Cl. Wilkerson et al., TOXICITY AND DOSE-RESPONSE STUDIES OF 1,25-(OH)(2)-16-ENE-23-YNE VITAMIN-D-3 IN TRANSGENIC MICE, Clinical cancer research, 4(9), 1998, pp. 2253-2256
The vitamin D-3 analogue 1,25-(OH)(2)-16-ene-23-yne vitamin D-3 (16,23
-D-3) in doses with low systemic toxicity has been demonstrated to inh
ibit retinoblastoma growth in transgenic mice. This study examines the
dose-dependent response for inhibition of tumor growth in transgenic
mice with retinoblastoma and evaluates the in vivo toxicity of 16,23-D
-3, in nontransgenic mice. Transgenic 8-10-week-old mice with retinobl
astoma (n = 119) were randomly assigned to groups receiving 1.0, 0.75,
0.5, 0.35, 0.2, or 0.05 mu g of 16,23-D-3, and a vehicle alone (contr
ol) group i,p, five times a week for 5 weeks, An additional control gr
oup received no injection, Eyes were enucleated one week after the end
of treatment, and tumor areas were measured. To determine the toxic d
ose, transgene-negative littermates received 0.5, 1.0, 1.5, 2.5, 3.5,
4.5, or 5.0 mu g of 16,23-D-3, and control groups received vehicle alo
ne, 5 days a week for 5 weeks, Serum calcium levels were measured, and
necropsies were performed on animals from each group, In the dose-res
ponse study, tumor growth inhibition was greatest in the group receivi
ng 0.35 mu g (55% inhibition; P = 0.0056) and was also significant in
the group receiving 0.5 mu g (42% inhibition; P = 0.036), The systemic
toxic effects due to hypercalcemia occurred at doses of greater than
or equal to 1.0 mu g. 16,23-D-3 inhibits tumor growth at doses greater
than or equal to 0.35 mu g and shows toxic effects at doses greater t
han or equal to 1.0 mu g related to hypercalcemia in mice fed an unres
tricted diet. No toxicity was observed with lower doses.