Three synthetic vitamin D analogues induce prostate-specific acid phosphatase and prostate-specific antigen while inhibiting the growth of human prostate cancer cells in a vitamin D receptor-dependent fashion.
Numerous studies have indicated that the secosteroid hormone 1alpha, 25-dihydroxyvitamin D3 protects against the development of clinical prostate cancer (PC). Whether this hormone also has therapeutic potential for patients with advanced PC has not yet been evaluated. Several synthetic vitamin D analogues are now available that have reduced hypercalcemic effects and yet effectively induce differentiation in some cell types. For these reasons, these analogues may be safer and more effective for cancer therapy than the natural hormone. In the current study, 13 such analogues were screened for their abilities to inhibit the growth of PC cell lines. Three of the most consistently effective analogues (Ro 23-7553, Ro 24-5531, and Ro 25-6760) were then chosen for further analysis. Growth studies using clones of the JCA-1 cell line that were transfected with the vitamin D receptor cDNA indicate that the antiproliferative effects of these analogues require vitamin D receptor expression. Furthermore, these three analogues induce the secretion of prostate-specific acid phosphatase and prostate-specific antigen (two markers of the differentiated prostatic phenotype) in the cell line LNCaP. These in vitro studies suggest that Ro 23-7553, Ro 24-5531, and Ro 25-6760 should be further evaluated as therapeutic agents for the treatment of PC.
Hedlund
T E
TE
Department of Pathology, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
Moffatt
K A
KA
Uskokovic
M R
MR
Miller
G J
GJ
D000135:Acid Phosphatase / Q000096:biosynthesis / Q000235:genetics*; D000970:Antineoplastic Agents / Q000633:toxicity*; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects; D002762:Cholecalciferol / Q000031:analogs & derivatives* / Q000633:toxicity; D004790:Enzyme Induction; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008297:Male; D011467:Prostate / Q000201:enzymology; D017430:Prostate-Specific Antigen / Q000096:biosynthesis / Q000235:genetics*; D018167:Receptors, Calcitriol / Q000187:drug effects / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D014162:Transfection; D014407:Tumor Cells, Cultured; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000633:toxicity*
D000970:Antineoplastic Agents; D018167:Receptors, Calcitriol; D011994:Recombinant Proteins; C086492:Ro 24-5531; C113532:Ro 25-6760; D014807:Vitamin D; D002762:Cholecalciferol; D000135:Acid Phosphatase; D017430:Prostate-Specific Antigen; D002117:Calcitriol; C064183:Ro 23-7553