Abstract
Farnesyl transferase inhibitors (FTIs) are anticancer agents that were designed to block the post-translational attachment of the prenyl moiety to C-terminal cysteine residue of Ras and thus inactivate it. Because Ras plays an important role in tumour progression and the ras mutation is one of the most frequent aberrations in cancer, FTIs have been expected to exert excellent therapeutic activities. Phase I and II clinical trials confirmed relevant antitumour activity and low toxicity; however, no improvement in overall survival has been reported in Phase III trials. The exact mechanism of action of this class of agents is currently unknown. Increasing lines of evidence indicate that the cytotoxic actions of FTIs are not due to the inhibition of Ras proteins exclusively, but to the modulation of other targets, including RhoB, the centromere-binding proteins and other proteins that have not yet been identified. This review describes the pharmacological and clinical data as well as mechanisms of action of FTIs, especially lonafarnib (SCH-66336), a non-peptidomimetic inhibitor that has shown anticancer activity.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Review
MeSH terms
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Animals
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / therapeutic use*
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Carcinoma, Non-Small-Cell Lung / drug therapy*
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Carcinoma, Non-Small-Cell Lung / enzymology
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Colorectal Neoplasms / drug therapy*
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Colorectal Neoplasms / enzymology
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Drug Administration Schedule
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Drug Evaluation, Preclinical
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Drug Therapy, Combination
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Enzyme Inhibitors / administration & dosage
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / therapeutic use*
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Farnesyltranstransferase / antagonists & inhibitors
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Humans
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Leukemia / drug therapy*
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Leukemia / enzymology
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Lung Neoplasms / drug therapy*
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Lung Neoplasms / enzymology
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Piperidines / administration & dosage
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Piperidines / pharmacokinetics
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Piperidines / therapeutic use*
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Pyridines / administration & dosage
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Pyridines / pharmacokinetics
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Pyridines / therapeutic use*
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Randomized Controlled Trials as Topic
Substances
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Antineoplastic Agents
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Enzyme Inhibitors
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Piperidines
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Pyridines
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Farnesyltranstransferase
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lonafarnib