Toxicity and dose-response studies of 1α-hydroxyvitamin D2 in a retinoblastoma xenograft model
Toxicity and dose-response studies of 1α-hydroxyvitamin D2 in a retinoblastoma xenograft model
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DOI：
10.1001/archopht.120.5.607
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发表时间：
2002-05-01
影响因子：
--
通讯作者：
Albert, DM
中科院分区：
文献类型：
--
作者：
Grostern, RJ;Bryar, PJ;Albert, DM
背景资料：虽然骨化三醇（1，25-二羟基胆钙化醇）和维生素D-2抑制无胸腺（裸）小鼠异种移植物中视网膜母细胞瘤生长（Y-79细胞系）模型，它们可引起严重的毒性。检查1 α-羟基维生素D-2抑制肿瘤生长的毒性和剂量依赖性反应（1 α-OH-D-2），一种具有降低的全身毒性的类似物，在无胸腺Y-79小鼠模型中。每周5次经口灌胃给药。剂量反应研究测量肿瘤抑制和药物血清水平。每周测量肿瘤大小和体重以及各种毒性标准。在给药期结束时对动物实施安乐死。肿瘤和肾脏被收获，血清中的钙和药物levels.Results：0.1至1.2 μ g/d的剂量进行了分析的基础上，毒性研究的剂量反应试验。0.2 μ g和0.3 μ g剂量组的肿瘤重量和体积显著低于对照组。死亡率和肾脏钙化的小鼠治疗剂量为0.1至0.3 μ g低于骨化三醇和维生素D-2的研究中所观察到的。结论：维生素D类似物，1 α-OH-D-2，抑制肿瘤生长在视网膜母细胞瘤的异种移植模型的毒性低于骨化三醇和维生素D-2。
Background: Although calcitriol (1,25-dihydroxycholecalciferol) and vitamin D-2 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 1alpha-hydroxyvitamin D-2 (1alpha-OH-D-2), 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 mug/d were selected on the basis of toxicity studies for the dose-response trial. Tumor weight and volume in the 0.2-mug and 0.3-mug doses were significantly lower than in controls. Mortality rates and kidney calcification in mice treated with doses of 0.1 to 0.3 mug were lower than those observed in studies of calcitriol and vitamin D-2.Conclusion: A vitamin D analogue, 1alpha-OH-D-2, inhibits tumor growth in this xenograft model of retinoblastoma with less toxicity than calcitriol and vitamin D-2.