title: Early growth inhibition is followed by increased metastatic disease with vitamin D (calcitriol) treatment in the TRAMP model of prostate cancer.
abstract: The active metabolite of vitamin D3, 1,25-dihydroxyvitamin D3 (calcitriol) has antiproliferative effects in non-aggressive prostate cancer, however, its effects in more aggressive model systems are still unclear. In these studies, effects of calcitriol and a less-calcemic vitamin D analog, QW-1624F2-2 (QW), were tested in vivo, using the aggressive autochthonous transgenic adenocarcinoma of mouse prostate (TRAMP) model. To study prevention of androgen-stimulated prostate cancer, vehicle, calcitriol (20 µg/kg), or QW (50 µg/kg) were administered to 4 week-old TRAMP mice intraperitoneal (i.p.) 3×/week on a MWF schedule for 14 weeks. Calcitriol and QW slowed progression of prostate cancer as indicated by reduced urogenital tract (p = 0.0022, calcitriol; p = 0.0009, QW) and prostate weights (p = 0.0178, calcitriol; p = 0.0086, QW). However, only calcitriol increased expression of the pro-differentiation marker, cadherin 1 (p = 0.0086), and reduced tumor proliferation (p = 0.0467). By contrast, neither vitamin D analog had any effect on castration resistant prostate cancer in mice treated pre- or post-castration. Interestingly, although vitamin D showed inhibitory activity against primary tumors in hormone-intact mice, distant organ metastases seemed to be enhanced following treatment (p = 0.0823). Therefore, TRAMP mice were treated long-term with calcitriol to further examine effects on metastasis. Calcitriol significantly increased the number of distant organ metastases when mice were treated from 4 weeks-of-age until development of palpable tumors (20-25 weeks-of-age)(p = 0.0003). Overall, data suggest that early intervention with vitamin D in TRAMP slowed androgen-stimulated tumor progression, but prolonged treatment resulted in development of a resistant and more aggressive disease associated with increased distant organ metastasis.
authors.affiliation: Department of Pharmacology, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
authors.forename: Adebusola Alagbala
authors.initials: AA
authors.lastname: Ajibade
authors.affiliation: Department of Pharmacology, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Kirk
authors.affiliation: Department of Pharmacology, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
authors.forename: Ellen
authors.initials: E
authors.lastname: Karasik
authors.affiliation: Department of Pharmacology, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
authors.forename: Bryan
authors.initials: B
authors.lastname: Gillard
authors.affiliation: Department of Pharmacology, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Moser
authors.affiliation: Department of Pharmacology, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
authors.forename: Candace S
authors.initials: CS
authors.lastname: Johnson
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
authors.forename: Donald L
authors.initials: DL
authors.lastname: Trump
authors.affiliation: Department of Pharmacology, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Foster
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000453:epidemiology / Q000556:secondary*; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D007124:Immunoenzyme Techniques; D015994:Incidence; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000453:epidemiology / Q000473:pathology*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000453:epidemiology / Q000556:secondary*; D014407:Tumor Cells, Cultured; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C118756:dihydroxy-vitamin D3; D014807:Vitamin D