两种新的维生素D_3类似物对白血病细胞的体外作用

STUDY ON TWO NOVEL VITAMIN D3 ANALOGUES WITHPOTENT EFFECTS ON THE GROWTH ANDDIFFERENTIATION OF LEUKEMIA CELLS

为了寻找更加有效的诱导分化剂，我们测试了两种新的维生素Ｄ＿３类似物（ＥＢ１０８９和ＭＣ９０３）对人早幼粒细胞白血病细胞系（ＨＬ－６０）和人巨核细胞白血病细胞系（ＨＩＭｅｇ－１）的体外抑制生长和诱导分化作用。集落形成试验结果显示ＥＢ１０８９，ＭＣ９０３和１，２５（ＯＨ）＿２Ｄ＿３抑制ＨＬ－６０细胞生长的ＥＤ＿（５０）分别为９×１０￣（－９）ｍｏｌ／Ｌ，１×１０￣（－８）ｍｏｌ／Ｌ和７×１０￣（－８）ｍｏｌ／Ｌ它们抑制ＨＩＭｅｇ－１细胞生长的ＥＤ＿（５０）则分别为７×１０￣（－１１）ｍｏｌ／Ｌ，４．５×１０￣（－１０）ｍｏｌ／Ｌ和１×１０￣（－８）ｍｏｌ／Ｌ。形态学检查、硝基四氮唑蓝反应以及细胞表面分化抗原检测表明三者均可促使白血病细胞向成熟单核细胞分化。ＥＢ１０８９诱导分化活性最强，ＭＣ９０３和１，２５（ＯＨ）＿２Ｄ＿３相近。流式细胞仪分析得知：经上述诱导剂作用后，Ｇ＿０／Ｇ＿１期细胞增加，Ｓ期细胞减少。点杂交结果表明：上述诱导剂可使ｃ－ｍｙｃ癌基因ｍＲＮＡ表达迅速下降。本研究结果提示：ＥＢ１０８９和ＭＣ９０３（特别是前者）对白血病细胞的逆转作用强于１，２５（ＯＨ）＿２Ｄ＿３，以往研究表明它们的毒性作用却低于?

n order to find out new more potent differentiationinducers, We tested the effects of two novel vitamin D3analogues-EB1089 and MC903, and compared themwith 1 , 25-dihydroxyvrtamin D3 ( 1 , 25 (OH )_2D_3 ) , on thegrowth and differentiation of two human leukemic celllines (HL-60 and HIMeg-1 ). Colony formation testshowed that EB1089, MC903 and 1 , 25 (OH)_2D_3 couldinhibit the clonal growth markedly with ED50 doses of 9× 10￣(-9)mol/L, 10 × 10 ￣(-9)mol/L , 70×10￣(-9)mol/L. for HL-60 cells and with that of 7 × 10￣(-11)mol/L, 45 × 10 ￣(-11)mol/L, 1000 × 10 ￣(-11) mol/L, for HIMeg-1 cells, respec-tively. Meanwhile, the leukemic cells could be inducedinto rnore mature cells in Monotoid lineage, which wereconfirnied hy morphology examination . nitro letrozoliumblue reduction test and differentiation antigens assay.The cell cycle analysis measured hy flow cytometry alsoshowed the decrease of S phase cells in company with in-crease of G0 /G1 phase cells. Dot blot analysis showedlow levels of C-myc mRNA after the treatment of the drugs on HIMeg-1 cells. It was concluded that EB1089was much more potent than 25 (OH)_2D_2. and MC903 wascomparable to it on the growth and differentiation of theleukemic cells. In contrast. these two novel cornooundsappeared to be markedly less toxic than 1 , 25 (OH)_2D_3 inthe tnduction of hypercalcemia. So , both of EB1089 andMC903, especially the former, might hold promise asnew therapeutic agents in the treatment of leukemia andOther cancers.