MDM2 oncogene as a target for cancer therapy: An antisense approach.

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.