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DG Dawson, J Gleiser, ML Zimbric, SR Darjatmoko, J Frisbie, JM Lokken, MJ Lindstrom, DM Albert; Toxicity and Dose-Response Studies of 1Alpha-Hydroxyvitamin-D2 in Transgenic Mice . Invest. Ophthalmol. Vis. Sci. 2002;43(13):2602.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose:Vitamin D2 and calcitriol have been shown to inhibit retinoblastoma in two mouse models of the disease, the athymic (nude) mouse with subcutaneously implanted human Y-79 retinoblastoma tumors, and the transgenic LHß-Tag mouse model that spontaneously develops intraocular retinoblastoma. A recently developed analogue, 1α-hydroxyvitamin-D2 (1α-OH-D2), causes less toxicity than previous compounds and has been shown to inhibit tumor growth in the athymic/Y-79 mouse model. This study examines the dose-dependent response of 1α-OH-D2 for inhibition of tumor growth and in vivo toxicity in LHß-Tag transgenic mice with retinoblastoma. Methods:LHß-Tag transgenic 8-10 week-old mice with retinoblastoma (n=142) were randomly assigned to treatment groups receiving a vehicle alone (control) or 0.1, 0.3, 0.5, or 1.0 ug of 1α-OH-D2 via oral gavage five times/week for 5 weeks. Animals were euthanized at the end of the treatment period. The eyes were enucleated and placed in formalin for standard permanent sections stained with H&E. Three representative sections of the tumors were microscopically examined and measured using Opitmus software. Mean tumor area of each treatment group was determined and compared statistically to each other. Toxicity was determined by mortality, weight loss, serum calcium levels, and kidney calcification. Results:Mean tumor area of each treatment group is 90,248(control), 31,545(0.1 ug), 16,750(0.3 ug), 30,245(0.5 ug), and 16,049 um2 (1.0 ug). Although no dose-dependent response curve is appreciated, each treatment group measurement of 1α-OH-D2 is smaller from a statistically significant standpoint (all p values < 0.02) compared to the control group. Statistically significant increases in mortality of the 0.5 and 1.0 ug treatment groups (all p values < 0.05) compared to other treatment groups are noted and statistically significant decreases in weight of the 0.3, 0.5, and 1.0 ug treatment groups are observed (all p values < 0.001) compared to the other treatment groups. Conclusion:1α-OH-D2, inhibits retinoblastoma growth in our transgenic mouse model. Although no dose-dependent response curve is appreciated, each treatment group of 1α-OH-D2 has a statistically significant effect compared to the control group. There is also a trend toward more toxicity as the dose of 1 α -OH-D2 increases.
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