MDM2 oncogene as a target for cancer therapy: An antisense approach.
MDM2 oncogene as a target for cancer therapy: An antisense approach.
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DOI：
10.3892/ijo.15.4.653
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发表时间：
1999-10
影响因子：
5.2
通讯作者：
Hui Wang;Xiaofei Zeng;P. Oliver;Long P. Le;Jiandong Chen;Lihong Chen;Wenqiang Zhou;Sudhir Agrawal;Ruiwen Zhang
中科院分区：
文献类型：
--
作者：
Hui Wang;Xiaofei Zeng;P. Oliver;Long P. Le;Jiandong Chen;Lihong Chen;Wenqiang Zhou;Sudhir Agrawal;Ruiwen Zhang
MDM 2癌基因在人类癌症中扩增或过表达。也有人认为MDM 2水平与几种人类癌症的预后不良有关。MDM 2癌蛋白与p53肿瘤抑制蛋白结合，并作为p53的负调节因子。p53肿瘤抑制因子在癌症治疗中也具有重要作用，p53介导的细胞凋亡是许多临床使用的癌症化疗剂和放射治疗的主要作用机制。因此，MDM 2对p53的负调节可能限制DNA损伤剂对p53活化的程度，从而限制其治疗效果。研究人员假设，通过抑制MDM 2表达，MDM 2癌蛋白水平将降低，MDM 2对p53的负反馈抑制将减弱，导致功能性p53水平显著增加，这将调节p53介导的治疗效果。本研究的总体目的是探讨MDM 2癌基因在肿瘤生长中的功能以及MDM 2作为肿瘤治疗药物靶点的潜在价值。MDM 2在肿瘤生长中的作用通过抑制人癌症的体内模型中的MDM 2表达来确定。还评价了MDM 2抑制剂和DNA损伤剂的体内协同治疗效果。显着的体外抗肿瘤活性，发现在细胞系，人骨肉瘤SJSA和绒毛膜癌ESTA，在时间，浓度和序列依赖性的方式。腹膜内给予抗MDM 2反义寡核苷酸后，以剂量依赖性方式在携带SJSA和PSMA异种移植物的裸鼠中观察到体内抗肿瘤活性。此外，还观察到MDM 2抑制剂和DNA损伤剂阿霉素和10-羟基喜树碱的体内协同治疗作用。本研究为抗MDM 2反义寡核苷酸单独或联合常规化疗药物作为肿瘤治疗药物的未来发展提供了基础。
The MDM2 oncogene is amplified or overexpressed in human cancers. It has also been suggested that MDM2 levels are associated with poor prognosis of several human cancers. The MDM2 oncoprotein binds to the p53 tumor suppressor protein and serves as a negative regulator of p53. The p53 tumor suppressor also has an important role in cancer therapy, with p53-mediated apoptosis being a major mechanism of action for many clinically used cancer chemotherapeutic agents and radiation therapy. Therefore, the negative regulation of p53 by MDM2 may limit the magnitude of p53 activation by DNA damaging agents, thereby limiting their therapeutic effectiveness. The investigators hypothesize that, by inhibiting MDM2 expression, the MDM2 oncoprotein level will be reduced and the MDM2 negative feedback inhibition of p53 will be diminished, resulting in a significant increase of functional p53 levels that will modulate p53-mediated therapeutic effects. The overall objective of the present study was to investigate the functions of MDM2 oncogene in tumor growth and the potential value of MDM2 as a drug target for cancer therapy. The role of MDM2 in tumor growth is determined by inhibiting MDM2 expression in in vivo models of human cancers. The in vivo synergistically therapeutic effects of MDM2 inhibition and DNA damaging agents were also evaluated. Significant in vitro antitumor activities were found in cell lines, human osteosarcoma SJSA and choriocarcinoma JAR, in a time-, concentration-, and sequence-dependent manner. Following i.p. administration of anti-MDM2 antisense oligonucleotides, in vivo antitumor activity was observed in nude mice bearing SJSA and JAR xenografts in a dose-dependent manner. Moreover, in vivo synergistically therapeutic effects of MDM2 inhibition and DNA damaging agents adriamycin and 10-hydroxycamptothecin were observed. This study should provide the basis for future development of anti-MDM2 antisense oligonucleotides as cancer therapeutic agents used alone or in combination with conventional chemotherapeutics.