Hickish T, Cunningham D, Colston K, Millar B C, Sandle J, Mackay A G, Soukop M, Sloane J
Lymphoma Unit, Royal Marsden Hospital, Sutton, Surrey, UK.
Br J Cancer. 1993 Oct;68(4):668-72. doi: 10.1038/bjc.1993.406.
1,25(OH)2D3 promotes differentiation and has an antiproliferative effect in a variety of cell lines derived from the immunohaematopoetic system. alpha-Calcidol which is metabolised to 1,25(OH)2D3 has been shown to produce tumour regression in follicular low grade non-Hodgkin's lymphoma (NHL) and the dose limiting toxicity is hypercalcaemia. The cellular action of 1,25(OH)2D3 is mediated by binding to an intracellular protein, the vitamin D receptor (VDR). We have evaluated the activity of 1,25(OH)2D3 and its non-calcaemogenic analogue MC903 in the SU-DHL4 and SU-DUL5 B cell lines which carry the 14;18 translocation characteristic of follicular NHL, and also the expression of the VDR in a range of B cell NHLs. Both agents induced differentiation and had an antiproliferative effect on the SU-DHL4 and SU-DUL5 cell lines. However this occurred at a relatively high concentration (10(-7) M) which exceeds the physiological concentration of 1,25(OH)2D3 by approximately 10(3)-10(4)-fold. Expression of the VDR was low in each cell line and in the low grade lymphoma tumour samples. To account for the observed clinical response to 1 alpha OHD3 (alpha-calcidol) in follicular NHL a network is suggested whereby 1,25(OH)2D3 modulates the activity of CD4+T cells which have previously been shown to promote follicle centre cell proliferation. Vitamin D3 analogues may enable serum levels to be achieved which produce a direct action on follicular lymphoma cells without disturbing calcium metabolism.
1,25(OH)₂D₃可促进分化，并对源自免疫造血系统的多种细胞系具有抗增殖作用。可代谢为1,25(OH)₂D₃的阿法骨化醇已显示可使滤泡性低级别非霍奇金淋巴瘤（NHL）出现肿瘤消退，其剂量限制性毒性为高钙血症。1,25(OH)₂D₃的细胞作用是通过与细胞内蛋白质维生素D受体（VDR）结合来介导的。我们评估了1,25(OH)₂D₃及其非致高钙血症类似物MC903在携带滤泡性NHL特征性14;18易位的SU - DHL4和SU - DUL5 B细胞系中的活性，以及VDR在一系列B细胞NHL中的表达。两种药物均可诱导分化，并对SU - DHL4和SU - DUL5细胞系具有抗增殖作用。然而，这发生在相对较高的浓度（10⁻⁷M），该浓度比1,25(OH)₂D₃的生理浓度高出约10³ - 10⁴倍。每个细胞系以及低级别淋巴瘤肿瘤样本中VDR的表达均较低。为了解释在滤泡性NHL中观察到的对1αOHD₃（阿法骨化醇）的临床反应，有人提出了一个网络，即1,25(OH)₂D₃调节CD4⁺T细胞的活性，此前已表明CD4⁺T细胞可促进滤泡中心细胞增殖。维生素D₃类似物可能使血清水平达到既能对滤泡性淋巴瘤细胞产生直接作用又不干扰钙代谢的程度。
