title: Inecalcitol, an analog of 1α,25(OH)(2) D(3) , induces growth arrest of androgen-dependent prostate cancer cells.
abstract: 19-nor-14-epi-23-yne-1,25(OH)(2) D(3)  (inecalcitol) is a unique vitamin D(3)  analog. We evaluated the activity of inecalcitol in a human prostate cancer model system. The analog was 11-fold more potent than 1,25(OH)(2) D(3)  in causing 50% clonal growth inhibition of androgen-sensitive human prostate cancer LNCaP cells. Inecalcitol, more than 1,25(OH)(2) D(3) , reduced in a dose-dependent manner the expression levels of the transcription factor ETS variant 1 and the serine/threonine protein kinase Pim-1, both of which are upregulated in prostate cancer. Remarkably, dose challenge experiments revealed that inecalcitol maximal tolerated dose (MTD) by intraperitoneal (i.p.) administration was 30 μg/mouse (1,300 μg/kg) three times per week, while we previously found that the MTD of 1,25(OH)(2) D(3)  is 0.0625 μg/mouse; therefore, inecalcitol is 480 times less hypercalcemic than 1,25(OH)(2) D(3) . Pharmacokinetic studies showed that plasma half-life of inecalcitol were 18.3 min in mice. A xenograft model of LNCaP cells was developed in immunodeficient mice treated with inecalcitol. The tumors of the diluent-treated control mice increased in size but those in the inecalcitol treatment group did not grow. Our data suggest that inecalcitol inhibits androgen-responsive prostate cancer growth in vivo and should be examined either alone or with other chemotherapy in clinical trials in individuals with rising serum prostate-specific antigen after receiving either surgery or irradiation therapy with curative intent.
authors: UCLA School of Medicine, Los Angeles, CA, USA. Ryoko.okamoto@cshs.org
authors: Ryoko
authors: R
authors: Okamoto
authors: Remi
authors: R
authors: Delansorne
authors: Naoki
authors: N
authors: Wakimoto
authors: Ngan B
authors: NB
authors: Doan
authors: Tadayuki
authors: T
authors: Akagi
authors: Michelle
authors: M
authors: Shen
authors: Quoc H
authors: QH
authors: Ho
authors: Jonathan W
authors: JW
authors: Said
authors: H Phillip
authors: HP
authors: Koeffler
mesh_terms: D000480:Alkynes / Q000627:therapeutic use*; D000728:Androgens / Q000502:physiology*; D000818:Animals; D045744:Cell Line, Tumor; D002762:Cholecalciferol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D051379:Mice; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000480:Alkynes; D000728:Androgens; C409043:inecalcitol; D002762:Cholecalciferol