Toxicity and dose-response studies of 1,25-(OH)2-16-ene-23-yne vitamin D3 in transgenic mice.
The vitamin D3 analogue 1,25-(OH)2-16-ene-23-yne vitamin D3 (16,23-D3) in doses with low systemic toxicity has been demonstrated to inhibit 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-D3 in nontransgenic mice. Transgenic 8-10-week-old mice with retinoblastoma (n = 119) were randomly assigned to groups receiving 1.0, 0.75, 0.5, 0.35, 0.2, or 0.05 microg of 16,23-D3 and a vehicle alone (control) group i.p. five times a week for 5 weeks. An additional control group received no injection. Eyes were enucleated one week after the end of treatment, and tumor areas were measured. To determine the toxic dose, transgene-negative littermates received 0.5, 1.0, 1.5, 2.5, 3.5, 4.5, or 5.0 microg of 16,23-D3, and control groups received vehicle alone, 5 days a week for 5 weeks. Serum calcium levels were measured, and necropsies were performed on animals from each group. In the dose-response study, tumor growth inhibition was greatest in the group receiving 0.35 microg (55% inhibition; P = 0.0056) and was also significant in the group receiving 0.5 microg (42% inhibition; P = 0.036). The systemic toxic effects due to hypercalcemia occurred at doses of > or =1.0 microg. 16,23-D3 inhibits tumor growth at doses > or =0.35 microg and shows toxic effects at doses > or =1.0 microg related to hypercalcemia in mice fed an unrestricted diet. No toxicity was observed with lower doses.
Wilkerson
C L
CL
Department of Ophthalmology and Visual Sciences, University of Wisconsin Medical School, Madison 53792-3220, USA.
Darjatmoko
S R
SR
Lindstrom
M J
MJ
Albert
D M
DM
D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000633:toxicity; D002118:Calcium / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D012175:Retinoblastoma / Q000188:drug therapy
D002117:Calcitriol; C064183:Ro 23-7553; D002118:Calcium