X-Message-Number: 31121
Date: Wed, 15 Oct 2008 11:48:33 -0700 (PDT)
From: 
Subject: tipifarnib versus progeria


[It is interesting that the anticancer drug tipifarnib is being considered for a
human antiaging clincal trial using progeria patients. However tipifarnib is 
too toxic to be used by life-extensionists, even if it proves effective in an 
antiaging role.]

Proc Natl Acad Sci U S A. 2008 Oct 6. [Epub ahead of print]

A farnesyltransferase inhibitor prevents both the onset and late progression of 
cardiovascular disease in a progeria mouse model.

    Capell BC, Olive M, Erdos MR, Cao K, Faddah DA, Tavarez UL, Conneely KN, Qu 
    X, San H, Ganesh SK, Chen X, Avallone H, Kolodgie FD, Virmani R, Nabel EG, 
    Collins FS. Genome Technology Branch, National Human Genome Research 
    Institute, National Institutes of Health, Bethesda, MD 20892-8004;

    Hutchinson-Gilford progeria syndrome (HGPS) is the most dramatic form of 
    human premature aging. Death occurs at a mean age of 13 years, usually from 
    heart attack or stroke. Almost all cases of HGPS are caused by a de novo 
    point mutation in the lamin A (LMNA) gene that results in production of a 
    mutant lamin A protein termed progerin. This protein is permanently modified
    by a lipid farnesyl group, and acts as a dominant negative, disrupting 
    nuclear structure. Treatment with farnesyltransferase inhibitors (FTIs) has 
    been shown to prevent and even reverse this nuclear abnormality in cultured 
    HGPS fibroblasts. We have previously created a mouse model of HGPS that 
    shows progressive loss of vascular smooth muscle cells in the media of the 
    large arteries, in a pattern that is strikingly similar to the 
    cardiovascular disease seen in patients with HGPS. Here we show that the 
    dose-dependent administration of the FTI tipifarnib (R115777, Zarnestra) to 
    this HGPS mouse model can significantly prevent both the onset of the 
    cardiovascular phenotype as well as the late progression of existing 
    cardiovascular disease. These observations provide encouraging evidence for 
    the current clinical trial of FTIs for this rare and devastating disease.
PMID: 18838683

Proc Natl Acad Sci U S A. 2005 Oct 4;102(40):14416-21. Epub 2005 Sep 26.

Inhibiting farnesylation reverses the nuclear morphology defect in a HeLa cell 
model for Hutchinson-Gilford progeria syndrome.

    Mallampalli MP, Huyer G, Bendale P, Gelb MH, Michaelis S. Department of Cell
    Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, 
    USA.

    Hutchinson-Gilford progeria syndrome (HGPS) is a devastating premature aging
    disease resulting from a mutation in the LMNA gene, which encodes nuclear 
    lamins A and C. Lamin A is synthesized as a precursor (prelamin A) with a 
    C-terminal CaaX motif that undergoes farnesylation, endoproteolytic 
    cleavage, and carboxylmethylation. Prelamin A is subsequently internally 
    cleaved by the zinc metalloprotease Ste24 (Zmpste24) protease, which removes
    the 15 C-terminal amino acids, including the CaaX modifications, to yield 
    mature lamin A. HGPS results from a dominant mutant form of prelamin A 
    (progerin) that has an internal deletion of 50 aa near the C terminus that 
    includes the Zmpste24 cleavage site and blocks removal of the CaaX-modified 
    C terminus. Fibroblasts from HGPS patients have aberrant nuclei with 
    irregular shapes, which we hypothesize result from the abnormal persistence 
    of the farnesyl and/or carboxylmethyl CaaX modifications on progerin. If 
    this hypothesis is correct, inhibition of CaaX modification by mutation or 
    pharmacological treatment should alleviate the nuclear morphology defect. 
    Consistent with our hypothesis, we find that expression in HeLa cells of 
    GFP-progerin or an uncleavable form of prelamin A with a Zmpste24 cleavage 
    site mutation induces the formation of abnormal nuclei similar to those in 
    HGPS fibroblasts. Strikingly, inhibition of farnesylation pharmacologically 
    with the farnesyl transferase inhibitor rac-R115777 or mutationally by 
    alteration of the CaaX motif dramatically reverses the abnormal nuclear 
    morphology. These results suggest that farnesyl transferase inhibitors 
    represent a possible therapeutic option for individuals with HGPS and/or 
    other laminopathies due to Zmpste24 processing defects.
PMID: 16186497

Blood. 2004 May 1;103(9):3271-7. Epub 2004 Jan 15.

Farnesyltransferase inhibitor tipifarnib is well tolerated, induces 
stabilization of disease, and inhibits farnesylation and oncogenic/tumor 
survival pathways in patients with advanced multiple myeloma.

    Alsina M, Fonseca R, Wilson EF, Belle AN, Gerbino E, Price-Troska T, Overton
    RM, Ahmann G, Bruzek LM, Adjei AA, Kaufmann SH, Wright JJ, Sullivan D, 
    Djulbegovic B, Cantor AB, Greipp PR, Dalton WS, Sebti SM. Experimental 
    Therapeutics Program, H. Lee Moffitt Cancer Center & Research Institute and 
    Department of Oncology, University of South Florida, Tampa, FL 33612, USA.

    Patients with multiple myeloma (MM) with mutated RAS are less likely to 
    respond to chemotherapy and have a shortened survival. Therefore, targeting 
    RAS farnesylation may be a novel approach to treatment of MM. We evaluated 
    the activity and tolerability of the farnesyltransferase (FTase) inhibitor 
    tipifarnib (Zarnestra) in a phase 2 trial as well as its ability to inhibit 
    protein farnesylation and oncogenic pathways in patients with relapsed MM. 
    Forty-three patients (median age, 62 years [range, 33-82 years]) with a 
    median of 4 (range, 1-6) chemotherapy regimens entered the study. 
    Tipifarnib, 300 mg orally twice daily, was administered for 3 weeks every 4 
    weeks. The most common toxicity was fatigue occurring in 66% of patients. 
    Other toxicities included diarrhea, nausea, neuropathy, anemia, and 
    thrombocytopenia. Sixty-four percent of the patients had disease 
    stabilization. Treatment with tipifarnib suppressed FTase (but not 
    geranylgeranyltransferase I) in bone marrow and peripheral blood mononuclear
    cells and also inhibited the farnesylation of HDJ-2 in unfractionated 
    mononuclear cells and purified myeloma cells. Inhibition of farnesylation 
    did not correlate with disease stabilization. Finally, tipifarnib decreased 
    the levels of phosphorylated Akt and STAT3 (signal transducer and activator 
    of transcription 3) but not Erk1/2 (extracellular signal regulated kinase 1 
    and 2) in bone marrow cells. We conclude that tipifarnib is tolerable, can 
    induce disease stabilization, and can inhibit farnesylation and 
    oncogenic/tumor survival pathways.
PMID: 14726402

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