TOXICITY AND DOSE-RESPONSE STUDIES OF 1,25-(OH)(2)-16-ENE-23-YNE VITAMIN-D-3 IN TRANSGENIC MICE

Citation
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
Citations number
28
Categorie Soggetti
Oncology
Journal title
ISSN journal
10780432
Volume
4
Issue
9
Year of publication
1998
Pages
2253 - 2256
Database
ISI
SICI code
1078-0432(1998)4:9<2253:TADSO1>2.0.ZU;2-1
Abstract
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.