Antineoplastic effect and toxicity of 1,25-dihydroxy-16-ene-23-yne-vitamin D3 in athymic mice with Y-79 human retinoblastoma tumors
Antineoplastic effect and toxicity of 1,25-dihydroxy-16-ene-23-yne-vitamin D3 in athymic mice with Y-79 human retinoblastoma tumors
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DOI：
10.1001/archopht.117.3.365
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发表时间：
1999-03-01
影响因子：
--
通讯作者：
Albert, DM
中科院分区：
文献类型：
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作者：
Sabet, SJ;Darjatmoko, SR;Albert, DM
目的：评价1，25-二羟基-16-烯-23-炔-维生素D-3(16，23-D-3)类似物(16，23-D-3)对裸鼠移植Y-79人视网膜母细胞瘤细胞的体内疗效和毒性，并与1，25-二羟基胆钙素(D-3，骨化三醇)进行比较。方法：将30只4-6周龄裸鼠皮下注射1×10(7)Y-79人视网膜母细胞瘤细胞悬液。注射肿瘤5天后，将小鼠随机分为3组，每组10只。第一组为对照组，每周5次，每次0.25m L矿物油(载药)。第二组：骨化三醇0.05 mg加入0.25mT矿物油中，每周5次。第三组：16，23-D-3 0.5 mg加入0.25mL矿物油中，每周5次。连续注射5周，在此期间分别测量肿瘤大小和小鼠体重。毒性通过临床指标进行评估，如嗜睡、体重减轻和死亡。然后处死小鼠，测定每个肿瘤的大小、体积和重量。此外，在每组具有代表性的动物中，评估肾脏的钙化情况，并测量血清钙浓度。结果：所有实验动物和对照组动物都发生了皮下肿瘤。16，23-D-3治疗组小鼠的平均肿瘤体积(1.55 cm(3))明显小于对照组(3.45 cm(3))(P=0.02)，从治疗开始平均体重增加(2.4g比5.5g)更少(P=0.06)，死亡率为40%。骨化三醇治疗的小鼠的平均肿瘤尺寸(1.26 cm(3))并没有明显小于16，23-D-3治疗的小鼠(P=.35)，与对照组相比(骨化三醇治疗的小鼠体重减轻了4.03克)，体重显著减轻(P=.001)，实验完成时死亡率为90%。组织学上，对照组和实验组小鼠的肿瘤坏死和钙化程度没有差异。血清钙浓度在对照组(2.15mmoL/L[8.6 mg/dL])和实验组(骨化三醇1.88mmoL/L[7.5mgdL][P=.97]；16，23-D-3，2.15mmoL/L[8.6mgdL][P=.42])之间相当。骨化三醇治疗组4只小鼠中3只出现轻度双侧肾小管钙化，16，23-D3治疗组4只小鼠中2只出现轻度双侧肾小管钙化。结论：16，23-D-3能显著抑制裸鼠皮下Y-79人视网膜母细胞瘤细胞的生长。骨化三醇的抗肿瘤作用在统计学上没有显着差异，但与明显更多的毒性有关。1，25-二羟基-16-烯-23-炔-维生素D-3可能是治疗视网膜母细胞瘤的一种有用的化疗辅助药物。
Objectives: To evaluate the in vivo efficacy and toxicity of the 1,25-dihydroxy-16-ene-23-yne-vitamin D-3 (16,23-D-3) analogue in athymic nude mice injected with Y-79 human retinoblastoma cells and to compare the efficacy and toxicity of this compound with those of 1,25-dihydroxycholecalcifeiol (D-3, calcitriol).Methods: Thirty athymic nude mice (4-6 weeks old) were injected subcutaneously with 1 x 10(7) Y-79 human retinoblastoma cells suspended in a 1:1 mixture of Iscove culture medium supplemented with 20% fetal bovine serum and basement membrane matrix suspension. Five days after tumor injection, the mice were randomized to 3 groups of 10 mice each. The first group served as a control group and received intraperitoneal injections of 0.25 mL of mineral oil (vehicle) 5 times a week. The second group received intraperitoneal injections of 0.05 mu g of calcitriol in 0.25 mt of mineral oil intraperitoneally 5 times a week. The third group received intraperitoneal injections of 0.5 mu g of 16,23-D-3 in 0.25 mL of mineral oil 5 times a week. Injections were continued for 5 weeks, during which tumor size and mouse weight were individually measured. Toxicity was assessed by clinical, measures such as lethargy, weight loss, and death. The mice were then killed and the size, volume, and weight of each tumor were determined. Also, in representative animals in each group, kidneys were evaluated for calcification and serum calcium concentration was measured.Results: All experimental and control animals developed tumors subcutaneously. The 16,23-D-3-treated mice had significantly smaller average tumor size (1.55 cm(3)) than the control mice (3.45 cm(3)) (P =.02), less gain in average body weight from the beginning of treatment (2.4 g vs 5.5 g) (P =.06), and a 40% mortality. The calcitriol-treated mice did not have significantly smaller average tumor size (1.26 cm(3)) than the 16,23-D-3-treated mice (P = .35), had significant body weight loss compared with the control animals (calcitriol-treated mice lost 4.03 g) (P=.001), and had a mortality of 90% by the completion of the experiment. Histologically, there was no difference in the degree of tumor necrosis and calcification between control and experimental mice. Serum calcium concentrations were equivalent between the control (2.15 mmol/L [8.6 mg/dL]) and experimental groups (calcitriol, 1.88 mmol/L [7.5 mg/dL] [P=.97]; 16,23-D-3, 2.15 mmol/L [8.6 mg/dL] [P=.42]). Mild bilateral renal tubular calcification occurred in 3 of 4 mice in the calcitriol-treated group and in 2 of 4 mice in the 16,23-D3-treated group.Conclusions: The growth of subcutaneous Y-79 human retinoblastoma cells in athymic nude mice is significantly reduced by treatment with intraperitoneal injections of 16,23-D-3. The antineoplastic effect of calcitriol is not statistically significantly different but is associated with significantly more toxicity. 1,25-Dihydroxy-16-ene-23-yne-vitamin D-3 may be a useful chemotherapeutic adjunct in the treatment of retinoblastoma.