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

Arch Ophthalmol. 2004;122:1357-1362.

Objective  To investigate the effectiveness of the vitamin D analogues 1,25-(OH)₂-16-ene-23-yne vitamin D₃ (16,23-D₃) and 1-hydroxyvitamin D₂ (1-OH-D₂) in inhibiting retinoblastoma growth in large tumors in a xenograft model and with prolonged use in a transgenic model.

Methods  For the large-tumor study, the xenograft athymic mouse/human retinoblastoma cell (Y-79) model was used. Subcutaneous tumors were allowed to grow to an average volume of 1600 mm³. Systemic treatment with 1 of the vitamin D analogues or with vehicle (control groups) was carried out for 5 weeks. For the long-term study, transgenic –luteinizing hormone–large T antigen (LH-Tag) mice were systemically treated with 1 of the 2 compounds or vehicle (control groups) for up to 15 weeks. Tumor size and signs of toxicity were assessed.

Results  In the large-tumor study, tumor volume ratios for the 1-OH-D₂ and 16,23-D₃ groups were significantly lower than those for controls (P<.002). No significant differences in tumor volume were seen between the 1-OH-D₂ and 16,23-D₃ groups (P = .15). In the long-term study, the 1-OH-D₂ group showed significantly smaller tumor size compared with its control (P<.001). No significant difference was seen between the 16,23-D₃ group and its control. Some toxic effects related to hypercalcemia were seen in both studies.

Conclusions  In athymic mice in the large-tumor study, both 1-OH-D₂ and 16,23-D₃ were effective in inhibiting tumor growth compared with controls. In the long-term study, 1-OH-D₂ inhibited tumor growth but 16,23-D₃ did not. Effective doses of both compounds caused hypercalcemia and a significant increase in mortality.

Clinical Relevance  Use of 1-OH-D₂ inhibited tumor growth in large tumors and with long-term treatment compared with controls. Because of hypercalcemia-related toxic effects seen in the present experiments, in clinical trials, serum calcium levels should be carefully monitored. This analogue may require use with drugs that lower serum calcium levels or use of relatively lower doses or skipped doses. The ideal alternative solution would be to identify vitamin D analogues that retain the antineoplastic action without the calcemic activity.

From the Departments of Ophthalmology and Visual Sciences (Drs Albert, Kumar, and Patel and Mss Darjatmoko and Lokken) and Biostatistics and Medical Informatics (Dr Lindstrom), University of Wisconsin Medical School, Madison; and Bone Care International, Middleton, Wis (Dr Strugnell).

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