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.