Senderowicz Adrian M
Molecular Therapeutics Unit Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Building 30, Room 212, Bethesda, Maryland 20892, USA.
Curr Opin Cell Biol. 2004 Dec;16(6):670-8. doi: 10.1016/j.ceb.2004.09.014.
Oncogenic transformation leads to cell cycle aberration and apoptosis dysregulation. Targeting cell cycle and apoptosis pathways has emerged as an attractive approach for the treatment of cancer. The activity of cdks can be modulated by targeting these kinases with small molecules that bind to the ATP binding pocket of cdks, or by altering the composition of the cdk/endogenous cdk inhibitor complexes by different mechanisms. Apoptosis can be modulated by targeting pro-apoptotic or pro-survival pathways. Several proteins relevant to oncogenic and proliferative processes, such as p53, bcl-2, AKT, ras and epidermal growth factor receptor, are also important in blocking apoptosis. Several small molecules that modulate cell cycle control and apoptosis have been approved recently and many will be approved in the near future. Several challenges remain, including finding ways of targeting these agents specifically to tumors (sparing normal cells), and the development of rationales for combining these new agents with standard therapies and for prioritizing the development of an overwhelming number of novel small molecules targeting cell cycle and apoptosis. Novel technologies such as genomics and proteomics will be instrumental in designing combinatorial regimens tailored to patients on the basis of the genetic makeup of tumors. Irrespective of all shortcomings, the future of modulation of apoptosis and cell cycle machinery for oncology therapy is quite exciting.
致癌转化会导致细胞周期异常和凋亡失调。靶向细胞周期和凋亡途径已成为一种有吸引力的癌症治疗方法。细胞周期蛋白依赖性激酶（cdks）的活性可以通过用与cdks的ATP结合口袋结合的小分子靶向这些激酶来调节，或者通过不同机制改变cdk/内源性cdk抑制剂复合物的组成来调节。凋亡可以通过靶向促凋亡或促生存途径来调节。几种与致癌和增殖过程相关的蛋白质，如p53、bcl-2、AKT、ras和表皮生长因子受体，在阻止凋亡方面也很重要。最近有几种调节细胞周期控制和凋亡的小分子已获批准，并且在不久的将来还会有许多小分子获批。仍然存在一些挑战，包括找到将这些药物特异性靶向肿瘤（避免损伤正常细胞）的方法，以及制定将这些新药物与标准疗法联合使用的基本原理，以及确定优先开发大量靶向细胞周期和凋亡的新型小分子的优先级。基因组学和蛋白质组学等新技术将有助于根据肿瘤的基因组成设计适合患者的联合治疗方案。尽管存在所有缺点，但用于肿瘤治疗的凋亡和细胞周期机制调节的未来仍然令人兴奋。
