Kubota T, Koshizuka K, Koike M, Uskokovic M, Miyoshi I, Koeffler H P
Division of Hematology/Oncology, Cedars-Sinai Research Institute, University of California at Los Angeles School of Medicine, 90048, USA.
Cancer Res. 1998 Aug 1;58(15):3370-5.
Vitamin D3 [1,25-dihydroxyvitamin-D3 (1,25(OH)2D3)] modulates the proliferation and differentiation of many cell types. Analogs of 1,25(OH)2D3 that have greater potency may become adjuvant therapy for breast and prostate cancers, myelodysplastic syndrome, acute myelogenous leukemia in remission and other cell types, especially in the setting of low disease burden. A new class of analogs of 1,25(OH)2D3 has been synthesized that has a novel 19-nor motif, as well as incorporating many structural elements previously shown to increase potency. These analogs were examined for their effects on prostate cancer cell lines (PC-3, LNCaP, and DU 145), a human breast cell line (MCF-7), and an acute myeloid leukemia cell line (HL-60). Dose-response clonogenic studies showed that each of these analogs had more potent antiproliferative activities against the cancer cells than 1,25(OH)2D3, and 1,25-(OH)2-16,23Z-diene-26,27-bishomo-19-nor-D3 (Ro 27-2014) was the most potent analog [10-fold increased activity compared to 1,25(OH)2D3]. Further studies were performed using Ro 27-2014. Pulse-exposure studies showed that a 5-day pulse-exposure to Ro 27-2014 (10(-7) M) in liquid culture was adequate to achieve a 50% inhibition of MCF-7 clonal growth in soft agar in the absence of the analog, suggesting that the growth inhibition mediated by the analog was irreversible. Cell cycle analyses using MCF-7 cells showed that Ro 27-2014 (10(-7) M for 4 days) induced a significant increase in the number of cells in G0-G1 (72.8+/-8.9% versus 49.9+/-3.5% in control cells), with a concomitant decrease in the percent of cells in S phase (13.1+/-6.2% versus 35.8+/-3.5% in control cells). The chief toxicity of vitamin D3 compounds is hypercalcemia, and therefore, we examined calcemic activity of Ro 27-2014 in mice and found it not to induce hypercalcemia at doses of 0.05 microg i.p. three times per week. In contrast, the same dose of a 19-nor vitamin D3 compound with 6 fluorines on the side chain (1,25-(OH)2-16-ene-23-yne-26,27-F6-19-nor-D3), although also having potent anticancer activity, caused severe hypercalcemia (18 mg/dl). In summary, 19-nor vitamin D3 compounds with desaturation and lengthening of their side chains result in a series of compounds with a good therapeutic index, having potent anticancer activity and low toxicity.
维生素D3 [1,25 - 二羟基维生素D3 (1,25(OH)2D3)] 可调节多种细胞类型的增殖和分化。效力更强的1,25(OH)2D3类似物可能成为乳腺癌、前列腺癌、骨髓增生异常综合征、缓解期急性髓性白血病及其他细胞类型的辅助治疗药物，尤其是在疾病负担较低的情况下。已合成了一类新型的1,25(OH)2D3类似物，其具有新颖的19 - 去甲结构基序，同时融入了许多先前已证明可增强效力的结构元素。研究了这些类似物对前列腺癌细胞系（PC - 3、LNCaP和DU 145）、人乳腺癌细胞系（MCF - 7）和急性髓性白血病细胞系（HL - 60）的影响。剂量反应克隆形成研究表明，这些类似物中的每一种对癌细胞的抗增殖活性均比1,25(OH)2D3更强，且1,25 - (OH)2 - 16,23Z - 二烯 - 26,27 - 双高 - 19 - 去甲 - D3（Ro 27 - 2014）是效力最强的类似物[与1,25(OH)2D3相比活性增加了10倍]。使用Ro 27 - 2014进行了进一步研究。脉冲暴露研究表明，在液体培养中对Ro 27 - 2014（10(-7) M）进行5天的脉冲暴露足以在无该类似物的情况下使软琼脂中MCF - 7克隆生长受到50%的抑制，这表明该类似物介导的生长抑制是不可逆的。使用MCF - 7细胞进行的细胞周期分析表明，Ro 27 - 2014（10(-7) M处理4天）使G0 - G1期细胞数量显著增加（72.8±8.9%，而对照细胞为49.9±3.5%），同时S期细胞百分比相应减少（13.1±6.2%，而对照细胞为35.8±3.5%）。维生素D3化合物的主要毒性是高钙血症，因此，我们检测了Ro 27 - 2014在小鼠体内的血钙活性，发现每周腹腔注射3次0.05微克的剂量不会诱导高钙血症。相比之下，相同剂量的侧链带有6个氟原子的19 - 去甲维生素D3化合物（1,25 - (OH)2 - 16 - 烯 - 23 - 炔 - 26,27 - F6 - 19 - 去甲 - D3），尽管也具有强大的抗癌活性，但会导致严重的高钙血症（18毫克/分升）。总之，侧链去饱和并延长的19 - 去甲维生素D3化合物产生了一系列治疗指数良好、具有强大抗癌活性且毒性低的化合物。
