Toxicity and dose-response studies of 1alpha-hydroxyvitamin D2 in a retinoblastoma xenograft model.
BACKGROUND
Although calcitriol (1,25-dihydroxycholecalciferol) and vitamin D(2) inhibit retinoblastoma growth in the athymic (nude) mouse xenograft (Y-79 cell line) model of retinoblastoma, they can cause severe toxicity.


OBJECTIVE
To examine the toxicity of and dose-dependent response for the inhibition of tumor growth for 1alpha-hydroxyvitamin D(2) (1alpha-OH-D(2)), an analogue with reduced systemic toxicity, in the athymic Y-79 mouse model.


METHODS
Mice were randomized into treatment and control groups for 5-week toxicity and dose-response studies. Treatment was via oral gavage 5 times per week. Dose-response studies measured tumor inhibition and drug serum levels. Tumor size and body weight were measured weekly together with various criteria for toxicity. Animals were euthanized at the end of the treatment period. Tumors and kidneys were harvested, and serum was analyzed for calcium and drug levels.


RESULTS
Doses of 0.1 to 1.2 microg/d were selected on the basis of toxicity studies for the dose-response trial. Tumor weight and volume in the 0.2-microg and 0.3-microg doses were significantly lower than in controls. Mortality rates and kidney calcification in mice treated with doses of 0.1 to 0.3 microg were lower than those observed in studies of calcitriol and vitamin D(2).


CONCLUSIONS
A vitamin D analogue, 1alpha-OH-D(2), inhibits tumor growth in this xenograft model of retinoblastoma with less toxicity than calcitriol and vitamin D(2).
Grostern
Richard J
RJ
Department of Ophthalmology, Rush University, Chicago, IL, USA.
Bryar
Paul J
PJ
Zimbric
Michele L
ML
Darjatmoko
Soesiawati R
SR
Lissauer
Boaz J
BJ
Lindstrom
Mary J
MJ
Lokken
Janice M
JM
Strugnell
Stephen A
SA
Albert
Daniel M
DM
D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004872:Ergocalciferols / Q000008:administration & dosage* / Q000097:blood / Q000633:toxicity*; D006801:Humans; D007668:Kidney / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D011897:Random Allocation; D019572:Retinal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D012175:Retinoblastoma / Q000188:drug therapy* / Q000473:pathology; D014183:Transplantation, Heterologous
D004872:Ergocalciferols; C042533:1 alpha-hydroxyergocalciferol; C003564:1,25-dihydroxyergocalciferol