Kufe D, Spriggs D, Egan E M, Munroe D
Blood. 1984 Jul;64(1):54-8.
Cytosine arabinoside (Ara-C) is the most effective agent in the treatment of acute myelogenous leukemia. This agent incorporates in leukemic cell DNA, and the extent of this incorporation correlates with loss of clonogenic survival. The incorporated Ara-C residue behaves as a relative DNA chain terminator, and the extent of (Ara-C)DNA formation correlates with inhibition of DNA synthesis. The incorporation of Ara-C into DNA requires the formation of Ara-CTP, and previous measurements of this metabolite have also been correlated with cytotoxicity. Because it is clinically relevant to define biochemical parameters predictive of Ara-C cytotoxicity, the present studies were undertaken to determine the relationship among Ara-CTP pools, formation of (Ara-C)DNA, and loss of clonogenic survival. The results demonstrate that the incorporation of Ara-C into DNA is the single most powerful predictor of cell lethality. Furthermore, although there is a correlation between Ara-CTP pools or continuous cellular exposure to Ara-CTP and cell kill, these relationships are less significant than that obtained with formation of (Ara-C)DNA. The extent of Ara-C incorporation into DNA can be predicted by the product of the Ara-CTP level and time (T), thus supporting the concept that Ara-C incorporation is dependent on continuous exposure to the triphosphate metabolite. These findings support the formation of (Ara-C)DNA as a highly predictive parameter of lethal cellular events.
阿糖胞苷（Ara-C）是治疗急性髓性白血病最有效的药物。该药物掺入白血病细胞DNA中，这种掺入的程度与克隆形成存活能力的丧失相关。掺入的阿糖胞苷残基表现为相对的DNA链终止剂，（Ara-C）DNA的形成程度与DNA合成的抑制相关。阿糖胞苷掺入DNA需要形成阿糖胞苷三磷酸（Ara-CTP），此前对这种代谢产物的测量也与细胞毒性相关。由于确定预测阿糖胞苷细胞毒性的生化参数具有临床相关性，因此开展了本研究以确定Ara-CTP池、（Ara-C）DNA的形成与克隆形成存活能力丧失之间的关系。结果表明，阿糖胞苷掺入DNA是细胞致死性的最有力单一预测指标。此外，虽然Ara-CTP池或细胞持续暴露于Ara-CTP与细胞杀伤之间存在相关性，但这些关系不如（Ara-C）DNA形成所得到的关系显著。阿糖胞苷掺入DNA的程度可通过Ara-CTP水平与时间（T）的乘积来预测，从而支持了阿糖胞苷掺入依赖于持续暴露于三磷酸代谢产物这一概念。这些发现支持将（Ara-C）DNA的形成作为致死性细胞事件的高度预测参数。
