Inhibition of CCRF-CEM human leukemic lymphoblasts by triciribine (tricyclic nucleoside, TCN, NSC-154020). Accumulation of drug in cells and comparison of effects on viability, protein synthesis and purine synthesis.
Inhibition of CCRF-CEM human leukemic lymphoblasts by triciribine (tricyclic nucleoside, TCN, NSC-154020). Accumulation of drug in cells and comparison of effects on viability, protein synthesis and purine synthesis.
复制标题
三西利宾（三环核苷，TCN，NSC-154020）对 CCRF-CEM 人白血病淋巴细胞的抑制作用。
DOI：
10.1016/0006-2952(89)90684-9
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发表时间：
1989
影响因子：
5.8
通讯作者：
Massia,SP
中科院分区：
文献类型：
--
作者：
Moore,EC;Hurlbert,RB;Massia,SP
已知实验性抗肿瘤剂triciribine（三环核苷，TCN）可被腺苷激酶激活为磷酸TCN-P，并抑制细胞生长、嘌呤核苷酸合成和氨基酸与蛋白质的结合。我们在这篇论文中的目的是比较人类细胞系的完整细胞中的这些效应，作为在配套论文中描述的先决条件[Mooreet al.，Biochem.Pharmac.38，4045（1989）]中对它们的相互关系进行了更详细的酶学研究。TCN处理在6、30和90 μM浓度下分别暴露8天、8小时和2小时后，对CCRF-CEM人白血病淋巴母细胞克隆的抑制率> 50%。200 μ M TCN作用24小时，细胞内TCN-P的形成迅速、集中且基本完成，但TCN-P浓度不超过1.4mM（1.4nmol/106细胞）。在暴露于50 μM TCN 1.25至24小时的细胞中，甲酸掺入ATP和GTP的抑制最为迅速和强烈; ATP和GTP池减少多达40%（与对照相比）;甲酸掺入RNA嘌呤的抑制多达65%。亮氨酸掺入到蛋白质中被更适度地抑制高达40%，显然与细胞内TCN-P的浓度成比例，而不是培养基中的TCN。这些抑制发生在第一个2-4小时最迅速，此后才逐渐增加，而克隆能力的抑制更缓慢，更均匀的一段较长的时间。这些代谢效应本身都没有表现出与活力丧失的明显相关性。甲酸盐掺入甲酰甘氨酰胺核苷酸（FGAR，当积累在一个封锁阿扎胞苷）被TCN抑制急剧。TCN使次黄嘌呤掺入ATP的速率增加，而掺入GTP的速率降低。因此，TCN-P抑制嘌呤合成的主要部位在这些完整细胞中，是在新途径中合成FGAR之前的一个步骤，也是在IMP和GTP之间的一个额外位点。
The experimental antineoplastic agent triciribine (tricyclic nucleoside, TCN) is known to be activated to its phosphate TCN-P by adenosine kinase and to inhibit cell growth, purine nucleotide synthesis, and incorporation of amino acids into proteins. Our objective in this paper was to compare these effects in intact cells of a human cell line as a prerequisite to describing in a companion paper [Mooreet al., Biochem. Pharmac.38, 4045 (1989)] more detailed enzymic studies of their interrelationships. TCN treatment inhibited cloning of CCRF-CEM human leukemic lymphoblasts 50% at concentrations of 6, 30 and 90 μM with 8-day, 8-hr, and 2-hr exposures respectively. However, 6–20% of the cells survived exposure to 200 μM TCN for 24 hr. The intracellular formation of TCN-P from TCN was rapid, concentrative and essentially complete, but TCN-P did not exceed about 1.4 mM (1.4 nmol/106cells) at 200 μM TCN. In cells exposed to 50 μM TCN for 1.25 to 24 hr, formate incorporation into ATP and GTP was inhibited the most rapidly and strongly; pools of ATP and GTP were decreased as much as 40% (as compared with controls); and incorporation of formate into RNA purines was inhibited as much as 65%. Incorporation of leucine into protein was more moderately inhibited up to 40%, apparently in proportion to the concentration of intracellular TCN-P, rather than of the TCN in the medium. These inhibitions occurred most rapidly during the first 2–4 hr and increased only gradually thereafter, whereas cloning ability was inhibited more slowly and uniformly over a longer time period. No one of these metabolic effects by itself showed a clear correlation with the loss of viability. The incorporation of formate into formylglycinamide ribotide (FGAR, when accumulated at a blockade by azaserine) was inhibited drastically by TCN. The rate of incorporation of hypoxanthine into ATP was increased by TCN, whereas incorporation into GTP was decreased. Thus, the principal sites of inhibition of purine synthesis by TCN-P were shown in these intact cells to be at a step prior to synthesis of FGAR in thede novopathway and also at an additional site between IMP and GTP.