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Effectiveness of 1-Hydroxyvitamin D₂ in Inhibiting Tumor Growth in a Murine Transgenic Pigmented Ocular Tumor Model

Daniel M. Albert, MD, MS; Amit Kumar, MD; Stephen A. Strugnell, PhD; Soesiawati R. Darjatmoko, MS; Janice M. Lokken; Mary J. Lindstrom, PhD; Christine M. Damico, BS; Sarit Patel, MD

Arch Ophthalmol. 2004;122:1365-1369.

Objective  To study the effectiveness of the vitamin D analogue 1-hydroxyvitamin D₂ (1-OH-D₂) in inhibiting ocular tumor growth in transgenic "Tyr-Tag" mice that developed pigmented ocular tumors produced with the simian virus 40 T and t antigens under the control of the mouse tyrosinase gene. These animals develop pigmented intraocular tumors primarily from the retinal pigment epithelium that closely resemble the histologic features and growth pattern of human choroidal melanoma.

Methods  A total of 73 Tyr-Tag transgenic mice between 6 and 7 weeks old were randomly assigned by sex and litter to 3 treatment groups to receive 0.05 µg/d, 0.1 µg/d, or 0.2 µg/d of 1-OH-D₂; a control group received vehicle (coconut oil). The drug was administered by oral gavage 5 times a week for 5 weeks. The animals were then euthanized and their eyes were enucleated and processed histologically. Three serial sections from each eye were examined microscopically and the mean tumor area measured using Optimus software version 6.5 (Media Cybernetics LP, Silver Spring, Md). Toxic adverse effects were assessed on the basis of mortality, weight loss, and serum calcium levels.

Results  The mean tumor size in the 0.1-µg/d and 0.2-µg/d dose groups was smaller than in the controls (P<.001). No significant difference was seen between the 0.05-µg/d dose group and the control group (P = .64). Survival for the 0.1-µg/d and 0.2-µg/d dose groups was lower than for the controls (95% in the controls vs 85.7% and 73.7%, respectively; P<.01).

Conclusion  In the Tyr-Tag transgenic mouse, 1-OH-D₂ inhibits pigmented ocular tumor growth at moderate drug levels with relatively low mortality.

Clinical Relevance  Vitamin D analogues merit further preclinical study in the treatment of ocular melanoma.

From the Department of Ophthalmology and Visual Sciences (Drs Albert, Kumar, and Patel, and Mss Darjatmoko, Lokken, and Damico) and the Department of Biostatistics and Medical Informatics (Dr Lindstrom), University of Wisconsin Medical School, Madison; and Bone Care International, Middleton, Wis (Dr Strugnell). The authors have no relevant financial interest in this article.

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Effectiveness of Vitamin D Analogues in Treating Large Tumors and During Prolonged Use in Murine Retinoblastoma Models
Daniel M. Albert, Amit Kumar, Stephen A. Strugnell, Soesiawati R. Darjatmoko, Janice M. Lokken, Mary J. Lindstrom, and Sarit Patel
Arch Ophthalmol. 2004;122(9):1357-1362.
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