Inhibitors of the ras oncogene as therapeutic targets
Section snippets
Post-translational modification of Ras
Ras proteins are synthesized as inactive hydrophilic precursor proteins and must undergo post-translational modification to be converted into lipophilic molecules that anchor into the cell membrane and become active. This “post-translational modification” involves four steps: prenylation, proteolysis, carboxymethylation, and palmitoylation (Fig. 1) [8].
Prenylation is the covalent addition of farnesyl (15-carbon) or geranylgeranyl (20-carbon) groups to the terminal cysteine at the carboxyl end
Inhibitors of ras signaling
The improved understanding of the molecular mechanisms of ras expression, processing, activation, and action on downstream effectors has provided an important background for the development of Ras-targeted therapies in attempts to control human tumor proliferation and metastasis. Ras inhibitors may also be used for the treatment of other diseases, including skin diseases (Psoriasis), vascular disorders (neovascularization), and autoimmune diseases (diabetes mellitus, multiple sclerosis,
Gene therapy
Regional administration of viral vectors expressing antisense K-ras results in the regression of large established tumors. The adenoviral K-ras H322a antisense vector has shown therapeutic potential in tumors in which K-ras is mutated. These data form the basis for a new clinical protocol to inactivate mutant K-ras by the expression of antisense K-ras mRNA. An adenoviral vector carrying the K-ras proto-oncogene is inserted in antisense orientation with respect to the virus promoter and is used
Summary
Advances in our understanding of the molecular pathways and genetic mutations that control tumor cell proliferation and metastasis present an opportunity to develop novel, mechanism-based therapeutic strategies. Ras mutations are the most frequently activated oncogenes in human tumors, with over 30% expressing ras mutations. Molecular dissection of the signaling pathway and the mechanisms of ras anchorage, post-translational modification, and downstream effector signaling of ras now under
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