AN APPROACH FOR NEW ANTICANCER DRUGS - ONCOGENE-TARGETED ANTISENSE DNA

Background: Ras oncogenes owe their transforming properties to single point mutations in the sequence coding for the catalytic part of the p 21 protein. These mutations lead to changes in cellular proliferation and tumorigenic properties. Point mutations represent a defined target for antisense oligonucleotides which specifically suppress translatio n of the targeted mRNA. However, the use of oligonucleotides in vivo h as, until now, been limited by their instability in serum. New techniq ues: Different strategies have been developed to protect the oligonucl eotides and increase their transport into the target cell. Linking int ercalating agents, hydrophobic groups or polycations to oligonucleotid es 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 al so be improved by associating them with polyalkylcyanoacrylate nanopar ticles. The polymeric nature renders these small particles more stable than liposomes in biological fluids and during storage. Method: Antis ense 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 sel ectively inhibited the proliferation of cells expressing this point mu tation and partially reversed their tumorigenicity in nude mice.