Zhang Ruiwen, Wang Hui, Agrawal Sudhir
Departments of Pharmacology and Toxicology, Division of Clinical Pharmacology, Comprehensive Cancer Center, and Gene Therapy Center, University of Alabama at Birmingham, 1670 University Boulevard, Birmingham, AL 35294, USA.
Curr Cancer Drug Targets. 2005 Feb;5(1):43-9. doi: 10.2174/1568009053332663.
The MDM2 oncogene has been suggested as a novel target for cancer therapy, based on the following observations: 1) MDM2 is overexpressed in many human cancers, including breast, colon, and prostate cancer; 2) high MDM2 levels are associated with poor prognosis in patients with cancer; 3) MDM2 overexpression is associated with advanced cancer phenotypes such as metastatic tumors and hormone-independent tumors; 4) MDM2 overexpression is associated with tumor resistance to chemotherapy and radiation therapy; and 5) inhibiting MDM2 expression or function results in tumor growth inhibition and regression. There are many options for inhibiting MDM2 function, including the use of gene silencing technologies, antibodies, peptides and small molecules. Considering the complexity of MDM2 functions, we have chosen to use gene silencing technologies including antisense oligonucleotides and RNA interference. In this article, we summarize the investigation of the antisense technology for inhibiting MDM2 expression. Antisense mixed-backbone oligonucleotides (MBO) specifically inhibit MDM2 expression in a dose- and time-dependent manner, resulting in significant anti-tumor activity in vitro and in vivo. The MBO also potentiates the therapeutic effects of chemotherapeutic agents and radiation therapy in various tumors, through both p53-dependent and p53-independent mechanisms, indicating that MDM2 inhibitors have a broad spectrum of anti-tumor activity in human cancers, regardless of p53 status. These results provide a basis for clinical evaluation of antisense anti-MDM2 oligonucleotides as chemosensitizers and radiosensitizers. In addition, the MBO has been successfully used to identify novel functions of MDM2.
基于以下观察结果，MDM2癌基因已被认为是癌症治疗的一个新靶点：1）MDM2在许多人类癌症中过度表达，包括乳腺癌、结肠癌和前列腺癌；2）MDM2高水平与癌症患者的不良预后相关；3）MDM2过表达与转移性肿瘤和激素非依赖性肿瘤等晚期癌症表型相关；4）MDM2过表达与肿瘤对化疗和放疗的抗性相关；5）抑制MDM2表达或功能会导致肿瘤生长抑制和消退。抑制MDM2功能有多种选择，包括使用基因沉默技术、抗体、肽和小分子。考虑到MDM2功能的复杂性，我们选择使用包括反义寡核苷酸和RNA干扰在内的基因沉默技术。在本文中，我们总结了抑制MDM2表达的反义技术的研究。反义混合骨架寡核苷酸（MBO）以剂量和时间依赖性方式特异性抑制MDM2表达，在体外和体内均产生显著的抗肿瘤活性。MBO还通过p53依赖性和p53非依赖性机制增强了化疗药物和放疗对各种肿瘤的治疗效果，表明MDM2抑制剂在人类癌症中具有广泛的抗肿瘤活性，与p53状态无关。这些结果为反义抗MDM2寡核苷酸作为化学增敏剂和放射增敏剂的临床评估提供了依据。此外，MBO已成功用于鉴定MDM2的新功能。
