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Vitamin D-related therapies in prostate cancer

  • Chapter
Prostate Cancer: New Horizons in Research and Treatment

Part of the book series: Developments in Oncology ((DION,volume 81))

  • 137 Accesses

Abstract

Calcitriol or 1,25-dihydroxycholecalciferol (vitamin D) is classically known for its effects on bone and mineral metabolism. Epidemiological data suggest that low vitamin D levels increase the risk and mortality from prostate cancer. Calcitriol is also a potent anti-proliferative agent in a wide variety of malignant cell types including prostate cancer cells. In prostate model systems (PC-3, LNCaP, DU145, MLL) calcitriol has significant anti-tumor activity in vitro and in vivo. Calcitriol’s effects are associated with an increase in cell cycle arrest, apoptosis, differentiation and in the modulation of growth factor receptors. Calcitriol induces asignificant Go/Gii arrest and modulates p21Waf1/Cip1 and p27Kip1, the cyclin dependent kinase inhibitors. Calcitriol induces PARP cleavage, increases the bax/bcl-2 ratio, reduces levels of phosphorylated mitogen-activated protein kinases (P-MAPKs, P-Erk-1/2) and phosphorylated Akt (P-Akt), induces caspase-dependent MEK cleavage and up-regula tion of MEKK-1, all potential markers of the apoptotic pathway. Glucocorticoids potentiate the anti-tumor effect of calcitriol and decrease calcitriol-induced hypercalcemia. In combination with calcitriol, dexamethasone results in a significant time- and dose-dependent increase in VDR protein and an enhanced apoptotic response as compared to calcitriol alone. Calcitriol can also significantly increase cytotoxic drug-mediated anti-tumor efficacy. As a result, phase I and II trials of calcitriol either alone or in combination with the carboplatin, paclitaxel, or dexamethasone have been initiated in patients with androgen-dependent and -independent prostate cancer and advanced cancer. Patients were evaluated for toxicity, maximum tolerated dose (MTD), schedule effects, and PSA response. Data from these studies indicate that high-dose calcitriol is feasible on an intermittent schedule, the MTD is still being delineated and dexamethasone or paclitaxel appear to ameliorate toxicity. Studies continue to define the MTD of calcitriol which can be safely administered on this intermittent schedule either alone or with other agents and to evaluate the mechanisms of calcitriol effects in prostate cancer.

This work is supported by grants from the NCI (CA47904 and CA67267) and CaPCURE.

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Authors and Affiliations

  1. Department of Pharmacology & Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA

    Candace S. Johnson

  2. Department of Pharmacology, University of Pittsburgh, Pittsburgh, PA, USA

    Pamela A. Hershberger

  3. Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY

    Donald L. Trump

Authors
  1. Candace S. Johnson
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  2. Pamela A. Hershberger
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  3. Donald L. Trump
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Editor information

Editors and Affiliations

  1. The Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA

    Michael L. Cher

  2. Wayne State University School of Medicine, Detroit, MI, USA

    Avraham Raz  & Kenneth V. Honn  & 

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© 2002 Kluwer Academic Publishers

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Johnson, C.S., Hershberger, P.A., Trump, D.L. (2002). Vitamin D-related therapies in prostate cancer. In: Cher, M.L., Raz, A., Honn, K.V. (eds) Prostate Cancer: New Horizons in Research and Treatment. Developments in Oncology, vol 81. Springer, Boston, MA. https://doi.org/10.1007/0-306-48143-X_25

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  • DOI: https://doi.org/10.1007/0-306-48143-X_25

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4020-7352-6

  • Online ISBN: 978-0-306-48143-7

  • eBook Packages: Springer Book Archive

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