Comparison of the toxicity and metabolism of 9-β-d-arabinofuranosyl-2-fluoroadenine and 9-β-d-arabinofuranosyladenine in human lymphobiastoid cells
Comparison of the toxicity and metabolism of 9-β-d-arabinofuranosyl-2-fluoroadenine and 9-β-d-arabinofuranosyladenine in human lymphobiastoid cells
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9-β-d-阿拉伯呋喃糖基-2-氟腺嘌呤和9-β-d-阿拉伯呋喃糖基腺嘌呤在人淋巴细胞中的毒性和代谢比较
DOI：
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发表时间：
1980
期刊：
影响因子：
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通讯作者：
J. Montgomery
中科院分区：
文献类型：
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作者：
W. Plunkett;S. Chubb;Lillie Alexander;J. Montgomery
在腺苷脱氨酶抑制剂脱氧考福霉素存在下，将 9-β-d-阿拉伯呋喃糖基-2-氟腺嘌呤 (F-ara-A)（一种腺苷脱氨酶抗性核苷类似物）的毒性和代谢与 9-β-d-阿拉伯呋喃糖基-2-氟腺嘌呤 (ara-A) 的毒性和代谢进行了比较。等浓度的 F-ara-A 和 ara-A 加脱氧考福霉素对 CCRF-CEM 人淋巴母细胞的生长产生类似的抑制作用。 9-β-d-阿拉伯呋喃糖基-2-氟腺嘌呤5′-三磷酸（F-ara-ATP）和9-β-d-阿拉伯呋喃糖基-2-氟腺嘌呤5′-三磷酸（F-ara-ATP）和9-β-d-阿拉伯呋喃糖基-2-氟腺嘌呤5′-三磷酸（ara-ATP）在细胞内集中积累，对DNA合成发挥主要抑制作用。使用两种方法来比较这些核苷酸类似物对全细胞 DNA 合成能力的影响。 (a)直接测定与各自核苷一起孵育的细胞中F-ara-ATP和ara-ATP的浓度，同时通过将[3H]胸苷掺入DNA来测量每种培养物中细胞的DNA合成能力。这两种化合物均不会显着影响细胞[3H]脱氧胸苷三磷酸的比活性。 (b) 测定了洗去核苷的细胞中 F-ara-ATP 和 ara-ATP 的消失率。这些值用于计算细胞中每种核苷酸类似物的细胞浓度，其中在与F-ara-A或ara-A加脱氧考福霉素一起孵育并洗入新鲜培养基后监测DNA合成能力。这些测定表明F-ara-ATP和ara-ATP的积累速率不同并且与外源核苷的浓度相关。 F-ara-ATP 在无药物培养基中从细胞中消失，其消失速度是 ara-ATP 消失速度的几倍。然而，在相同的细胞浓度下，F-ara-ATP 对胸苷掺入测量的过程的抑制作用比 ara-ATP 稍强。我们得出结论，F-ara-ATP 和 ara-ATP 具有相似的作用机制和抑制 DNA 合成的效力。事实上，F-ara-A 在没有腺苷脱氨酶抑制剂的情况下仍保留其细胞毒功效，这为进一步研究其抗肿瘤特性提供了依据。
The toxicity and metabolism of 9-β-d-arabinofuranosyl-2-fluoroadenine (F-ara-A), an adenosine deaminase-resistant nucleoside analog, have been compared to those of 9-β-d-arabinofuranosyladenine (ara-A) in the presence of the adenosine deaminase inhibitor, deoxycoformycin. Equal concentrations of F-ara-A and ara-A plus deoxycoformycin produced similar inhibition of growth of CCRF-CEM human lymphoblastoid cells. 9-β-d-Arabinofuranosyl-2-fluoroadenine 5′-triphosphate (F-ara-ATP) and 9-β-d-arabinofuranosyladenine 5′-triphosphate (ara-ATP), were concentratively accumulated intracellularly and exerted their major inhibitory effect on DNA synthesis. Two approaches were used to compare the effect of these nucleotide analogs on the DNA-synthetic capacity of whole cells. ( a ) The concentrations of F-ara-ATP and ara-ATP in cells incubated with the respective nucleosides were determined directly at the same time that the DNA-synthetic capacity of the cells in each culture was measured by incorporation of [3H]thymidine into DNA. Neither compound significantly affected the specific activity of cellular [3H]deoxythymidine triphosphate. ( b ) The rates of disappearance of F-ara-ATP and ara-ATP from cells washed free of the nucleosides were determined. These values were used to calculate the cellular concentration of each nucleotide analog in cells in which DNA-synthetic capacity was monitored after incubation with F-ara-A or ara-A plus deoxycoformycin and washed into fresh media. These determinations indicated that the rates of accumulation of F-ara-ATP and ara-ATP differed and were related to the concentration of the exogenous nucleoside. F-ara-ATP disappeared from cells in drug-free media at several times the rate of the disappearance of ara-ATP. However, at equal cellular concentrations, F-ara-ATP was slightly more inhibitory to the processes measured by thymidine incorporation than was ara-ATP. We conclude that F-ara-ATP and ara-ATP share a similar mechanism of action and potency of inhibition of DNA synthesis. The fact that F-ara-A retains its cytotoxic efficacy in the absence of inhibitors of adenosine deaminase provides a rationale for investigating its antitumor properties further.