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Abstract
Ras plays a central role in the development and progression of human cancer. Ras function depends on its ability to associate with cellular membranes. Nascent Ras is targeted to membranes by virtue of a series of posttranslational modifications of a C-terminal "CAAX" motif that include farnesylation, proteolysis, and carboxyl methylation. This pathway is an attractive target for anti-Ras drug development. Farnesyltransferase inhibitors have been developed and are in clinical trials. Their success has prompted interest in developing pharmacologically useful inhibitors of the other two enzymes in the Ras processing pathway. Ironically, it now appears that methotrexate, one of the oldest chemotherapeutic drugs, may work, in part, by inhibiting carboxyl methylation of Ras.
