Antisense Approaches for the Treatment of Cancer
Antisense Approaches for the Treatment of Cancer
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治疗癌症的反义方法
作者：
B. Monia;J. Holmlund;F. Dorr
现有的癌症疗法对大多数实体癌症类型的价值仍然非常有限，并且通常与多药耐药肿瘤相关。因此，迫切需要治疗替代品来鉴定在有效剂量下具有更好耐受性的化合物，所述有效剂量针对限定的疾病相关分子靶标。在理解哺乳动物细胞转化的分子基础方面取得的进展已经导致了癌细胞中废除生长调节的统一概念。它现在是公认的，许多产品的“癌基因”编码的蛋白质，调节正常的有丝分裂和细胞凋亡，致癌过程是一个渐进的信号转导障碍（16）。事实上。在癌细胞中突变或丢失的许多基因（包括癌基因和肿瘤抑制基因）编码的蛋白质是细胞内信号转导的关键调节物（1 - 6）。这一概念框架为开发新的抗癌策略和治疗模式提供了基础，这些策略和治疗模式旨在通过阻断促有丝分裂信号转导或特异性诱导癌细胞凋亡来抑制癌症生长。虽然这些方法尚未得到临床验证，但这些策略可能会识别出与标准化疗药物相比具有更少不良副作用和更高疗效的抗癌药物。致癌基因产物的特异性抑制原则上可以通过适当设计的小分子来实现，条件是所选择的靶标显示出合理的酶功能（例如，某些蛋白激酶、细胞外基质降解蛋白酶、法尼基转移酶的抑制剂）。然而，大部分推定的致癌或与癌症相关的癌蛋白不具有内在的酶功能，例如各种转录因子（例如，RNY，JUN，FIX），细胞死亡抑制剂（例如，Bcl-2或Bcl-X）。和衔接蛋白（例如，Grb 2，TRAF蛋白）或其整体结构和酶功能是高度保守的（例如，蛋白质的多基因家族，如蛋白激酶、GTP结合蛋白），从而消除了获得可接受的特异性的可能性。反义作用是基于使用与蛋白质编码RNA结合的合成寡核苷酸抑制特定蛋白质的合成，从而阻止RNA功能（图I）。反义寡核苷酸（ASO）对mRNA功能的抑制作用有多种机制。这些包括剪接的抑制、蛋白质翻译的抑制，以及最常见的通过利用细胞中的RNase H酶降低稳态mRNA水平（7-12）。因为反义寡核苷酸可以抑制基因
Available cancer therapies still exhibit very limited value against most solid cancer types and are commonly associated with multidrug-resistant tumors. Because of this, an urgent need exists for therapeutic alternatives to identify compounds with better tolerability at efficacious doses that are directed at defined disease-relevant tnolecular targets. The progress made in understanding the molecular basis of mammalian cell transformation has led to unifying concepts of abrogated growth regulation in cancer cells. I t is now well recognized that many products of “cancer genes” encode proteins that regulate normal mitogenesis and apoptosis and that the carcinogenic process is a progressive disorder of signal transduction ( 1 6). In fact. many of the genes that are mutated or lost in cancer cells, including both oncogenes and tumor suppressor genes, encode proteins that are crucial regulators of intracellular signal transduction (1 -6). This conceptual framework has provided a basis for the development of novel anticancer strategies and therapeutic modalities aimed at inhibiting cancer growth either by blocking mitogenic signal transduction or specifically inducing apoptosis of cancer cells. Although these approaches have not yet been clinically validated, these strategies are likely to identify anticancer agents with fewer undesirable side effects and greater efficacy compared with standard chemotherapeutic agents. Specific inhibition of cancer-causing gene products can in principle be accomplished by appropriately designed small molecules, provided that the chosen targets display reasonable enzymatic functions (e.g., inhibitors of some protein kinases, extracellular matrix-degrading proteases, farnesyl transferases). However, a large proportion of putative cancer-causing or cancer-associated oncoproteins either do not have intrinsic enzymatic functions, such as various transcription factors (e.g., r n y , jun , f i x ) , cell death suppressors (e.g., Bcl-2 or Bcl-X). and adaptor proteins (e.g., Grb2, TRAF proteins) or their overall structure and enzymatic functions are highly conserved (e.g., multigene families of proteins such as protein kinases, GTP-binding proteins), thereby eliminating the possibility of achieving acceptable specificity. Antisense action is based on inhibiting the synthesis of a particular protein using synthetic oligonucleotides that bind to protein-encoding RNA, thereby preventing RNA function (Fig. I ) . A number of mechanisms have been demonstrated by which antisense oligonucleotides (ASOs) exert their inhibitory effects on mRNA function. These include inhibition of splicing, inhibition of protein translation, and, most commonly, reduction of steadystate mRNA levels through the utilization of RNase H enzymes in cells (7-12). Because ASOs can inhibit gene
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影响因子：
8
作者：
Hong-Gang Wang;T. Miyashita;S. Takayama;T. Sato;T. Torigoe;S. Krajewski;S. Tanaka;Hovey L rd;J. Troppmair;U. Rapp
通讯作者：
Hong-Gang Wang;T. Miyashita;S. Takayama;T. Sato;T. Torigoe;S. Krajewski;S. Tanaka;Hovey L rd;J. Troppmair;U. Rapp
影响因子：
11.2
作者：
Joyce Bos
通讯作者：
Joyce Bos
通过气管内滴注逆转录病毒反义 K-ras 构建体来预防原位人肺癌生长。
影响因子：
11.2
作者：
Georges,RN;Mukhopadhyay,T;Zhang,Y;Yen,N;Roth,JA
通讯作者：
Roth,JA
使用 c-myb 反义寡脱氧核苷酸在 scid 小鼠模型中体内治疗人白血病。
DOI：
10.1073/pnas.89.24.11823
发表时间：
1992
影响因子：
11.1
作者：
Ratajczak,MZ;Kant,JA;Luger,SM;Hijiya,N;Zhang,J;Zon,G;Gewirtz,AM
通讯作者：
Gewirtz,AM
反义硫代磷酸寡脱氧核糖核苷酸对 Raf-1 蛋白激酶的抑制与人喉鳞状细胞癌细胞对 γ 辐射的敏感性有关。
DOI：
--
发表时间：
1997
期刊：
The cancer journal from Scientific American.
影响因子：
--
作者：
Soldatenkov,VA;Dritschilo,A;Wang,FH;Olah,Z;Anderson,WB;Kasid,U
通讯作者：
Kasid,U