Kaubisch A, Schwartz G K
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Cancer J. 2000 Jul-Aug;6(4):192-212.
Malignant cells have acquired adaptations, which give them a growth and survival advantage over normal cells. One effect of many of these adaptations is that many cancerous cells are less likely to undergo programmed cell death (apoptosis) and, moreover, are resistant to chemotherapy-induced apoptosis. Other features of neoplastic cells are the loss of regulated or orderly progression through the cell cycle. In normal and cancerous cells, a balance between proapoptotic and antiapoptotic signals exists. Protein kinase C (PKC) is a cellular serine/threonine kinase with a central role in the mediation of mitogenic signals as well as the regulation of antiapoptotic signals. Inhibition of PKC by a novel group of chemical agents (PKC inhibitors) can induce apoptosis in some malignant cell lines, act as differentiating agents, and enhance the effect of cytotoxic chemotherapy. Other kinase inhibitors are potent inhibitors of kinases involved in the control of cell cycle progression (cyclin-dependent kinases [cdks]). Cdk inhibitors are able to induce cell cycle arrest in neoplastic cells and also act as enhancers of chemotherapy-induced apoptosis. The catalytic domain of different classes of kinases (PKC and cdk) share considerable homology. As a result, many kinase inhibitors that act by blocking the catalytic site are not highly specific and may act as inhibitors of both PKC and cdks. Preclinical studies point to potential applications for some of these PKC/cdk inhibitors, and current clinical trials are exploring the role these agents might have in cancer therapy. In this article, we discuss the rationale for the development of this novel class of agents and highlight those drugs, which have shown promise in clinical testing.
恶性细胞获得了一些适应性变化，使其相对于正常细胞具有生长和生存优势。其中许多适应性变化的一个影响是，许多癌细胞不太可能发生程序性细胞死亡（凋亡），而且对化疗诱导的凋亡具有抗性。肿瘤细胞的其他特征是在细胞周期中失去了受调控的或有序的进程。在正常细胞和癌细胞中，促凋亡信号和抗凋亡信号之间存在平衡。蛋白激酶C（PKC）是一种细胞丝氨酸/苏氨酸激酶，在有丝分裂信号的介导以及抗凋亡信号的调节中起核心作用。一类新型化学试剂（PKC抑制剂）对PKC的抑制可诱导某些恶性细胞系凋亡，起到分化剂的作用，并增强细胞毒性化疗的效果。其他激酶抑制剂是参与细胞周期进程控制的激酶（细胞周期蛋白依赖性激酶[cdk]）的强效抑制剂。Cdk抑制剂能够诱导肿瘤细胞发生细胞周期停滞，并且也可作为化疗诱导凋亡的增强剂。不同类别的激酶（PKC和cdk）的催化结构域具有相当大的同源性。因此，许多通过阻断催化位点起作用的激酶抑制剂并非高度特异性，可能同时作为PKC和cdk的抑制剂。临床前研究指出了其中一些PKC/cdk抑制剂的潜在应用，目前的临床试验正在探索这些药物在癌症治疗中可能发挥的作用。在本文中，我们讨论了开发这类新型药物的基本原理，并重点介绍了那些在临床试验中显示出前景的药物。
