Vitamin D2 analog 19-nor-1,25-dihydroxyvitamin D2:: Antitumor activity against leukemia, myeloma, and colon cancer cells
Vitamin D2 analog 19-nor-1,25-dihydroxyvitamin D2:: Antitumor activity against leukemia, myeloma, and colon cancer cells
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DOI：
10.1093/jnci/95.12.896
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发表时间：
2003-06-18
期刊：
影响因子：
--
通讯作者：
Koeffler, HP
中科院分区：
文献类型：
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作者：
Kumagai, T;O'Kelly, J;Koeffler, HP
背景资料：1，25-二羟基维生素D-3在体外抑制几种类型的人类癌细胞的生长，但其治疗用途受到阻碍，因为它会导致高钙血症。19-去甲-1，25-二羟基维生素D-2（帕立骨化醇）是一种非钙维生素D类似物，经美国食品药品监督管理局批准用于治疗继发性甲状旁腺功能亢进。我们研究了帕立骨化醇的体外和体内抗肿瘤活性和作用机制。方法：检测帕立骨化醇对癌细胞系增殖、细胞周期、分化和凋亡的影响。在裸鼠中用结肠癌细胞异种移植物检查对肿瘤生长的影响（实验组5只，对照组5只）。在野生型和维生素D受体（VDR）敲除小鼠的单核脾细胞和骨髓干细胞中检查了帕立骨化醇与VDR的相互作用。所有统计检验均为双侧检验。结果如下：帕立骨化醇通过诱导细胞周期停滞和分化，在2.4-5.8 x 10（-9）M的有效剂量下抑制生长50%（ED 50），抑制髓性白血病细胞系HL-60、NB-4和THP-1细胞的增殖。帕立骨化醇通过诱导细胞周期阻滞和细胞凋亡抑制NCI-H929骨髓瘤细胞的增殖，ED 50为2.0 x 10（-10）M。帕立骨化醇还可抑制结肠癌细胞系HT-29（ED 50 = 1.7 x 10（-8）M）和SW 837（ED 50 = 3.2 x 10（-8）M）的增殖。帕立骨化醇治疗的裸鼠中HT-29结肠癌异种移植物较小（1044 mm 3和1752 mm（3），差值708 mm 3，95%置信区间= 311至1104 mm（3）; P = 0.03）和体重低于（1487 mg和4162 mg，差异= 2675 mg，95%置信区间= 2103至3248 mg; P <0.001）。帕立骨化醇诱导野生型但非VDR敲除小鼠的定向髓系造血干细胞分化为巨噬细胞。结论：帕立骨化醇对髓性白血病、骨髓瘤和结肠癌细胞具有抗癌活性，可能通过VDR介导。因为它已经被食品和药物管理局批准，这种药物在某些癌症中的临床试验是合理的。
Background: 1,25-Dihydroxyvitamin D-3 inhibits growth of several types of human cancer cells in vitro, but its therapeutic use is hampered because it causes hypercalcemia. 19-nor-1,25-Dihydroxyvitamin D-2 (paricalcitol) is a noncalcemic vitamin D analog that is approved by the Food and Drug Administration for the treatment of secondary hyperparathyroidism. We investigated the antitumor activity and mechanism of action of paricalcitol in vitro and in vivo. Methods: Effects of paricalcitol on proliferation, the cell cycle, differentiation, and apoptosis were examined in cancer cell lines. Effects on tumor growth were examined with colon cancer cell xenografts in nude mice (five in the experimental group and five in the control group). The interaction of paricalcitol with the vitamin D receptor (VDR) in mononuclear spleen cells and myeloid stem cells from wild-type and VDR knockout mice was examined. All statistical tests were two-sided. Results: Paricalcitol inhibited the proliferation of myeloid leukemia cell lines HL-60, NB-4, and THP-1 cells at an effective dose that inhibited growth 50% (ED50) of 2.4-5.8 x 10(-9) M by inducing cell cycle arrest and differentiation. Paricalcitol inhibited the proliferation of NCI-H929 myeloma cells at an ED50 of 2.0 x 10(-10) M by inducing cell cycle arrest and apoptosis. Paricalcitol also inhibited the proliferation of colon cancer cell lines HT-29 (ED50 = 1.7 x 10(-8) M) and SW837 (ED50 = 3.2 x 10(-8) M). HT-29 colon cancer xenografts in paricalcitol-treated nude mice were smaller (1044 mm 3 and 1752 mm(3), difference 708 MM3, 95% confidence interval = 311 to 1104 mm(3); P = .03) and weighed less (1487 mg and 4162 mg, difference = 2675 mg, 95% confidence interval = 2103 to 3248 mg; P < .001) than those in vehicle-treated mice. Paricalcitol induced committed myeloid hematopoietic stem cells from wild-type but not from VDR knockout mice to differentiate as macrophages. Conclusion: Paricalcitol has anticancer activity against myeloid leukemia, myeloma, and colon cancer cells that may be mediated through the VDR. Because it has been approved by the Food and Drug Administration, clinical trials of this agent in certain cancers are reasonable.