PT - JOURNAL ARTICLE AU - JOHN N. FLANAGAN AU - SHASHA ZHENG AU - KUN-CHUN CHIANG AU - ATSUSHI KITTAKA AU - TOSHIYUKI SAKAKI AU - SACHIE NAKABAYASHI AU - XIANSI ZHAO AU - REMCO A. SPANJAARD AU - KELLY S. PERSONS AU - JEFFREY S. MATHIEU AU - MICHAEL F. HOLICK AU - TAI C. CHEN TI - Evaluation of 19-Nor-2α-(3-hydroxypropyl)-1α,25-dihydroxyvitamin D<sub>3</sub> as a Therapeutic Agent for Androgen-dependent Prostate Cancer DP - 2009 Sep 01 TA - Anticancer Research PG - 3547--3553 VI - 29 IP - 9 4099 - http://ar.iiarjournals.org/content/29/9/3547.short 4100 - http://ar.iiarjournals.org/content/29/9/3547.full SO - Anticancer Res2009 Sep 01; 29 AB - The high incidence of prostate cancer and lack of an effective, long-term treatment for metastatic disease highlights the need for more potent non-calcemic vitamin D analogs as potential alternative or combinational prostate cancer therapies. Among the analogs, 19-nor-1α,25-dihydroxyvitamin D2 (19-nor-1α,25(OH)2D2) known as paricalcitol or Zempler, has less calcemic effects and an equipotential activity as 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) in several in vivo and in vitro systems. It was recently demonstrated that a modified analog of paricalcitol, 19-nor-2α-(3-hydroxypropyl)-1α,25-dihydroxyvitamin D3 (MART-10) compared to 1α,25(OH)2D3 was more effective in inhibiting proliferation of an immortalized normal prostate cell line (PZ-HPV-7) (1,000-fold) and invasion of PC-3 prostate cancer cells (10-fold). In this study, the effects of MART-10 and 1α,25(OH)2D3 on proliferation, vitamin D receptor transactivation, vitamin D-binding protein (DBP) binding, CYP24A1 (24-OHase) substrate hydroxylation kinetics, and induction of CYP24A1 gene expression were compared in an androgen-dependent prostate cancer cell model, LNCaP. The results demonstrated that MART-10 was 1,000-fold more active than 1α,25(OH)2D3 in inhibiting LNCaP cell proliferation. MART-10 was more active than 1α,25(OH)2D3 in up-regulating a vitamin D receptor-responsive Luciferase construct and inducing CYP24A1 gene expression in LNCaP prostate cancer cells. In addition, MART-10 has a lower affinity for DBP and less substrate degradation by CYP24A1 compared to 1α,25(OH)2D3, indicating that MART-10 has more bioavailability and a longer half-life. Thus, these data suggest that MART-10 may be a potential candidate as a therapeutic agent for prostate cancer, especially for patients who fail in conventional therapies.