Toxicity and dose-response studies of 1-α hydroxyvitamin D2 in LH-β-Tag transgenic mice

Daniel G. Dawson, Joel Gleiser, Michele L. Zimbric, Soesiawaiti R. Darjatmoko, Mary J. Lindstrom, Stephen A. Strugnell, Daniel M. Albert

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Abstract

Purpose: To determine the effectiveness of a vitamin D analog, 1α-hydroxyvitamin D2 (1α-OH-D2), in inhibiting retinoblastoma in a transgenic retinoblastoma model (LHβ-Tag mouse) and to evaluate its toxicity. Design: Experimental study using an animal (LHβ-Tag transgenic mouse) randomized (controlled) trial. Participants and Controls: Two hundred seventeen LHβ-Tag transgene-positive 8- to 10-week-old mice total; 179 drug-treated animals, 38 control animals. Methods: Mice were fed a vitamin D- and calcium-restricted diet and were randomized to treatment groups receiving control (vehicle), or 0.1, 0.3, 0.5, or 1.0 μg/day of 1α-OH-D2 via oral gavage 5 times weekly for 5 weeks. Body weight was measured at the start of treatment and twice weekly during treatment. Animals were euthanized on the last day of treatment. The eyes were enucleated, processed histologically, and serially sectioned. Representative sections from the superior, middle, and inferior regions of each globe were examined microscopically and tumor areas were measured using Optimas software. Serum was collected for serum calcium levels. Kidneys were removed for histologic processing and were analyzed microscopically for kidney calcification. Main Outcome Measures: Mean tumor area was measured to determine drug effectiveness. Toxicity was assessed by survival, weight loss over the treatment period, serum calcium, and kidney calcification. Results: The mean tumor size in each 1α-OH-D2 group was smaller than controls (all P values < 0.02): control, 90,248 μm2; 0.1 μg, 31,545 μm2; 0.3 μg, 16,750 μm2; 0.5 μg, 30,245 μm2; and 1.0 μg, 16,049 μm2. No dose-dependent response curve was evident. The survival percentage for each group was as follows: control, 97%; 0.1 μg, 91%; 0.3 μg, 88%; 0.5 μg, 70%; and 1.0 μg, 63%. Mortality was higher in the 0.5-μg and 1.0-μg doses (P values < 0.01) compared with other treatment groups and with the control group. Serum calcium levels were significant in all treatment groups compared with controls (all P values < 0.0001). Conclusions: In the LHβ-Tag mouse, 1α-OH-D2 inhibits retinoblastoma with no significant increase in mortality in lower doses (0.1-0.3 μg). 1α-OH-D2 has approval by the Food and Drug Administration as an investigative drug for cancer treatment, and has shown efficacy with low toxicity in adult cancer trials. 1α-OH-D2 meets the criteria for human clinical trials.

Original languageEnglish (US)
Pages (from-to)835-839
Number of pages5
JournalOphthalmology
Volume110
Issue number4
DOIs
StatePublished - Apr 1 2003

ASJC Scopus subject areas

  • Ophthalmology

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    Dawson, D. G., Gleiser, J., Zimbric, M. L., Darjatmoko, S. R., Lindstrom, M. J., Strugnell, S. A., & Albert, D. M. (2003). Toxicity and dose-response studies of 1-α hydroxyvitamin D2 in LH-β-Tag transgenic mice. Ophthalmology, 110(4), 835-839. https://doi.org/10.1016/S0161-6420(02)01934-6