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Toxicity and dose-response studies of 1 alpha-hydroxyvitamin D2 in LH beta-Tag transgenic mice
Daniel G Dawson1, Joel Gleiser, Michele L Zimbric
1Department of Ophthalmology and Visual Sciences, University of Wisconsin Medical School, Madison, USA.
Purpose:
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.
Conclusion:
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.
Insights
This study shows that 1 alpha-hydroxyvitamin D2 (1 alpha-OH-D2) effectively inhibits retinoblastoma in mice at lower doses. The vitamin D analogue demonstrated tumor suppression with acceptable toxicity, supporting its potential for human clinical trials.
Area of Science:
- Oncology
- Pharmacology
- Ophthalmology
Background:
- Retinoblastoma is a pediatric eye cancer.
- Vitamin D analogues are being investigated for cancer treatment.
- 1 alpha-hydroxyvitamin D2 (1 alpha-OH-D2) has shown promise in preclinical models.
Purpose of the Study:
- To evaluate the efficacy of 1 alpha-hydroxyvitamin D2 (1 alpha-OH-D2) in inhibiting retinoblastoma in a transgenic mouse model.
- To assess the toxicity of 1 alpha-OH-D2 in this model.
- To determine the suitability of 1 alpha-OH-D2 for human clinical trials.
Main Methods:
- 142 LH beta-Tag mice were randomized into groups receiving vehicle control or varying doses of 1 alpha-OH-D2 (0.1-1.0 microgram/day) orally for 5 weeks.
- Tumor area was measured histologically after euthanasia.
- Toxicity was assessed via mortality, weight loss, serum calcium, and kidney calcification.
Main Results:
- All 1 alpha-OH-D2 doses significantly reduced mean tumor area compared to controls (P < .02).
- No clear dose-dependent response was observed.
- Higher doses (0.5 and 1.0 microgram) were associated with increased mortality (P < .01).
Conclusions:
- 1 alpha-OH-D2 inhibits retinoblastoma in the LH beta-Tag mouse model.
- Lower doses (0.1-0.3 microgram) showed efficacy without increased mortality.
- 1 alpha-OH-D2 demonstrates potential for human clinical trials in cancer treatment.