细胞对Bcl-2反义寡核苷酸的反应。在48小时的培养期内，反义分子诱导Bcl-2 mRNA和蛋白表达特异性降低，并与细胞凋亡增加有关。该研究表明，Bcl-2蛋白是B-CLL中抗凋亡介导的核心。因此，Bcl-2反义寡核苷酸可能对B-CLL的治疗有用。
