Farnesyltransferase inhibitor
 |
This article may require cleanup to meet Wikipedia's quality standards. (Consider using more specific cleanup instructions.) Please help improve this article if you can. The talk page may contain suggestions. (October 2009) |
The farnesyltransferase inhibitors (FTIs) are a class of experimental cancer drugs that target protein farnesyltransferase with the downstream effect of preventing the proper functioning of the Ras (protein), which is commonly abnormally active in cancer.
Contents |
[edit] Background
Studies have suggested that interference with certain post-translational modification processes seem to have quite a high selectivity for targeting cells displaying tumour phenotypes although the reason for this is a matter of controversy (as will be explained below).
After translation, Ras goes through four steps of modification: isoprenylation, proteolysis, methylation and palmitoylation. Isoprenylation involves the enzyme farnesyltransferase (FTase) transferring a farnesyl group from farnesyl pyrophosphate (FPP) to the pre-Ras protein. Also, a related enzyme geranylgeranyltransferase I (GGTase I) has the ability to transfer a geranylgeranyl group to K and N-Ras (the implications of this are discussed below). Farnesyl is necessary to attach Ras to the cell membrane. Without attachment to the cell membrane, Ras is not able to transfer signals from membrane receptors.[1]
[edit] Development of FTIs
After a program of high-throughput screening of a class of drugs targeting the first step, the farnesyltransferase inhibitors (FTIs) were developed.[1] A number of molecules were found to have FTI activity. Some earlier compounds were found to have major side effects, and their development was discontinued. The others have entered clinical trials for different cancers. SCH66336 (Lonafarnib) was the first to do so, followed by R115777 (Zarnestra, Tipifarnib).[2]
Unfortunately, the predicted “early potential [of FTIs] has not been realised”.[3] The anti-tumour properties of FTIs were attributed to their action on Ras processing; however this assumption has now been questioned. Of the three members (H, N and K) of the Ras family, K-Ras is the form found most often mutated in cancer. As noted above, as well as modification by FFTase an alternative route to creation of biologically active Ras is through GGTase modification. When FFTase is blocked by FFTase inhibitors this pathway comes in to operation – both K and N-Ras are able to be activated through this mechanism. In recognition of this a joint administration of FTIs and GTIs was tried, however this resulted in high toxicity. It is in fact thought that the lack of FTI toxicity may be due to a failure to fully inhibit Ras: FTIs actually target normal cells but alternative pathway allow these cells to survive (Downward J, 2003).
[edit] Explaining success
So how to explain the preclinical successes showing that many N- or K-Ras transformed cell lines (and even tumor cell lines that do not harbor Ras mutations) are sensitive to FTase inhibitors? It has been suggested that this is due to inhibition of farnesylation of a number of other proteins.[1] Therefore it is hoped that FTIs, whilst not Ras specific, still have potential for cancer therapy.
[edit] Products in Development
[edit] Investigation of FTIs for alternative uses
[edit] FTIs and protozoan parasites
FTIs can also be used to inhibit farnesylation in parasites[4] such as Trypanosoma brucei (African sleeping sickness) and Plasmodium falciparum (malaria). Interestingly, these parasites seem to be more vulnerable to inhibition of Farnesyltransferase than humans, even though the drugs tested selectively target human FTase. In some cases the reason for this may be the parasites lack Geranylgeranyltransferase I. This vulnerability may pave the way for the development of selective, low toxicity, FTI based anti-parasitic drugs 'piggybacking' on the development of FTIs for cancer research.
[edit] Use in progeria
Recently studies have been published indicating that farnesyltransferase inhibitors can act to reverse instability of nuclear structure due to the genetic mutation of the LMNA gene. It is being tested as a potential drug treatment in children suffering from Hutchinson-Gilford Progeria Syndrome.[5]
[edit] References
- ^ a b c Reuter CW, Morgan MA, Bergmann L (September 2000). "Targeting the Ras signaling pathway: a rational, mechanism-based treatment for hematologic malignancies?". Blood 96 (5): 1655–69. PMID 10961860. http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=10961860.
- ^ Caponigro F, Casale M, Bryce J. (2003). "Farnesyl transferase inhibitors in clinical development". Expert Opin Investig Drugs. 12:943-54
- ^ Downward J. (2003). "Targeting the Ras Signalling Pathway in Cancer Therapy". Nat Rev Cancer, 3:11-22
- ^ Eastman RT, Buckner FS, Yokoyama K, Gelb MH, Van Voorhis WC (February 2006). "Thematic review series: lipid posttranslational modifications. Fighting parasitic disease by blocking protein farnesylation". J. Lipid Res. 47 (2): 233–40. doi:10.1194/jlr.R500016-JLR200. PMID 16339110. http://www.jlr.org/cgi/pmidlookup?view=long&pmid=16339110.
- ^ Mehta IS, Bridger JM, Kill IR (February 2010). "Progeria, the nucleolus and farnesyltransferase inhibitors". Biochem. Soc. Trans. 38 (Pt 1): 287–91. doi:10.1042/BST0380287. PMID 20074076. http://www.biochemsoctrans.org/bst/038/0287/bst0380287.htm.
Anuj G. Agrawal and Rakesh R. Somani (2011). Farnesyltransferase Inhibitor in Cancer Treatment, Current Cancer Treatment - Novel Beyond Conventional Approaches, Öner Özdemir (Ed.), ISBN: 978-953-307-397-2, InTech, Available from: http://www.intechopen.com/articles/show/title/farnesyltransferase-inhibitor-in-cancer-treatment
|
|||||||||||||||||||
