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Drugs

, Volume 61, Issue 6, pp 723–732 | Cite as

Farnesyltransferase Inhibitors

Potential Role in the Treatment of Cancer
  • Adrienne D. Cox
Leading Article

Abstract

New targets for drug discovery have been identified rapidly as a result of the many recent and rapid advances in the understanding of signal transduction pathways that contribute to oncogenesis. In particular, oncogenic Ras proteins have been seen as an important target for novel anti-cancer drugs. Since the decade-old identification and cloning of farnesyltransferase (FTase), a critical enzyme that post-translationally modifies Ras and other farnesylated proteins, FTase inhibitors (FTIs) have been under intense investigation designed to bring them to clinical practice for cancer therapy.

FTIs can inhibit the growth of tumour cells in culture and in animal models, and are now in clinical trials. Interestingly, their mechanism of action is not as simple as originally envisioned, and Ras is probably not the most important farnesylated protein whose modification is inhibited as a result of FTI treatment. Although K-Ras can escape inhibition of processing by FTIs, tumours with oncogenically mutated K-Ras proteins can still be inhibited by FTI treatment. Indeed, Ras mutation status does not correlate with FTI sensitivity or resistance. Instead, it now appears likely that inhibition of the processing of other farnesylated proteins such as RhoB and the centromere-binding proteins CENP-E and CENP-F can explain the ability of FTIs to cause cell cycle arrest and apoptosis in preclinical studies, and even to cause regression in animal tumour models.

Preclinical studies suggest the likelihood that FTIs will be useful in combination therapies with conventional treatment modalities including cytotoxics (especially paclitaxel) and radiation. Phase I combination trials are underway, and early phase II/III trials using FTIs as monotherapy are open for patients with a wide variety of cancers. Early preclinical results also suggest the possibility of using FTIs as chemopreventive agents.

Studies to be completed over the next 2 or 3 years should define the appropriate patient populations, administration and scheduling necessary to optimise the use of these novel anticancer agents.

Keywords

Human Tumour Cell Line Epothilones Perillyl Alcohol FTase Inhibitor FTase Activity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

Helpful discussions with members of the laboratory and with our collaborators Channing Der, Saïd Sebti and Andy Hamilton are gratefully acknowledged. Our research is supported by NIH grants (CA67771 and CA 76092).

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Copyright information

© Adis International Limited 2001

Authors and Affiliations

  1. 1.Departments of Radiation Oncology and Pharmacology, Lineberger Cancer Center, Curriculum in Genetics and Molecular Biology, School of Medicine, CB #7512University of North Carolina at Chapel HillChapel HillUSA

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