Vink-van Wijngaarden T, Pols H A, Buurman C J, van den Bemd G J, Dorssers L C, Birkenhäger J C, van Leeuwen J P
Department of Internal Medicine III, Erasmus University, Rotterdam, The Netherlands.
Cancer Res. 1994 Nov 1;54(21):5711-7.
The steroid hormone 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] has potential to be used as an antitumor agent, but its clinical application is restricted by the strong calcemic activity. Therefore, new vitamin D3 analogues are developed with increased growth inhibitory and reduced calcemic activity. In the present study, we have examined the antiproliferative effects of four novel vitamin D3 analogues (CB966, EB1089, KH1060, and 22-oxa-calcitriol) on breast cancer cells, either alone or in combination with the antiestrogen tamoxifen. The estrogen-dependent ZR-75-1 and estrogen-responsive MCF-7 cell lines were used as a model. It was shown that, with EB1089 and KH1060, the same growth inhibitory effect as 1,25-(OH)2D3 could be reached at up to 100-fold lower concentrations, whereas CD966 and 22-oxa-calcitriol were nearly equipotent with 1,25-(OH)2D3. The growth inhibition by the vitamin D3 compounds could be augmented by combined treatment with tamoxifen. At the maximal effective concentrations of the vitamin D3 compounds, the effect of combined treatment was addictive (MCF-7 cells) or less than additive (ZR-75-1 cells). Tamoxifen increased the sensitivity of the cells to the vitamin D3 compounds 2- to 4000-fold, which was expressed by a shift to lower median effective concentration values. Thereby, the vitamin D3 compounds may be used at even lower dosages in combination therapy with tamoxifen. A major problem of tamoxifen therapy is the development of tamoxifen resistance. We have observed that tamoxifen-resistant clones of ZR-75-1 cells retain their response to the vitamin D3 compounds. Regulation of the growth-related oncogene c-myc (mRNA level) and the estrogen receptor (protein level) were studied but appeared not to be related to the antiproliferative action of the vitamin D3 compounds. Together, our data point to a potential benefit of combination therapy with 1,25-(OH)2D3 or vitamin D3 analogues and tamoxifen for the treatment of breast cancer.
类固醇激素1,25 - 二羟基维生素D3 [1,25-(OH)2D3] 有潜力用作抗肿瘤药物，但其临床应用受到强烈的血钙升高活性的限制。因此，人们开发了具有增强生长抑制作用和降低血钙活性的新型维生素D3类似物。在本研究中，我们研究了四种新型维生素D3类似物（CB966、EB1089、KH1060和22 - 氧杂骨化三醇）对乳腺癌细胞单独或与抗雌激素他莫昔芬联合使用时的抗增殖作用。以雌激素依赖性ZR - 75 - 1和雌激素反应性MCF - 7细胞系作为模型。结果表明，对于EB1089和KH1060，在浓度低至100倍的情况下就能达到与1,25-(OH)2D3相同的生长抑制效果，而CD966和22 - 氧杂骨化三醇与1,25-(OH)2D3几乎等效。维生素D3化合物与他莫昔芬联合治疗可增强生长抑制作用。在维生素D3化合物的最大有效浓度下，联合治疗的效果在MCF - 7细胞中是相加的，在ZR - 75 - 1细胞中则小于相加。他莫昔芬使细胞对维生素D3化合物的敏感性提高了2至4000倍，这表现为中位有效浓度值向更低水平偏移。因此，在与他莫昔芬的联合治疗中，维生素D3化合物可以使用更低的剂量。他莫昔芬治疗的一个主要问题是产生他莫昔芬耐药性。我们观察到ZR - 75 - 1细胞的他莫昔芬耐药克隆对维生素D3化合物仍有反应。我们研究了生长相关癌基因c - myc（mRNA水平）和雌激素受体（蛋白质水平）的调节，但似乎与维生素D3化合物的抗增殖作用无关。总之，我们的数据表明1,25-(OH)2D3或维生素D3类似物与他莫昔芬联合治疗乳腺癌可能有益。
