Blagosklonny Mikhail V
Brander Cancer Research Institute, New York Medical College, 19 Bradhurst Ave, Hawthorne, Valhalla, NY 10532, USA.
Oncogene. 2004 Apr 12;23(16):2967-75. doi: 10.1038/sj.onc.1207520.
Although induction of apoptosis (cell death mediated by caspases) determines response to cancer therapy, this approach is limited by lack of selectivity in available apoptosis-inducing agents. Furthermore, most cancers, almost by definition, are resistant to apoptosis, growth arrest and cell senescence. Then, how can anticancer agents kill cancer cell without unacceptable toxicity to a patient? The potential therapeutic approaches range from selective inhibition of antiapoptotic pathways, antiangiogenic therapy, tissue-selective therapy (including immunotherapy) to exploitation of, for example, drug resistance, oncoprotein addiction, unrestricted cell cycles, hypermitogenic and hypoxic features of cancer cells. These overlapping and complementary approaches rely on rational drug combinations (at mechanism-based doses and sequences) aimed at matching targets. To ensure killing of cancer cells selectively, we may combine apoptosis- and senescence-inducing agents with inhibitors of apoptosis (to protect normal cells), inhibitors of signal transduction with cell cycle-dependent chemotherapy, antiangiogenic agents with hypoxia-inducible factor-1 inhibitors, tissue-selective therapy with differentiating agents and activators of death receptors with chemotherapy. In theory, consecutive use of these drug combinations may control cancer.
尽管诱导凋亡（由半胱天冬酶介导的细胞死亡）决定了癌症治疗的反应，但这种方法受到现有凋亡诱导剂缺乏选择性的限制。此外，几乎根据定义，大多数癌症对凋亡、生长停滞和细胞衰老具有抗性。那么，抗癌药物如何在不对患者产生不可接受毒性的情况下杀死癌细胞呢？潜在的治疗方法包括选择性抑制抗凋亡途径、抗血管生成疗法、组织选择性疗法（包括免疫疗法），以及利用例如癌细胞的耐药性、癌蛋白成瘾、不受限制的细胞周期、高增殖性和缺氧特征等。这些相互重叠和互补的方法依赖于旨在匹配靶点的合理药物组合（基于机制的剂量和顺序）。为了确保选择性地杀死癌细胞，我们可以将诱导凋亡和衰老的药物与凋亡抑制剂（以保护正常细胞）、信号转导抑制剂与细胞周期依赖性化疗药物、抗血管生成药物与缺氧诱导因子-1抑制剂、组织选择性疗法与分化剂以及死亡受体激活剂与化疗药物联合使用。理论上，连续使用这些药物组合可能控制癌症。
