Modulation of metabolism and cytotoxicity of cytosine arabinoside with N-(phosphon)-acetyl-L-aspartate in human leukemic blast cells and cell lines
Modulation of metabolism and cytotoxicity of cytosine arabinoside with N-(phosphon)-acetyl-L-aspartate in human leukemic blast cells and cell lines
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DOI：
10.1016/0145-2126(95)00071-2
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发表时间：
1996-02-01
影响因子：
2.7
通讯作者：
Peters, GJ
中科院分区：
文献类型：
--
作者：
Noordhuis, P;Kazemier, KM;Peters, GJ
胞嘧啶阿糖苷 (Ara-C) 活化为胞嘧啶阿糖苷三磷酸 (Ara-CTP) 以及随后掺入 DNA 的过程受嘧啶核苷酸 UTP、CTP 和 dCTP 的调节。 N-(膦)-乙酰基-L-天冬氨酸 (PALA) 抑制这些嘧啶核苷酸的从头合成可能会增强 Ara-C 的细胞毒性。因此，我们研究了 PALA 对 Ara-C 细胞毒性以及 Ara-CTP 积累和掺入细胞系和患者样本 DNA 的影响。预孵育和共孵育时，50 微摩尔 PALA 使 U937 细胞中 Ara-C 的生长抑制作用增加数倍。 PALA 在 HL60 细胞中并未增强 Ara-C 细胞毒性。然而，与 PALA 共孵育并不会增强 HL60 和 U937 细胞中 Ara-CTP 的积累，也不会影响 Ara-C 掺入 DNA。仅在 2 例病例中，Ara-C 对来自 11 名未经治疗的不同类型白血病患者的白血病母细胞的细胞毒性仅在很小程度上受到高 PALA 浓度的调节。白血病母细胞中 Ara-CTP 的积累量从不可检测的水平到 200 pmol/10(6) 细胞不等。 50 微摩尔 PALA 仅在一名患者中显着增强了 Ara-CTP 的积累，但对 UTP 和 CTP 水平没有明显影响。将 PALA 提高至 500 μM，UTP 和 CTP 水平降低至 50%，但对 Ara-CTP 水平没有影响。 总之，PALA 对 Ara-C 细胞毒性和代谢的调节在培养物和患者的白血病细胞中都是有限的。这表明 PALA 对非血液细胞选择性调节其他药物的可能性。
Cytosine arabinoside (Ara-C) activation to cytosine arabinoside triphosphate (Ara-CTP) and subsequent incorporation into DNA is regulated by the pyrimidine nucleotides UTP, CTP and dCTP. Inhibition of the de novo synthesis of these pyrimidine nucleotides by N-(phosphon)-acetyl-L-aspartate (PALA) may enhance the cytotoxicity of Ara-C. We therefore studied the effect of PALA on Ara-C cytotoxicity and on Ara-CTP accumulation and incorporation into DNA on cell lines and patient samples. Fifty micromolar PALA increased the growth inhibitory effect of Ara-C in U937 cells several fold both with pre- and coincubation. Ara-C cytotoxicity was not potentiated by PALA in HL60 cells. However, coincubation with PALA did not enhance Ara-CTP accumulation both in HL60 and U937 cells, nor affect Ara-C incorporation into DNA.Ara-C cytotoxicity to leukemic blast cells from 11 untreated patients with different types of leukemia was only modulated to a small extent by high PALA concentrations in only two cases. Ara-CTP accumulation in leukemic blast cells varied from non-detectable levels to 200 pmol/10(6) cells. Fifty micromolar PALA enhanced the accumulation of Ara-CTP significantly in only one patient with no apparent effect on UTP and CTP levels. Raising PALA to 500 mu M decreased UTP and CTP levels to 50% but had no effect on Ara-CTP levels.In conclusion, modulation by PALA of Ara-C cytotoxicity and metabolism is limited in leukemic cells, both in culture and from patients. This suggests the possibility for selective modulation of other agents by PALA on non-hematological cells.