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Toxicity and Dose-Response Studies of 1-Hydroxyvitamin D₂ in a Retinoblastoma Xenograft Model

Richard J. Grostern, MD; Paul J. Bryar, MD; Michele L. Zimbric, BS; Soesiawati R. Darjatmoko, MS; Boaz J. Lissauer, MD; Mary J. Lindstrom, PhD; Janice M. Lokken; Stephen A. Strugnell, PhD; Daniel M. Albert, MD, MS

Arch Ophthalmol. 2002;120:607-612.

Background  Although calcitriol (1,25-dihydroxycholecalciferol) and vitamin D₂ 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 1-hydroxyvitamin D₂ (1-OH-D₂), 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 µg/d were selected on the basis of toxicity studies for the dose-response trial. Tumor weight and volume in the 0.2-µg and 0.3-µg doses were significantly lower than in controls. Mortality rates and kidney calcification in mice treated with doses of 0.1 to 0.3 µg were lower than those observed in studies of calcitriol and vitamin D₂.

Conclusion  A vitamin D analogue, 1-OH-D₂, inhibits tumor growth in this xenograft model of retinoblastoma with less toxicity than calcitriol and vitamin D₂.

From the Departments of Ophthalmology, Rush University (Dr Grostern) and Northwestern University (Dr Bryar) Chicago, Ill, the Department of Ophthalmology & Visual Sciences, School of Medicine (Drs Lissauer and Albert and Mss Zimbric, Darjatmoko, and Lokken), and Department of Biostatistics (Dr Lindstrom), University of Wisconsin, Madison, and BoneCare International Inc, Madison (Dr Strugnell).

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