Toxicity and dose-response studies of 1 alpha-hydroxyvitamin D2 in LH beta-Tag transgenic mice.
OBJECTIVE
The study objective is to determine the effectiveness of a vitamin D analogue, 1 alpha-hydroxyvitamin D2 (1 alpha-OH-D2), in inhibiting retinoblastoma in a transgenic retinoblastoma model (LH beta-Tag mouse) and to evaluate its toxicity. Previous studies of 1 alpha-OH-D2 in athymic mice with human retinoblastoma xenografts suggested efficacy in tumor suppression and suitability for human treatment.


METHODS
LH beta-Tag mice (N = 142), 8 to 10 weeks old, were randomly assigned to treatment groups receiving either control (vehicle) or 0.1, 0.3, 0.5, or 1.0 microgram/day of 1 alpha-OH-D2 via oral gavage five times a week for 5 weeks. Animals were then euthanized. The eyes were enucleated, processed histologically, and serially sectioned. Three sections of each eye were microscopically examined, and mean tumor area was measured using Optimus software. Toxicity was assessed by mortality, weight loss, serum calcium levels, and kidney calcification.


RESULTS
The mean tumor size in each 1 alpha-OH-D2 group was smaller than in controls (P values < .02): control, 90,248 microns 2; 0.1 microgram, 31,545 microns 2; 0.3 microgram, 16,750 microns 2; 0.5 microgram, 30,245 microns 2; and 1.0 microgram, 16,049 microns 2. No dose-dependent response curve was evident. Mortality was higher in the groups receiving the 0.5 microgram and 1.0 microgram doses (P values < .01) than in the other treatment groups and the control group.


CONCLUSIONS
In the LH beta-Tag mouse, 1 alpha-OH-D2 inhibits retinoblastoma with no increased mortality at lower doses (0.1 to 0.3 microgram). 1 alpha-OH-D2 has been approved by the Food and Drug Administration as an investigative drug for cancer treatment and has shown efficacy with low levels of toxicity in adult cancer trials. 1 alpha-OH-D2 meets the criteria for human clinical trials.
Dawson
Daniel G
DG
Department of Ophthalmology and Visual Sciences, University of Wisconsin Medical School, Madison, USA.
Gleiser
Joel
J
Zimbric
Michele L
ML
Darjatmoko
Soesiawaiti R
SR
Frisbie
Jared C
JC
Lokken
Janice M
JM
Lindstrom
Mary J
MJ
Audo
Isabelle
I
Strugnell
Stephen A
SA
Albert
Daniel M
DM
D000818:Animals; D002118:Calcium / Q000097:blood; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004872:Ergocalciferols / Q000008:administration & dosage* / Q000633:toxicity*; D051379:Mice; D008822:Mice, Transgenic; D019572:Retinal Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D012175:Retinoblastoma / Q000097:blood / Q000188:drug therapy* / Q000473:pathology
D004872:Ergocalciferols; C042533:1 alpha-hydroxyergocalciferol; D002118:Calcium