Selective vitamin D receptor modulators and their effects on colorectal tumor growth.
The active form of vitamin D, 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], is an endocrine hormone whose classic role is the maintenance of calcium homeostasis. It is well documented that 1,25(OH)(2)D(3) also has anti-tumor effects on a number of cancers and cancer cell lines including breast, colorectal, gastric, liver, ovarian, prostate, and non-melanoma skin cancers. Included in the anti-tumor activities of 1,25(OH)(2)D(3) are its ability to cause antiproliferation, prodifferentation and decrease angiogenesis. Furthermore, through regulation of the plaminogen activator (PA) system and a class of proteolytic enzymes called matrix metalloproteinases (MMPs), 1,25(OH)(2)D(3) reduces the invasive spread of tumor cells. Because of the calcemic limitations of using 1,25(OH)(2)D(3) as a therapy, we have tested the effects of a novel Gemini vitamin D analogue, Deuterated Gemini (DG), on mouse colorectal cancer. We demonstrated that DG is more potent in reducing tumor volume and mass, compared to control and 1,25(OH)(2)D(3). DG significantly prevented (100% reduction, p<0.05) the invasive spread of colorectal tumor cells into the surrounding muscle, and had no effect on serum calcium levels. Thus, DG acts as a selective vitamin D receptor modulator (SVDRM) by enhancing select anti-tumor characteristic 1,25(OH)(2)D(3) activities, without inducing hypercalcemia. Thus, DG shows promise in the development of colorectal cancer therapies.
Spina
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CS
Vitamin D, Skin and Bone Research Laboratories, Endocrine Section, Department of Medicine, Physiology and Biophysics, Boston University Medical Center, 715 Albany Street, M-1013, Boston, MA 02118, USA. kspina@bu.edu
Ton
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Yao
M
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Maehr
H
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Wolfe
M M
MM
Uskokovic
M
M
Adorini
L
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Holick
M F
MF
D000818:Animals; D002117:Calcitriol / Q000627:therapeutic use*; D002118:Calcium / Q000097:blood; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019042:Muscle Neoplasms / Q000378:metabolism / Q000473:pathology; D009361:Neoplasm Invasiveness; D018167:Receptors, Calcitriol / Q000378:metabolism*
D018167:Receptors, Calcitriol; D002117:Calcitriol; D002118:Calcium