Ras genes encode proteins that activate in an intracellular signaling network controlling differentiation, proliferation and cell survival. Mutated Ras oncogenes encoding proteins that are constitutively active can induce malignancies in a variety of laboratory models. In human malignancies, Ras mutations are common, having been identified in approximately 30% of cancers. Given the importance of Ras and downstream targets Raf and MEK in the development of malignancies and their frequent expression in human cancers, it is not surprising that a variety of agents disrupting signaling through Ras and downstream proteins are under development. These agents can be broadly classified structurally as small molecules and anti-sense oligonucleotides. They can be characterized functionally as those inhibiting Ras protein expression such as the oligodeoxynucleotide ISIS 2503, those inhibiting Ras processing, in particular the farnesyl transferase inhibitors R115777, SCH 66336 and BMS 214662, and those inhibi ting downstream effectors Raf, such as ISIS 5132 and MEK, which is inhibited by CI-1040. The purpose of this review is to highlight recent advances in the development of these agents.
ras pathway, inhibitors, oligonucleotides, farnesyl transferase
Cancer Therapy Evaluation Program, National Cancer Institute, 6130 Executive Blvd, EPN 7131, Rockville MD, 20852