Effect of calcitriol on prostate-specific antigen in vitro and in humans

Tomasz (Tom) Beer, Mark Garzotto, Byung Park, Motomi (Tomi) Mori, Anne Myrthue, Nicole Janeba, David Sauer, Kristine Eilers

Research output: Contribution to journalArticle

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Abstract

Background: Calcitriol, the natural ligand for the vitamin D receptor, has significant potential in prostate cancer treatment. Measurement of its antineoplastic activity in prostate cancer clinical trials may be complicated by effects of calcitriol on prostate-specific antigen (PSA) production. We examined the effects of calcitriol at similar concentration on cell proliferation, androgen receptor (AR) expression, and PSA production in vitro and on PSA concentrations in prostate cancer patients. Experimental Design: LNCaP prostate cancer cell proliferation was examined by cell counts 6 days after exposure to a range of concentrations of calcitriol, AR and PSA protein was quantified in LNCaP cells over 96 hours after exposure to 1 nmol/L calcitriol. Serum PSA and free PSA was serially measured by immunoassay over a period of 8 days in patients with hormone-naive prostate cancer after a single dose of 0.5 μg/kg calcitriol. Results: Calcitriol treatment resulted in dose-dependent growth inhibition of LNCaP with ∼50% growth inhibition at the clinically achievable concentration of 1 nmol/L. Time-dependent up-regulation of AR expression and of PSA production in LNCaP cells was shown at the same concentration. No significant change in serum PSA or free PSA over 8 days was seen in eight subjects treated with a single dose of 0.5 μg/kg calcitriol. The analysis was powered to detect a 1.23-fold change between the baseline and day 8 serum PSA. Conclusions: At clinically achievable concentrations, calcitriol inhibits growth and induces AR and PSA expression in LNCaP cells. We did not detect similar changes in serum PSA or free PSA in patients exposed to similar concentrations of calcitriol.Thus, a PSAflare, predicted by preclinical systems, is unlikely to occur in patients and therefore unlikely to complicate interpretation of clinical trial outcomes.

Original languageEnglish (US)
Pages (from-to)2812-2816
Number of pages5
JournalClinical Cancer Research
Volume12
Issue number9
DOIs
StatePublished - May 1 2006

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Calcitriol
Prostate-Specific Antigen
Androgen Receptors
Prostatic Neoplasms
Calcitriol Receptors
Serum
In Vitro Techniques
Growth
Cell Proliferation
Clinical Trials
Immunoassay
Antineoplastic Agents
Research Design
Up-Regulation
Cell Count

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Effect of calcitriol on prostate-specific antigen in vitro and in humans. / Beer, Tomasz (Tom); Garzotto, Mark; Park, Byung; Mori, Motomi (Tomi); Myrthue, Anne; Janeba, Nicole; Sauer, David; Eilers, Kristine.

In: Clinical Cancer Research, Vol. 12, No. 9, 01.05.2006, p. 2812-2816.

Research output: Contribution to journalArticle

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abstract = "Background: Calcitriol, the natural ligand for the vitamin D receptor, has significant potential in prostate cancer treatment. Measurement of its antineoplastic activity in prostate cancer clinical trials may be complicated by effects of calcitriol on prostate-specific antigen (PSA) production. We examined the effects of calcitriol at similar concentration on cell proliferation, androgen receptor (AR) expression, and PSA production in vitro and on PSA concentrations in prostate cancer patients. Experimental Design: LNCaP prostate cancer cell proliferation was examined by cell counts 6 days after exposure to a range of concentrations of calcitriol, AR and PSA protein was quantified in LNCaP cells over 96 hours after exposure to 1 nmol/L calcitriol. Serum PSA and free PSA was serially measured by immunoassay over a period of 8 days in patients with hormone-naive prostate cancer after a single dose of 0.5 μg/kg calcitriol. Results: Calcitriol treatment resulted in dose-dependent growth inhibition of LNCaP with ∼50{\%} growth inhibition at the clinically achievable concentration of 1 nmol/L. Time-dependent up-regulation of AR expression and of PSA production in LNCaP cells was shown at the same concentration. No significant change in serum PSA or free PSA over 8 days was seen in eight subjects treated with a single dose of 0.5 μg/kg calcitriol. The analysis was powered to detect a 1.23-fold change between the baseline and day 8 serum PSA. Conclusions: At clinically achievable concentrations, calcitriol inhibits growth and induces AR and PSA expression in LNCaP cells. We did not detect similar changes in serum PSA or free PSA in patients exposed to similar concentrations of calcitriol.Thus, a PSAflare, predicted by preclinical systems, is unlikely to occur in patients and therefore unlikely to complicate interpretation of clinical trial outcomes.",
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AU - Garzotto, Mark

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AU - Janeba, Nicole

AU - Sauer, David

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AB - Background: Calcitriol, the natural ligand for the vitamin D receptor, has significant potential in prostate cancer treatment. Measurement of its antineoplastic activity in prostate cancer clinical trials may be complicated by effects of calcitriol on prostate-specific antigen (PSA) production. We examined the effects of calcitriol at similar concentration on cell proliferation, androgen receptor (AR) expression, and PSA production in vitro and on PSA concentrations in prostate cancer patients. Experimental Design: LNCaP prostate cancer cell proliferation was examined by cell counts 6 days after exposure to a range of concentrations of calcitriol, AR and PSA protein was quantified in LNCaP cells over 96 hours after exposure to 1 nmol/L calcitriol. Serum PSA and free PSA was serially measured by immunoassay over a period of 8 days in patients with hormone-naive prostate cancer after a single dose of 0.5 μg/kg calcitriol. Results: Calcitriol treatment resulted in dose-dependent growth inhibition of LNCaP with ∼50% growth inhibition at the clinically achievable concentration of 1 nmol/L. Time-dependent up-regulation of AR expression and of PSA production in LNCaP cells was shown at the same concentration. No significant change in serum PSA or free PSA over 8 days was seen in eight subjects treated with a single dose of 0.5 μg/kg calcitriol. The analysis was powered to detect a 1.23-fold change between the baseline and day 8 serum PSA. Conclusions: At clinically achievable concentrations, calcitriol inhibits growth and induces AR and PSA expression in LNCaP cells. We did not detect similar changes in serum PSA or free PSA in patients exposed to similar concentrations of calcitriol.Thus, a PSAflare, predicted by preclinical systems, is unlikely to occur in patients and therefore unlikely to complicate interpretation of clinical trial outcomes.

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