Chemosensitization and radiosensitization of human cancer by antisense Anti-MDM2 oligonucleotides -: In vitro and in vivo activities and mechanisms
Chemosensitization and radiosensitization of human cancer by antisense Anti-MDM2 oligonucleotides -: In vitro and in vivo activities and mechanisms
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DOI：
10.1196/annals.1281.025
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发表时间：
2003-01-01
期刊：
影响因子：
--
通讯作者：
Zhang, RW
中科院分区：
文献类型：
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作者：
Wang, H;Oliver, P;Zhang, RW
MDM 2癌基因在包括乳腺癌、结肠癌和前列腺癌在内的许多人类癌症中过表达，并且MDM 2水平与癌症患者的不良预后相关。本文综述了MDM 2癌基因在人类肿瘤生长中的作用，以及利用反义技术抑制MDM 2表达，以MDM 2作为前列腺癌治疗药物靶点的价值。在体外和体内人癌症模型中测试反义抗人MDM 2寡核苷酸和错配对照的抗肿瘤活性。分析靶向基因产物和相关蛋白，并确定当寡核苷酸单独使用或与癌症化疗和放疗联合使用时的抗肿瘤活性。该反义寡核苷酸以剂量和时间依赖性方式特异性地抑制MDM 2表达，从而在体外和体内产生显著的抗肿瘤活性。反义寡核苷酸还增强了化疗药物10-羟基喜树碱、阿霉素、5-氟尿嘧啶和紫杉醇对p53激活和p21诱导的作用。在剂量依赖性的方式中，反义寡核苷酸显示出抗肿瘤活性，在荷人癌异种移植物的裸鼠和化疗药物伊立替康，紫杉醇，和Rituxan和放射治疗的治疗效果增加。这些结果表明，MDM 2通过p53依赖性和p53非依赖性机制在各种肿瘤生长中发挥作用，表明MDM 2抑制剂在人类癌症中具有广谱抗肿瘤活性，而与p53状态无关。这些结果为反义抗MDM 2寡核苷酸作为化疗增敏剂和放射增敏剂的临床评价提供了依据。
MDM2 oncogene is overexpressed in many human cancers including breast, colon, and prostate cancer, and MDM2 levels are associated with poor prognosis in patients with cancer. Here, we summarize the investigation of the functions of MDM2 oncogene in human cancer growth and the value of MDM2 as a drug target for prostate cancer therapy by using antisense to inhibit MDM2 expression. Antisense anti-human-MDM2 oligonucleotides and mismatch controls were tested in in vitro and in vivo human cancer models for antitumor activity. Targeted gene products and related proteins were analyzed and the antitumor activity was determined when the oligonucleotides were used alone or in combination with cancer chemotherapeutics and radiation therapy. The antisense oligonucleotide specifically inhibited MDM2 expression in a dose- and time-dependent manner, resulting in significant antitumor activity in vitro and in vivo. The antisense oligonucleotides also potentiated the effects of p53 activation and p21 induction by chemotherapeutic agents 10-hydroxycamptothecin, adriamycin, 5-fluorouracil, and paclitaxel. In a dose-dependent manner, the antisense oligonucleotide showed antitumor activity in nude mice bearing human cancer xenografts and increased therapeutic effectiveness of the chemotherapeutic agents irinotecan, paclitaxel, and Rituxan and radiation therapy. These results indicate that MDM2 has a role in various tumor growth through both p53-dependent and p53-independent mechanisms, indicating that MDM2 inhibitors have a broad spectrum of antitumor activities in human cancers regardless of p53 status. These results provide a basis for clinical evaluation of antisense anti-MDM2 oligonucleotides as chemosensitizer and radiosensitizer.