Transscleral delivery of a vitamin D analog in a heriditary murine model for the treatment of retinoblastoma

Abstract

Abstract: : Purpose:To evaluate the transscleral delivery of a vitamin D analog in a hereditary murine model to determine its efficacy and safety in the treatment of retinoblastoma Background:In mice, systemic administration of vitamin D analogs can inhibit retinoblastoma growth but has not been used in children due to hypercalcemia. Transscleral delivery has the potential to inhibit tumor growth without systemic toxicity. Methods:14 LHB–TAG transgenic retinoblastoma mice were randomized into 4 groups. One treatment group of 5 mice received a subconjunctival injection to the right eye once per week of 0.25 ug calcitriol (vitamin D analog, Amersham pharmacia biotech, Buckinghamshire, England) in 10 ul of mineral oil. A control group of 2 mice received a subconjunctival injection to the right eye once per week of 10 ul of mineral oil only. Another treatment group of 5 mice received a subconjunctival injection to the right eye three times per week of 0.083 ug calcitriol in 10 ul of mineral oil. A control group of 2 mice recieved a subconjunctival injection to the right eye three times per week of 10 ul of mineral oil only. The mice were 8 to 10 weeks at the start and euthanized after five weeks of treatment. Tumor area and the standard error of the mean were measured from histologic sections. Toxicity was assessed by mortality, measurement of serum calcium, and kidney calcification. Results:Tumor area of the right eye in the 3 times per week treated group was 22495.48 +/– 14461.90 um² (mean+/– SE, n=5). Tumor area of the right eye in the control group was 40450.75 +/– 35559.01 um² (n=2). Two mice were euthanized due to hypercalcemia with one of those two exhibiting significant kidney calcifications. Tumor area of the right eye in the once per week treated group was 78517 +/– 31392.18 um² (n=5). Tumor area of the right eye in the control group was 98308.41 +/– 60781.49 um² (n=2). One mouse was euthanized due to anesthetic complication. No mice exhibited hypercalcemia or significant kidney calcification. Conclusions:Tumor growth was inhibited by 44% in the 3 times per week treated group but 2 of 5 mice died due to hypercalcemia. Tumor growth was inhibited by 20% in the once per week treated group and exhibited no mortality due to hypercalcemia. Transscleral delivery of a vitamin D analog in a hereditary murine model appears to be effective in inhibiting tumor growth of retinoblastoma. Mortality was a complication with more frequent dosing. Further investigation is needed to determine ideal dose and frequency of injection while monitoring for systemic complications.

Keywords: retinoblastoma • drug toxicity/drug effects • sclera