An approach for new anticancer drugs: Oncogene-targeted antisense DNA

Abstract

Background: Ras oncogenes owe their transforming properties to single point mutations in the sequence coding for the catalytic part of the p21 protein. These mutations lead to changes in cellular proliferation and tumorigenic properties. Point mutations represent a defined target for antisense oligonucleotides which specifically suppress translation of the targeted mRNA. However, the use of oligonucleotides in vivo has, until now, been limited by their instability in serum. New techniques: Different strategies have been developed to protect the oligonucleotides and increase their transport into the target cell. Linking intercalating agents, hydrophobic groups or polycations to oligonucleotides or encapsulating them in liposomes resulted in a higher resistance to exonucleases and increased oligonucleotide penetration into cells. The stability and cellular uptake of antisense oligonucleotides can also be improved by associating them with polyalkylcyanoacrylate nanoparticles. The polymeric nature renders these small particles more stable than liposomes in biological fluids and during storage. Method: Antisense oligonucleotides directed to the point mutation (G to T) in codon 12 of the Ha-ras mRNA were adsorbed to nanoparticles in the presence of hydrophobic cations. Results: These stabilized oligonucleotides selectively inhibited the proliferation of cells expressing this point mutation and partially reversed their tumorigenicity in nude mice.