1,25-DIHYDROXY-16-ENE-23-YNE-VITAMIN-D3 PROLONGS SURVIVAL-TIME OF LEUKEMIC MICE
1,25-DIHYDROXY-16-ENE-23-YNE-VITAMIN-D3 PROLONGS SURVIVAL-TIME OF LEUKEMIC MICE
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DOI：
10.1073/pnas.87.10.3929
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发表时间：
1990-05-01
影响因子：
11.1
通讯作者：
KOEFFLER, HP
中科院分区：
文献类型：
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作者：
ZHOU, JY;NORMAN, AW;KOEFFLER, HP
1,25-二羟基-16-烯-23-炔-维生素D3 [1,25(OH)2-16-烯-23-炔-D3]是一种维生素D类似物，在体外抑制髓系白血病细胞增殖和诱导分化方面非常有效。此外，1,25(OH)2-16-ene-23-yne-D3在调节肠道钙吸收和骨钙动员方面的活性是1,25-二羟基维生素D3 [1,25(OH)2D3]的300倍，后者是一种生理活性代谢物。此外，1,25(OH)2-16-ene-23-yne-D3在BALB/c小鼠中引起高钙血症的效果比1,25(OH)2D3低10-25倍，每隔一天（q.o.d）腹腔注射6周。我们通过开发和使用以下三种白血病模型来探索1,25(OH)2-16-ene-23-yne-D3的治疗潜力。(i)注射2.5次。将105个髓系白血病细胞（WEHI 3BD+）注入同基因BALB/c小鼠体内，在第26天，所有稀释剂注射小鼠均出现白血病死亡。小鼠接受相同数量的白血病细胞，同时也接受1,25(OH)2D3 (0.1 .mu。gqo.d., i.p.)的生存曲线几乎相同。接受白血病细胞和1,25(OH)2-16-ene-23-yne-D3 (1.6 .mu。（g qo.d, i.p.）的存活时间明显延长（P = 0.003），最后一只小鼠在第50天死于白血病。（ii）白血病细胞注射减少50%(1。105个细胞)注入同基因BALB/c小鼠，结果在51天内86%的白血病死亡。实验小鼠接受相同数量的白血病细胞和1,25(OH)2-16-ene-23-yne-D3 (0.8 .mu。（g q.o.d）组患者的生存期显著长于对照组（P = 0.0006）；到第100天，只有53%的小鼠死亡。（iii）注射1.5次后。104个白血病细胞，13%的同基因BALB/c小鼠在180天无疾病。相比之下，43%的小鼠接受白血病细胞和1,25(OH)2-16-ene-23-yne-D3 (1.6 .mu。在第180天，G qo.d)仍无疾病。总之，1,25(OH)2-16-ene-23-yne-D3是一种维生素D类似物，可显著提高骨髓性白血病小鼠的存活率。
The 1,25-dihydroxy-16-ene-23-yne-vitamin D3 [1,25(OH)2-16-ene-23-yne-D3] is a vitamin D analog that is very potent in inhibiting proliferation and inducing differentiation of myeloid leukemic cells in vitro. Also, 1,25(OH)2-16-ene-23-yne-D3 is 300 times less active in mediating intestinal calcium absorption and bone calcium mobilization as compared to 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the physiologically active metabolite. Furthermore, 1,25(OH)2-16-ene-23-yne-D3 is 10-25 times less potent than 1,25(OH)2D3 in causing hypercalcemia in BALB/c mice injected intraperitoneally (i.p.) every other day (q.o.d.) for 6 weeks. We explored the therapeutic potential of 1,25(OH)2-16-ene-23-yne-D3 by developing and using the following three leukemia models. (i) Injection of 2.5 .times. 105 myeloid leukemic cells (WEHI 3BD+) into syngeneic BALB/c mice resulted in leukemic death of all diluent-injected mice by day 26. Mice who received the same number of leukemic cells and also received 1,25(OH)2D3 (0.1 .mu.g q.o.d., i.p.) had nearly an identical survival curve. Those who received the leukemic cells and 1,25(OH)2-16-ene-23-yne-D3 (1.6 .mu.g q.o.d., i.p.) had a significantly (P = 0.003) longer survival, with the last mouse dying of leukemia on day 50. (ii) Injection of 50% fewer leukemic cells (1 .times. 105 cells) into syngeneic BALB/c mice resulted in 86% dead of leukemia at 51 days. Experimental mice who received the same number of leukemic cells and 1,25(OH)2-16-ene-23-yne-D3 (0.8 .mu.g q.o.d.) had a significantly (P = 0.0006) longer survival than controls; only 53% of the mice were dead by day 100. (iii) After injection of 1.5 .times. 104 leukemic cells, 13% of syngeneic BALB/c mice were free of disease at day 180. In contrast, 43% of mice who received leukemic cells and 1,25(OH)2-16-ene-23-yne-D3 (1.6 .mu.g q.o.d.) were still free of disease at day 180. In summary, 1,25(OH)2-16-ene-23-yne-D3 is a vitamin D analog that significantly increased survival of mice who had myeloid leukemia.