Antisense oligonucleotide modulation of human mdm2 expression

DETAILED DESCRIPTION OF THE INVENTION Tumors often result from genetic changes in cellular regulatory genes.
Among the most important of these are the tumor suppressor genes, of which p53 is the most widely studied.
Approximately half of all human tumors have a mutation in the p53 gene.
This mutation disrupts the ability of the p53 protein to bind to DNA and act as a transcription factor.
Hyperproliferation of cells occurs as a result.
Another mechanism by which p53 can be inactivated is through overexpression of mdm2, which regulates p53 activity in a feedback loop.
The mdm2 protein binds to p53 in its DNA binding region, preventing its activity.
Mdm2 is amplified in some human tumors, and this amplification is diagnostic of neoplasia or the potential therefor.
Over one third of human sarcomas have elevated mdm2 sequences.
Elevated expression may also be involved in other tumors including but not limited to those in which p53 inactivation has been implicated.
These include colorectal carcinoma, lung cancer and chronic myelogenous leukemia.
Many abnormal proliferative conditions, particularly hyperproliferative conditions, are believed to be associated with mdm2 expression and are, therefore believed to be responsive to inhibition of mdm2 expression.
Examples of hyperproliferative conditions are cancers, psoriasis, blood vessel stenosis (e.
g.
, restenosis or atherosclerosis), and fibrosis, e.
g.
, of the lung or kidney.
The present invention employs antisense compounds, particularly oligonucleotides, for use in inhibiting the function of nucleic acid molecules encoding mdm2, ultimately modulating the amount of mdm2 produced.
This is accomplished by providing oligonucleotides which specifically hybridize with nucleic acids, preferably mRNA, encoding mdm2.
This relationship between an antisense compound such as an oligonucleotide and its complementary nucleic acid target, to which it hybridizes, is commonly referred to as "antisense".
"Targeting" an oligonucleotide to a chosen nucleic acid target, in the context of this invention, is a multistep process