REVERSAL OF CHEMORESISTANCE OF LYMPHOMA-CELLS BY ANTISENSE-MEDIATED REDUCTION OF BCL-2 GENE-EXPRESSION
REVERSAL OF CHEMORESISTANCE OF LYMPHOMA-CELLS BY ANTISENSE-MEDIATED REDUCTION OF BCL-2 GENE-EXPRESSION
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DOI：
10.1089/ard.1994.4.71
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发表时间：
1994-06-01
期刊：
影响因子：
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通讯作者：
REED, JC
中科院分区：
文献类型：
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作者：
KITADA, S;TAKAYAMA, S;REED, JC
bcl-2基因在许多类型的人类肿瘤中表达，并且由于t（14;18）染色体易位而在大多数非霍奇金淋巴瘤中转录失调。26-kDa Bcl-2蛋白已显示出阻断由许多类型的刺激（包括多种化疗药物和辐射）诱导的程序性细胞死亡（凋亡）。肿瘤细胞中bcl-2的存在与某些类型癌症患者对治疗的不良反应有关。为了进一步探索bcl-2与耐药性的相关性，我们使用反义（As）方法来降低含t（14; 18）的人淋巴瘤细胞系中稳态Bcl-2蛋白水平。合成的bcl-2-As寡核苷酸和产生bcl-2-As转录物的诱导表达质粒均诱导bcl-2表达减少，导致肿瘤细胞对常规化疗药物如阿糖胞苷（ara-C）和甲氨蝶呤（MTX）的敏感性显著增强。这些结果表明，针对bcl-2的新疗法可以通过影响细胞毒性药物靶点远端的生理途径来提供改善癌症治疗的手段。
The bcl-2 gene is expressed in many types of human tumors and becomes transcriptionally deregulated in the majority of non-Hodgkin's lymphomas as the result of t(14;18) chromosomal translocations. The 26-kDa Bcl-2 protein has been shown to block programmed cell death (apoptosis) induced by many types of stimuli, including a wide variety of chemotherapeutic drugs and radiation. The presence of bcl-2 in tumor cells has been correlated with poor responses to therapy in patients with some types of cancer. To explore further the relevance of bcl-2 to drug resistance, we used antisense (As) approaches to achieve reductions in the levels of steady state Bcl-2 protein levels in t(14; 18)-containing human lymphoma cell lines. Both synthetic bcl-2-As oligonucleotides and inducible expression plasmids that produce bcl-2-As transcripts induced reductions in bcl-2 expression, resulting in a marked enhancement in the sensitivity of neoplastic cells to conventional chemotherapeutic drugs such as cytosine arabinoside (ara-C) and methotrexate (MTX). These results suggest that novel therapeutics targeted against bcl-2 could provide the means for improved treatment of cancer by affecting physiological pathways distal to the targets of cytotoxic drugs.