Ho P T, Parkinson D R
Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, MD 20852, USA.
Semin Oncol. 1997 Apr;24(2):187-202.
The continued progress in our understanding of the biology of neoplasia and in the identification, cloning, and sequencing of genes critical to tumor cell function permits the exploitation of this information to develop specific agents that may directly modulate the function of these genes or their protein products. Antisense oligonucleotides are being investigated as a potential therapeutic modality that takes direct advantage of molecular sequencing. The antisense approach uses short oligonucleotides designed to hybridize to a target mRNA transcript through Watson-Crick base pairing. The formation of this oligonucleotide: RNA heteroduplex results in mRNA inactivation and consequent inhibition of synthesis of the protein product. A fundamental attraction of the antisense approach is that this method potentially may be applied to any gene product, in theory, for the treatment of malignant and non-malignant diseases. However, this simple and attractive model has proven to be much more complex in practice. A number of important challenges in the preclinical development of antisense oligonucleotides have been identified, including stability, sequence length, cellular uptake, target sequence selection, appropriate negative controls, oligonucleotide: protein interactions, and cost of manufacture. Although the biological activity of an oligonucleotide against its molecular target is theoretically sequence-dependent, the animal pharmacokinetics and toxicology of phosphorothioate analogues directed against vastly disparate gene products appear relatively non-sequence-specific. In oncology, a number of clinical trials have been initiated with antisense oligonucleotides directed against molecular targets including: p53; bcl-2; raf kinase; protein kinase C-alpha; c-myb. The experience gained from these early clinical trials will be applicable to the next generation of antisense agents in development. These may include molecules with novel backbones or other structural modifications, chimeric oligonucleotides, or peptide nucleic acids. Continued progress in this arena will require that many of the preclinical challenges confronting antisense development are satisfactory resolved.
我们对肿瘤形成生物学的理解不断进步，在识别、克隆和测序对肿瘤细胞功能至关重要的基因方面也不断取得进展，这使得我们能够利用这些信息开发特定药物，这些药物可能直接调节这些基因或其蛋白质产物的功能。反义寡核苷酸正作为一种潜在的治疗方式进行研究，它直接利用了分子测序技术。反义方法使用设计为通过沃森-克里克碱基配对与靶mRNA转录本杂交的短寡核苷酸。这种寡核苷酸：RNA异源双链体的形成导致mRNA失活，从而抑制蛋白质产物的合成。反义方法的一个根本吸引力在于，从理论上讲，这种方法可能适用于任何基因产物，用于治疗恶性和非恶性疾病。然而，这个简单且有吸引力的模型在实践中已被证明要复杂得多。已经确定了反义寡核苷酸临床前开发中的一些重要挑战，包括稳定性、序列长度、细胞摄取、靶序列选择、合适的阴性对照、寡核苷酸：蛋白质相互作用以及生产成本。尽管寡核苷酸对其分子靶标的生物学活性理论上依赖于序列，但针对截然不同的基因产物的硫代磷酸酯类似物的动物药代动力学和毒理学似乎相对不依赖于序列。在肿瘤学领域，已经启动了多项针对包括p53、bcl-2、raf激酶、蛋白激酶C-α、c-myb等分子靶标的反义寡核苷酸临床试验。从这些早期临床试验中获得的经验将适用于正在开发的下一代反义药物。这些药物可能包括具有新型骨架或其他结构修饰的分子、嵌合寡核苷酸或肽核酸。在这个领域取得持续进展将需要令人满意地解决反义开发面临的许多临床前挑战。
