Novel nonsecosteroidal vitamin D receptor modulator inhibits the growth of LNCaP xenograft tumors in athymic mice without increased serum calcium.
BACKGROUND
We recently reported on novel vitamin D receptor (VDR) modulators that are structurally distinct from the secosteroid 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), the endogenous activator of VDR. One of these compounds, LG190119, was tested for the ability to inhibit the growth of LNCaP human prostate cancer cell-derived tumors in athymic mice.


METHODS
In one study, athymic mice with established LNCaP xenograft tumors were dosed orally every day with LG190119 (3 or 10 mg/kg) or with a synthetic analog of 1,25(OH)(2)D(3), EB1089 (1 microg/kg), for 15 days. In another study ("prevention mode"), oral administration (every other day) of 10 mg/kg LG190119 or a non-hypercalcemic dose of 1,25(OH)(2)D(3) (0.5 microg/kg) was initiated prior to tumor development and continued for 84 days. In both studies, tumor volumes, mouse weights, and serum calcium levels were measured.


RESULTS
In the established tumor study, LG190119 at each dose resulted in significant tumor growth inhibition without hypercalcemia at both 10 and 15 days. EB1089 treatment resulted in significant tumor growth inhibition only at Day 10 and resulted in hypercalcemia at Day 15. In the prevention-mode study, LG190119 markedly slowed tumor growth without increased serum calcium in comparison with either vehicle or 1,25(OH)(2)D(3) treatment (P < 0.001).


CONCLUSIONS
LG190119 effectively inhibited LNCaP xenograft tumor growth without increased serum calcium levels or any other apparent side effects. Compounds of this class may represent promising new therapeutics for treatment of prostate cancer and other cancers with fewer undesirable side effects than currently used drugs.
Polek
T C
TC
Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas, USA.
Murthy
S
S
Blutt
S E
SE
Boehm
M F
MF
Zou
A
A
Weigel
N L
NL
Allegretto
E A
EA
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001835:Body Weight; D002118:Calcium / Q000097:blood*; D002455:Cell Division / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D007659:Ketones / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D011897:Random Allocation; D018167:Receptors, Calcitriol / Q000819:agonists*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D006131:Growth Inhibitors; D007659:Ketones; C443159:LG 190119; D018167:Receptors, Calcitriol; D002118:Calcium