Niitsu N, Yamamoto-Yamaguchi Y, Kanatani Y, Shuto S, Matsuda A, Umeda M, Honma Y
Department of Chemotherapy, Saitama Cancer Center Research Institute, Ina, Japan.
Exp Hematol. 1997 Nov;25(12):1296-303.
Several neplanocin A analogs were synthesized and their growth-inhibiting and differentiation-inducing activities on myelogenous leukemia cells were examined. An adenosine kinase-ineffective analog of neplanocin A was effective in inducing differentiation, suggesting that phosphorylation of the nucleoside is not essential for inducing the differentiation of leukemia cells. Neplanocin A induced functional and morphological differentiation of HL-60 cells, but did not effectively induce differentiation of NB4, a cell line derived from a leukemia patient with t(15;17). However, these cells have been known to undergo granulocytic differentiation upon treatment with all-trans retinoic acid (ATRA), and are used as a model for differentiation therapy in acute promyelocytic leukemia. Preexposure of NB4 cells to low concentrations of neplanocin A greatly enhanced the ATRA-induced differentiation of the cells, whereas representative antileukemic drugs such as cytosine arabinoside and daunomycin did not enhance this differentiation. A clinical strategy that combines intermittent treatment with neplanocin A analogs and a low dose of ATRA may increase the clinical response and decrease the adverse effects of ATRA.
合成了几种奈拉滨A类似物，并检测了它们对髓性白血病细胞的生长抑制和诱导分化活性。一种对腺苷激酶无效的奈拉滨A类似物在诱导分化方面有效，这表明核苷的磷酸化对于诱导白血病细胞分化并非必不可少。奈拉滨A诱导HL-60细胞发生功能和形态学分化，但不能有效诱导源自一名患有t(15;17)白血病患者的NB4细胞系的分化。然而，已知这些细胞在用全反式维甲酸（ATRA）处理后会发生粒细胞分化，并被用作急性早幼粒细胞白血病分化治疗的模型。将NB4细胞预先暴露于低浓度的奈拉滨A可极大地增强ATRA诱导的细胞分化，而代表性的抗白血病药物如阿糖胞苷和柔红霉素则不会增强这种分化。将奈拉滨A类似物的间歇治疗与低剂量ATRA相结合的临床策略可能会提高临床反应并减少ATRA的不良反应。
