Wang Wenge, El-Deiry Wafik S
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
Curr Opin Oncol. 2008 Jan;20(1):90-6. doi: 10.1097/CCO.0b013e3282f31d6f.
p53 mutation occurs in over half of all human tumors. Among the remaining tumors, although they may process a wild-type p53, the pathways of p53-induced cell-cycle arrest and apoptosis are deficient. Therefore, p53 serves as a unique molecular target for cancer therapy. This review focuses on the current progress regarding restoration of p53 function in human tumors for molecularly targeted therapy.
Targeting p53 for cancer therapy has been intensively pursued. CP-31398 was the first small molecule identified with the ability to restore the wild-type conformation to mutant p53. Subsequently, PRIMA-1 and ellipticine were found to be able to induce mutant p53-dependent cell death. Nutlin was developed to rescue wild-type p53 from degradation mediated by MDM2. More recently, p53 family members can be activated and therefore serve as substitutes of p53 in tumor cells and induce cell death.
Loss of p53 function is a characteristic of almost all human tumors. Recent advances demonstrate that reconstitution of p53 function is possible and practical as a promising antitumor strategy.
超过半数的人类肿瘤中存在p53突变。在其余肿瘤中，尽管它们可能具有野生型p53，但p53诱导细胞周期停滞和凋亡的途径存在缺陷。因此，p53是癌症治疗的一个独特分子靶点。本综述聚焦于人类肿瘤中p53功能恢复用于分子靶向治疗的当前进展。
针对p53进行癌症治疗已受到广泛关注。CP-31398是首个被鉴定出能够将突变型p53恢复为野生型构象的小分子。随后，发现PRIMA-1和玫瑰树碱能够诱导依赖突变型p53的细胞死亡。Nutlin被开发用于挽救野生型p53免受MDM2介导的降解。最近，p53家族成员可被激活，因此可作为肿瘤细胞中p53的替代物并诱导细胞死亡。
p53功能丧失是几乎所有人类肿瘤的一个特征。最近的进展表明，恢复p53功能作为一种有前景的抗肿瘤策略是可行且实际的。
