Antisense anti-MDM2 oligonucleotides as a novel therapeutic approach to human breast cancer: In vitro and in vivo activities and mechanisms

The mouse double minute 2 (MDM2) oncogene has been suggested as a target fo r cancer therapy. It is amplified or overexpressed in many human cancers, i ncluding breast cancer, and MDM2 levels are associated with poor prognosis of several human cancers, including breast cancer, ovarian cancer, osteosar coma, and lymphoma. In the present study, we investigated the functions of MDM2 oncogene in the growth of breast cancer and the potential value of MDM 2 as a drug target for cancer therapy by inhibiting MDM2 expression with a specific antisense antihuman-MDM2 oligonucleotide (oligo). The selected ant isense mixed-backbone oligo was evaluated for its in vitro and in vivo anti tumor activity in human breast cancer models: MCF-7 cell line containing wi ld-type p53 and MDA-MB-468 cell line containing mutant p53. In MCF-7 cells, p53 and p21 levels were elevated, resulting from specific inhibition of MD M2 expression by the antisense oligo (AS). In MDA-MB-468 cells, after inhib ition of MDM2 expression, p21 levels were elevated, although p53 levels rem ained unchanged. After i.p. administration of the antisense anti-MDM2 oligo , in vivo antitumor activity occurred in a dose-dependent manner in nude mi ce bearing MCF-7 or MDA-MB-468 xenografts. In both models, in vivo synergis tically or additive therapeutic effects of MDM2 inhibition and the clinical ly used cancer chemotherapeutic agents irinotecan, 5-fluorouracil, and pacl itaxel (Taxol) were observed. These results suggest that MDM2 have a role i n tumor growth through both p53-dependent and p53-independent mechanisms. W e speculate that MDM2 inhibitors, such as ASs, have a broad spectrum of ant itumor activities in human breast cancers, regardless of p53 status. This s tudy should provide a basis for future development of anti-MDM2 ASs as canc er therapeutic agents used alone or in combination with conventional chemot herapeutics.