Development of weekly high-dose calcitriol based therapy for prostate cancer

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    34 Citations (Scopus)

    Abstract

    Calcitriol, the principal biologically active ligand of the Vitamin D receptor (VDR), has been shown to inhibit cancer cell proliferation in in vitro and in vivo models of prostate cancer and a wide range of other neoplasms. In addition, calcitriol's activity appears to be additive, and in some experimental systems, synergistic with dexamethasone and several cytotoxic chemotherapy agents. While effects on progression through the cell cycle, induction of apoptosis, inhibition of angiogenesis, and reduction in tumor invasiveness have been demonstrated, the exact mechanisms of VDR-mediated antineoplastic activity remain incompletely understood. Antineoplastic activity of calcitriol requires substantially supraphysiologic concentrations of this compound. Dose escalation of calcitriol administered daily was severely limited by predictable hypercalcemia and/or hypercalcuria. This limitation has been overcome with intermittent dosing of calcitriol. At Oregon Health & Science University, weekly oral administration of calcitriol allowed the attainment of peak serum calcitriol concentrations well above 1 nM, a concentration that inhibits prostate cancer proliferation by more than 50% in vitro. Weekly high-dose calcitriol was then combined with weekly docetaxel in a Phase II clinical trial carried out in men with metastatic androgen-independent prostate cancer. Treatment resulted in PSA response (defined as a confirmed 50% reduction) in 81% of patients. This level of activity, as well as the median time to progression of 11.4 months and median survival of 19.5 months, compared favorably to results with docetaxel alone and led to the development of a recently initiated randomized trial of docetaxel with calcitriol or placebo in the same patient population.

    Original languageEnglish (US)
    Pages (from-to)399-405
    Number of pages7
    JournalUrologic Oncology: Seminars and Original Investigations
    Volume21
    Issue number5
    DOIs
    StatePublished - Sep 2003

    Fingerprint

    Calcitriol
    Prostatic Neoplasms
    docetaxel
    Calcitriol Receptors
    Therapeutics
    Antineoplastic Agents
    Neoplasms
    Phase II Clinical Trials
    Cytotoxins
    Hypercalcemia
    Dexamethasone
    Androgens
    Oral Administration
    Cell Cycle
    Placebos
    Cell Proliferation
    Apoptosis
    Ligands
    Drug Therapy
    Survival

    ASJC Scopus subject areas

    • Oncology
    • Urology

    Cite this

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    abstract = "Calcitriol, the principal biologically active ligand of the Vitamin D receptor (VDR), has been shown to inhibit cancer cell proliferation in in vitro and in vivo models of prostate cancer and a wide range of other neoplasms. In addition, calcitriol's activity appears to be additive, and in some experimental systems, synergistic with dexamethasone and several cytotoxic chemotherapy agents. While effects on progression through the cell cycle, induction of apoptosis, inhibition of angiogenesis, and reduction in tumor invasiveness have been demonstrated, the exact mechanisms of VDR-mediated antineoplastic activity remain incompletely understood. Antineoplastic activity of calcitriol requires substantially supraphysiologic concentrations of this compound. Dose escalation of calcitriol administered daily was severely limited by predictable hypercalcemia and/or hypercalcuria. This limitation has been overcome with intermittent dosing of calcitriol. At Oregon Health & Science University, weekly oral administration of calcitriol allowed the attainment of peak serum calcitriol concentrations well above 1 nM, a concentration that inhibits prostate cancer proliferation by more than 50{\%} in vitro. Weekly high-dose calcitriol was then combined with weekly docetaxel in a Phase II clinical trial carried out in men with metastatic androgen-independent prostate cancer. Treatment resulted in PSA response (defined as a confirmed 50{\%} reduction) in 81{\%} of patients. This level of activity, as well as the median time to progression of 11.4 months and median survival of 19.5 months, compared favorably to results with docetaxel alone and led to the development of a recently initiated randomized trial of docetaxel with calcitriol or placebo in the same patient population.",
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