>>Published online before print September 16, 2003
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.1934692100
Medical Sciences
Antisense therapy targeting MDM2 oncogene in prostate cancer: Effects on proliferation, apoptosis, multiple gene expression, and chemotherapy
( p53 | p21 | Bax | E2F1 | oligonucleotides )
Zhuo Zhang *, Mao Li *, Hui Wang *, Sudhir Agrawal , and Ruiwen Zhang *
*Department of Pharmacology and Toxicology and Comprehensive Cancer Center, University of Alabama at Birmingham, VH 113, 1670 University Boulevard, Birmingham, AL 35294; and Hybridon, Inc., Cambridge, MA 02139
Communicated by Paul C. Zamecnik, Massachusetts General Hospital, Charlestown, MA, July 24, 2003 (received for review May 19, 2003)
This study was undertaken to investigate the role of mouse double minute 2 (MDM2) oncogene in prostate cancer growth and the potential of MDM2 as a target for prostate cancer therapy. An antisense anti-human-MDM2 mixed-backbone oligonucleotide was tested in human prostate cancer models with various p53 statuses, LNCaP (p53wt/wt), DU145 (p53mt/mt), and PC3 (p53null). In a dose- and time-dependent manner, it specifically inhibited MDM2 expression and modified expression of several genes, at both mRNA and protein levels. In LNCaP cells, p53, p21, Bax, and hypophosphorylated retinoblastoma tumor suppressor protein (pRb) levels increased, whereas Bcl2, pRb protein, and E2F transcription factor 1 (E2F1) levels decreased. In DU145 cells, p21 levels were elevated and E2F1 levels decreased, although mutant p53, Rb, and Bax levels remained unchanged. In PC3 cells, MDM2 inhibition resulted in elevated p21, Bax, and pRb levels and decreased ppRb and E2F1 levels. In all three cell lines, MDM2 inhibition reduced cell proliferation, induced apoptosis, and potentiated the effects of the chemotherapeutic agents 10-hydroxycamptothecin and paclitaxel. The anti-MDM2 oligonucleotide showed antitumor activity and increased therapeutic effectiveness of paclitaxel in both LNCaP and PC3 xenografts, causing changes in gene expression similar to those seen in vitro. In summary, this study demonstrates that MDM2 has a role in prostate cancer growth via p53-dependent and p53-independent mechanisms and that multiple genes are involved in the process. MDM2 inhibitors such as second-generation antisense oligonucleotides have a broad spectrum of antitumor activities in human cancers regardless of p53 status, providing novel approaches to therapy of human prostate cancer.<<
Not sure if this adds much to the AACR abstracts from July. Can't say I follow the company, but it looks interesting (for example, CpG islands are suspected to be involved in the MOA behind GenaSense, so HYBN's interest in that is intriguing). Quite the roller coaster of late . . .
Cheers, Tuck |
