Bianco Roberto, Ciardiello Fortunato, Tortora Giampaolo
Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica, Università di Napoli Federico II, Via S. Pansini 5, 80131 Naples, Italy.
Curr Cancer Drug Targets. 2005 Feb;5(1):51-6. doi: 10.2174/1568009053332681.
The MDM2 oncogene is overexpressed in many human cancers, including sarcomas, certain hematologic malignancies, and breast, colon and prostate cancers. The p53-MDM2 interaction pathway has been suggested as a novel target for cancer therapy. To that end, several strategies have been explored, including the use of small polypeptides targeted to the MDM2-p53 binding domain, anti-MDM2 antisense oligonucleotides, and natural agents. Different generations of anti-human-MDM2 oligonucleotides have been tested in in vitro and in vivo human cancer models, revealing specific inhibition of MDM2 expression and significant antitumor activity. Use of antisense oligos potentiated the effects of growth inhibition, p53 activation and p21 induction by several chemotherapeutic agents. Increased therapeutic effectiveness of chemotherapeutic drugs in human cancer cell lines carrying p53 mutations or deletions have shown the ability of MDM2 inhibitors to act as chemosensitizers in various types of tumors through both p53-dependent and p53-independent mechanisms. Inhibiting MDM2 appears to also have a role in radiation therapy for human cancer, regardless of p53 status, providing a rationale for the development of a new class of radiosensitizers. Moreover, MDM2 antisense oligonucleotides potentiate the effect of epidermal growth factor receptor (EGFR) inhibitors by affecting in vitro and in vivo proliferation, apoptosis and protein expression in hormone-refractory and hormone-dependent human prostate cancer cells. These data support the development, among other MDM2 inhibitors, of anti-MDM2 antisense oligonucleotides as a novel class of anticancer agents, and suggest a potentially relevant role for the oligonucleotides when integrated with conventional treatments and/or other signaling inhibitors in novel therapeutic strategies.
MDM2癌基因在许多人类癌症中过表达，包括肉瘤、某些血液系统恶性肿瘤以及乳腺癌、结肠癌和前列腺癌。p53-MDM2相互作用途径已被认为是癌症治疗的一个新靶点。为此，人们探索了多种策略，包括使用靶向MDM2-p53结合域的小多肽、抗MDM2反义寡核苷酸和天然药物。不同代的抗人MDM2寡核苷酸已在体外和体内人类癌症模型中进行了测试，显示出对MDM2表达的特异性抑制和显著的抗肿瘤活性。反义寡核苷酸的使用增强了几种化疗药物的生长抑制、p53激活和p21诱导作用。在携带p53突变或缺失的人类癌细胞系中，化疗药物治疗效果的提高表明MDM2抑制剂能够通过p53依赖性和p53非依赖性机制在各种类型的肿瘤中作为化学增敏剂发挥作用。抑制MDM2似乎在人类癌症的放射治疗中也发挥作用，无论p53状态如何，这为开发一类新的放射增敏剂提供了理论依据。此外，MDM2反义寡核苷酸通过影响激素难治性和激素依赖性人类前列腺癌细胞的体外和体内增殖、凋亡及蛋白表达，增强了表皮生长因子受体（EGFR）抑制剂的作用。这些数据支持将抗MDM2反义寡核苷酸作为一类新型抗癌药物进行开发，并且表明在新的治疗策略中，当与传统治疗和/或其他信号抑制剂联合使用时，这些寡核苷酸可能具有潜在的相关作用。
