Hofer H, Ho G m, Peterlik M, Uskokovic M R, Lee J K, White M C, Posner G H, Cross H S
Department of General and Experimental Pathology, University of Vienna, Vienna, Austria.
J Pharmacol Exp Ther. 1999 Nov;291(2):450-5.
1alpha,25-dihydroxyvitamin D(3) and two synthetic analogs, 1alpha, 25-dihydroxy-16-ene-23-yne-vitamin D(3) (Ro 23-7553) and 1alpha, 25-dihydroxy-16-ene-24-oxo-vitamin D(3) (JK-1624-3), were tested for their ability to specifically inhibit growth and promote differentiation of human colon cancer cells in comparison with a series of 1beta-(hydroxymethyl) congeners of the natural hormone, such as 1beta-(hydroxymethyl)-3alpha,25(OH)(2)-16-ene,24-oxo-vitamin D(3) (JK-1624-2), 1beta-(hydroxymethyl)-3alpha, 25-dihydroxy-16-ene-26,27-dihomo vitamin D(3) (JK-1626-2), and 1beta-(hydroxymethyl)-3alpha,25-dihydroxy-22,24-diene-26,27- dihomo vitamin D(3) (MCW-EE). Western blot analysis revealed that reduction of cyclin D1 levels is a key mechanism by which the vitamin D compounds under investigation inhibit Caco-2 tumor cell growth. Both the 1alpha-hydroxy- as well as the 1beta-hydroxymethyl-type vitamin D compounds, which exhibit only low affinity for the vitamin D receptor, significantly reduced [(3)H]thymidine DNA labeling in confluent Caco-2 cell cultures. This suggests that high-affinity binding to the vitamin D receptor is not an absolute prerequisite for genomic action on tumor cell growth. Hybrid analogs JK-1624-2 and MCW-EE, although antimitotically active, were rather ineffective in promoting phenotypic differentiation of human colon cancer cells. However, because both compounds also do not promote osteoclast differentiation from hematopoetic bone marrow cells, they still could be used as antimitotic agents in cancer therapy, even at dose levels that, with other analogs, could cause hypercalcemia.
将1α,25 - 二羟基维生素D(3)及其两种合成类似物，即1α,25 - 二羟基 - 16 - 烯 - 23 - 炔 - 维生素D(3)（Ro 23 - 7553）和1α,25 - 二羟基 - 16 - 烯 - 24 - 氧代 - 维生素D(3)（JK - 1624 - 3），与一系列天然激素的1β - (羟甲基)类似物，如1β - (羟甲基) - 3α,25(OH)(2) - 16 - 烯,24 - 氧代 - 维生素D(3)（JK - 1624 - 2）、1β - (羟甲基) - 3α,25 - 二羟基 - 16 - 烯 - 26,27 - 二高维生素D(3)（JK - 1626 - 2）和1β - (羟甲基) - 3α,25 - 二羟基 - 22,24 - 二烯 - 26,27 - 二高维生素D(3)（MCW - EE）相比较，测试它们特异性抑制人结肠癌细胞生长和促进其分化的能力。蛋白质免疫印迹分析表明，细胞周期蛋白D1水平的降低是所研究的维生素D化合物抑制Caco - 2肿瘤细胞生长的关键机制。1α - 羟基型以及1β - 羟甲基型维生素D化合物对维生素D受体仅表现出低亲和力，但在汇合的Caco - 2细胞培养物中显著降低了[³H]胸腺嘧啶DNA标记。这表明与维生素D受体的高亲和力结合并非对肿瘤细胞生长产生基因组作用的绝对先决条件。杂合类似物JK - 1624 - 2和MCW - EE虽然具有抗有丝分裂活性，但在促进人结肠癌细胞的表型分化方面相当无效。然而，由于这两种化合物也不促进造血骨髓细胞分化为破骨细胞，即使在与其他类似物相比可能导致高钙血症的剂量水平下，它们仍可作为癌症治疗中的抗有丝分裂剂使用。
