Histone deacetylase inhibitors very potent anti-cancer agents but nontoxic to normal cells

Discussion in 'Health and medical' started by Roger, Mar 15, 2004.

  1. Roger

    Roger Guest

    Sounds like ideal anti-cancer agents. The pharmaceutical
    industry ought to have ongoing trials right now so they can
    be approved. Here's some abstracts that show why these
    things probably should be approved as soon as possible.

    Roger

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    Expert Opin Investig Drugs. 2002 Dec;11(12):1695-713.

    Histone deacetylase inhibitors: from target to
    clinical trials.

    Kelly WK, O'Connor OA, Marks PA. Memorial Sloan-Kettering
    Cancer Center, 1275 York Avenue, New York, NY 10021, USA.

    Transformed cells, characterised by inappropriate cell
    proliferation, do not necessarily lose the capacity to
    undergo growth arrest under certain stimuli. DNA, genetic
    information, is packaged in chromatin proteins, for example,
    histones. The structure of chromatin may be altered by post-
    translational modifications (e.g., acetylation,
    phosphorylation, methylation and ubiquitylation) which play
    a role in regulating gene expression. Two groups of enzymes,
    histone deacetylases (HDACs) and acetyl transferases,
    determine the acetylation status of histones. This review
    focuses on compounds that inhibit HDAC activity. These
    agents have been shown to be active in vitro and in vivo in
    causing cancer cell growth arrest, differentiation and/or
    apoptosis. Several HDAC inhibitors are currently in clinical
    trials as anticancer agents and, in particular, hydroxamic
    acid-based HDAC inhibitors have shown activity against
    cancers at well-tolerated doses.

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    Curr Opin Oncol. 2001 Nov;13(6):477-83. Related
    Articles, Links

    Histone deacetylase inhibitors as new cancer drugs.

    Marks PA, Richon VM, Breslow R, Rifkind RA.

    Cell Biology Program, Memorial Sloan-Kettering Cancer
    Center, New York, New York 10021, USA. [email protected]

    Histone deacetylase inhibitors are potent inducers of growth
    arrest, differentiation, or apoptotic cell death in a
    variety of transformed cells in culture and in tumor bearing
    animals. Histone deacetylases and the family of histone
    acetyl transferases are involved in determining the
    acetylation of histones, which play a role in regulation of
    gene expression. Radiograph crystallographic studies reveal
    that the histone deacetylase inhibitors, suberoylanilide
    hydroxamic acid and trichostatin A, fit into the catalytic
    site of histone deacetylase, which has a tubular structure
    with a zinc atom at its base. The hydroxamic acid moiety of
    the inhibitor binds to the zinc. Histone deacetylase
    inhibitors cause acetylated histones to accumulate in both
    tumor and peripheral circulating mononuclear cells.
    Accumulation of acetylated histones has been used as a
    marker of the biologic activity of the agents. Hydroxamic
    acid-based histone deacetylase inhibitors limit tumor cell
    growth in animals with little or no toxicity. These
    compounds act selectively on genes, altering the
    transcription of only approximately 2% of expressed genes in
    cultured tumor cells. A number of proteins other than
    histones are substrates for histone deacetylases. The role
    that these other targets play in histone deacetylase
    inducement of cell growth arrest, differentiation, or
    apoptotic cell death is not known. This review summarizes
    the characteristics of a variety of inhibitors of histone
    deacetylases and their effects on transformed cells in
    culture and tumor growth in animal models. Several
    structurally different histone deacetylase inhibitors are in
    phase I or II clinical trials in patients with cancers.

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    Curr Opin Investig Drugs. 2003 Dec;4(12):1422-7. Related
    Articles, Links

    HDAC inhibitors for the treatment of cancer.

    Secrist JP, Zhou X, Richon VM.

    Aton Pharma Inc., 765 Old Saw Mill River Road, Tarrytown, NY
    10591, USA. [email protected]

    Histone deacetylase (HDAC) inhibitors are a new class of
    cancer chemotherapeutics in clinical development that target
    the family of enzymes that catalyze the removal of the
    acetyl modification on lysine residues of proteins,
    including the core nucleosomal histones H2A, H2B, H3 and H4.
    The balance of nucleosomal histone acetylation is maintained
    through the opposing actions of histone acetyltransferases
    (HATs) and HDACs, and plays an important regulatory role in
    gene transcription. Alterations in both HATs and HDACs have
    been identified in tumor cells and may contribute to the
    altered gene expression found in many cancers. Inhibitors of
    HDAC activity induce cell cycle arrest, differentiation or
    apoptosis in tumor cells, and inhibit tumor growth in a
    variety of rodent models of cancer. Several structurally
    diverse HDAC inhibitors have entered clinical trials and are
    demonstrating encouraging antitumor activity in a variety of
    cancer types. As we learn more about these enzymes and the
    biological processes that they regulate, a strong rationale
    is emerging for the development of HDAC inhibitors as
    anticancer agents.

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    Anticancer Drugs. 2002 Jan;13(1):1-13. Related
    Articles, Links

    Histone deacetylase inhibitors in cancer treatment.

    Vigushin DM, Coombes RC.

    Department of Cancer Medicine, Imperial College of Science,
    Technology and Medicine, Hammersmith Hospital Campus, London
    W12 0NN, UK.
    [email protected]

    Histone deacetylase (HDAC) inhibitors are emerging as an
    exciting new class of potential anticancer agents for the
    treatment of solid and hematological malignancies. In recent
    years, an increasing number of structurally diverse HDAC
    inhibitors have been identified that inhibit proliferation
    and induce differentiation and/or apoptosis of tumor cells
    in culture and in animal models. HDAC inhibition causes
    acetylated nuclear histones to accumulate in both tumor and
    normal tissues, providing a surrogate marker for the
    biological activity of HDAC inhibitors in vivo. The effects
    of HDAC inhibitors on gene expression are highly selective,
    leading to transcriptional activation of certain genes such
    as the cyclin-dependent kinase inhibitor p21WAF1/CIP1 but
    repression of others. HDAC inhibition not only results in
    acetylation of histones but also transcription factors such
    as p53, GATA-1 and estrogen receptor-alpha. The functional
    significance of acetylation of non-histone proteins and the
    precise mechanisms whereby HDAC inhibitors induce tumor cell
    growth arrest, differentiation and/or apoptosis are
    currently the focus of intensive research. Several HDAC
    inhibitors have shown impressive antitumor activity in vivo
    with remarkably little toxicity in preclinical studies and
    are currently in phase I clinical trial. The focus of this
    review is the development and clinical application of HDAC
    inhibitors for the treatment of cancer.

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    Curr Med Chem. 2003 Nov;10(22):2351-8. Related
    Articles, Links

    From discovery to the coming generation of histone
    deacetylase inhibitors.

    Yoshida M, Matsuyama A, Komatsu Y, Nishino N.

    Chemical Genetics Laboratory, RIKEN and CREST, JST, Saitama,
    Japan. [email protected]

    Trichostatin A (TSA) is a Streptomyces metabolite that
    causes differentiation of murine erythroleukemia cells as
    well as specific inhibition of the cell cycle of some lower
    eukaryotes and mammalian cells. The targeted molecule of TSA
    has been shown by genetic and biochemical analyses to be
    histone deacetylases (HDACs). Histone acetylation is a key
    modification to control transcription, and HDACs are
    profoundly involved in pathogenesis of cancer through
    removing acetyl groups from histones and other
    transcriptional regulators. Trapoxin (TPX) and FK228 (also
    known as FR901228 and depsipeptide because FK228 = FR901228
    = depsipeptide), structurally unrelated microbial
    metabolites, were also shown to inhibit HDACs. These HDAC
    inhibitors cause cell cycle arrest, differentiation and/or
    apoptosis of many tumors, suggesting their usefulness for
    chemotherapy and differentiation therapy. In addition, HDAC
    inhibitors play important roles in identifying the specific
    function of the enzymes. Indeed, we identified tubulin as
    one of the substrates of HDAC6 by means of differential
    sensitivity to HDAC inhibitors. Since recent studies have
    revealed that HDACs are structurally and functionally
    diverse, it should be important to develop inhibitors
    specific to individual enzymes as more promising agents for
    cancer therapy. We have synthesized novel TSA/TPX hybrids,
    which will serve as a basis for developing enzyme-specific
    HDAC inhibitors.
     
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