摘要：

The ras proteins have been the subject of intense research in recent times, and comprehensive reviews of their structural properties and biochemical function have appeared. Mutant ras oncogenes are found in approximately 25% of all human cancers, including 90% of pancreatic, 50% of colon, and 50% of thyroid tumors. Several potential strategies for interfering with ras function, such as anti-sense oligonucleotides, ras-specific antibodies, and blockers of radprotein interactions, have been under investigation for a long time, with emphasis on the inhibition of post-translational modification of ras. Since its identification, the enzyme protein farnesyl transferase (FTase) that catalyzes the first of these processing steps has emerged as the most promising target for therapeutic intervention. Substantial progress has been made toward proof-of-principle in animals, especially with the carboxyl terminal motif, CAAX, mimics. Potency, specificity, and surprising lack of toxicity have been found. The FTase inhibitors appear to impede more processes that are essential for the transformed cells than for the normal cells. The lack of cytotoxicity in normal cells and in animals has been attributed to a variety of factors, but is still not well understood. Ongoing in vitro studies with ras, corroborate some of the results observed with the inhibitors. Unfarnesylated, oncogenic, GTP-bound ras, forms a stable complex with raf that accumulates in the cytosol and inhibits aberrant signaling even with only partial inhibition of farnesylation, whereas GDP-bound, unfarnesylated normal ras does not sequester raf and normal signaling continues. Further elucidation of protein/protein interactions, such as ras/raf and ras/GAP, in the ras-signaling pathway, may provide other feasible approaches for the inhibition of mutant ras and a clarification of its complex role in the transforming cells.

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