Pre-clinical development of farnesyltransferase inhibitors

• Published in: Cancer and metastasis reviews 1998-06, Vol.17 (2), p.203
• Main Authors: Lobell, R B, Kohl, N E
• Format: Article
• Language: English
• Subjects: Alkyl and Aryl Transferases - antagonists & inhibitors; Animals; Cell Division - drug effects; Drug Design; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Farnesyltranstransferase; Humans; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - pathology; ras Proteins - antagonists & inhibitors; ras Proteins - metabolism
• ISSN: 0167-7659; 1573-7233
• DOI: 10.1023/A:1006018922878

ras is the oncogene most frequently found in human cancers, being detected in 30% of most human cancers and at significantly higher rates in certain cancers including pancreatic (90%) and colon (50%) [1]. Almost 10 years ago it was shown that a C-terminal lipid modification of Ras, catalyzed by a specific farnesyl-protein transferase (FPTase), was required for the function of both normal and oncogenic Ras proteins. This finding spurred the development of FPTase inhibitors (FTIs) as a potential cancer therapy directed at the ras oncogene. FTIs have exhibited potent antiproliferative activity in cell culture and animal tumor models with a surprising lack of toxicity to normal tissues. However, while FTIs were originally conceptualized as Ras-specific agents, their mechanism of action is significantly more complicated than originally envisioned.