Antisense Oligonucleotide Inhibitors of MDM2 Oncogene Expression
Antisense therapy represents a novel genetic-based therapeutic approach, initiated by Zamecnik et al. about 20 years ago (1 ). The rationale for antisense oligonucleotide therapeutics is straightforward: to identify a specific inhibitor of an mRNA of interest on the basis of the nucleotide sequence of the mRNA and design a complementary oligonucleotide (oligo). Thus, antisense approaches offer the possibility of specific, rational drugs. Over the years, although there have been many concerns that have limited enthusiasm for the development of these drugs from the preclinical to the clinical level (2 ,3 ), significant advances have been made in this field of research. The development of improved synthetic methods yielding sufficient quantities of antisense oligos has allowed extensive preclinical and clinical pharmacologic and toxicologic studies. Advanced antisense chemistry providing various modifications of oligos has resulted in improved pharmacokinetic, pharmacodynamic, and toxicologic profiles of antisense oligos. Extensive studies examining both specific and non-specific effects of oligos have led to a better design of antisense sequences to target genes. More recently, several antisense oligos have entered clinical use or clinical trials, including those targeted to genes important in human cancers (4 –10 ), with the first antisense drug Vitravene being approved for the treatment of patients with cytomegalovirus-induced retinitis (5 ). Research in the antisense field has been reviewed periodically (3 –9 ).