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Preclinical characterization of a novel diphenyl benzamide selective ERα agonist for hormone therapy in prostate cancer.

Abstract

Androgen deprivation therapy (ADT) is the mainstay of treatment for advanced prostate cancer. ADT improves overall and disease-free survival rates, but long-term therapy is associated with severe side effects of androgen and estrogen depletion including hot flashes, weight gain, depression, and osteoporosis. Effective hormone reduction can be achieved without estrogen deficiency-related side effects by using therapy with estrogenic compounds. However, cardiovascular complications induced by estrogens coupled with the availability of LHRH agonists led to discontinuation of estrogen use for primary androgen deprivation therapy in the 1980s. New treatments for prostate cancer that improve patient outcomes without the serious estrogen deficiency-related toxicities associated with ADT using LHRH analogs are needed. Herein we describe a novel nonsteroidal selective estrogen receptor-α agonist designed for first-line therapy of advanced prostate cancer that in animal models induces medical castration and minimizes many of the estrogen deficiency-related side effects of ADT. The present studies show that orally administered GTx-758 reversibly suppressed testosterone to castrate levels and subsequently reduced prostate volume and circulating prostate-specific antigen in relevant preclinical models without inducing hot flashes, bone loss, thrombophilia, hypercoagulation, or increasing fat mass.

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  • Publisher Full Text
  • Authors

    Coss CC, Jones A, Parke DN, Narayanan R, Barrett CM, Kearbey JD, Veverka KA, Miller DD, Morton RA, Steiner MS, Dalton JT

    Institution

    Preclinical Research and Development, GTx, Inc., 3 North Dunlap Street, Memphis, Tennessee 38163, USA.

    Source

    Endocrinology 153:3 2012 Mar pg 1070-81

    MeSH

    Androgen Antagonists
    Animals
    Antineoplastic Agents, Hormonal
    Benzamides
    Body Composition
    Cell Proliferation
    Disease-Free Survival
    Estrogen Receptor alpha
    Estrogen Receptor beta
    Estrogens
    Female
    Follicle Stimulating Hormone
    Humans
    Luteinizing Hormone
    Macaca fascicularis
    Male
    Prostatic Neoplasms
    Rats
    Testosterone
    Transcriptional Activation

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    22294742