Tibes Raoul, Trent Jonathan, Kurzrock Razelle
Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Annu Rev Pharmacol Toxicol. 2005;45:357-84. doi: 10.1146/annurev.pharmtox.45.120403.100124.
The clinical application of tyrosine kinase inhibitors for cancer treatment represents a therapeutic breakthrough. The rationale for developing these compounds rests on the observation that tyrosine kinase enzymes are critical components of the cellular signaling apparatus and are regularly mutated or otherwise deregulated in human malignancies. Novel tyrosine kinase inhibitors are designed to exploit the molecular differences between tumor cells and normal tissues. Herein, we will review the current state-of-the-art using agents that target as prototypes Bcr-Abl, platelet-derived growth factor receptor (PDGFR), KIT (stem cell factor receptor), and epidermal growth factor receptor (EGFR). These compounds are remarkably effective in treating diverse cancers that are highly resistant to conventional treatment, including various forms of leukemia, hypereosinophilic syndrome, mast cell disease, sarcomas, and lung cancer. It is now clear that the molecular defects underlying cancer can be targeted with designer drugs that yield striking salutary effects with minimal toxicity.
酪氨酸激酶抑制剂在癌症治疗中的临床应用代表了一项治疗突破。开发这些化合物的理论依据基于以下观察结果：酪氨酸激酶酶是细胞信号传导装置的关键组成部分，并且在人类恶性肿瘤中经常发生突变或以其他方式失调。新型酪氨酸激酶抑制剂旨在利用肿瘤细胞与正常组织之间的分子差异。在此，我们将以靶向Bcr-Abl、血小板衍生生长因子受体（PDGFR）、KIT（干细胞因子受体）和表皮生长因子受体（EGFR）的药物为原型，综述当前的先进技术。这些化合物在治疗对传统治疗高度耐药的多种癌症方面非常有效，包括各种形式的白血病、嗜酸性粒细胞增多综合征、肥大细胞病、肉瘤和肺癌。现在很清楚，癌症潜在的分子缺陷可以用设计药物来靶向，这些药物能产生显著的有益效果且毒性最小。
