Kanatani Y, Makishima M, Ishikawa I, Ogasawara Y, Kawahara N, Motoyoshi K, Nagata N, Honma Y
Department of Chemotherapy, Saitama Cancer Center Research Institute, Japan.
Exp Hematol. 1998 Mar;26(3):198-206.
The novel uracil analog, 6-chloro-5-(2-propenyl)uracil (TI90), inhibited the growth of myeloid leukemia cells and induced morphologic and functional differentiation of the cells. Although TI90 was a weak inducer of differentiation, it greatly enhanced the growth inhibition and differentiation of the leukemia cells previously induced by 1alpha,25-dihydroxyvitamin D3 (VD3) or all-trans retinoic acid (ATRA). TI90 cooperated with VD3 much more effectively than with ATRA in inhibiting cell growth and inducing differentiation. It also decreased the effective concentration of VD3 to the 10(-10) M level. On the other hand, there was no significant synergy between VD3 and the other uracil analogs. TI90 did not affect VD3 metabolism or the number and affinity of VD3 receptors (VDR) in HL-60 cells. Signals from VD3 are predominantly mediated by VDR and the ligand-activated binding of VDR to vitamin D-responsive element (VDRE) as a heterodimer with the retinoid X receptor (RXR). According to the results of a gel shift assay, TI90 enhanced the intensity of the retarded band with synthetic VDRE oligomer in the presence of VD3, suggesting that TI90 increases the number of phosphorylated receptors by inhibiting phosphatase activity, and also stimulates the formation of a functional complex of VDR with RXR.
新型尿嘧啶类似物6-氯-5-(2-丙烯基)尿嘧啶（TI90）可抑制髓系白血病细胞的生长，并诱导这些细胞发生形态学和功能分化。尽管TI90是一种较弱的分化诱导剂，但它能极大地增强先前由1α,25-二羟基维生素D3（VD3）或全反式维甲酸（ATRA）诱导的白血病细胞的生长抑制和分化。在抑制细胞生长和诱导分化方面，TI90与VD3协同作用比与ATRA更有效。它还将VD3的有效浓度降低到10(-10) M水平。另一方面，VD3与其他尿嘧啶类似物之间没有明显的协同作用。TI90不影响HL-60细胞中VD3的代谢或VD3受体（VDR）的数量和亲和力。VD3的信号主要由VDR介导，且VDR作为与视黄酸X受体（RXR）的异二聚体与维生素D反应元件（VDRE）进行配体激活结合。根据凝胶迁移试验的结果，在VD3存在的情况下，TI90增强了与合成VDRE寡聚体结合的阻滞带强度，这表明TI90通过抑制磷酸酶活性增加了磷酸化受体的数量，并且还刺激了VDR与RXR形成功能性复合物。
