APOPTOTIC CELL-DEATH DURING TREATMENT OF LEUKEMIAS
APOPTOTIC CELL-DEATH DURING TREATMENT OF LEUKEMIAS
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DOI：
10.3109/10428199409052678
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发表时间：
1994-01-01
影响因子：
2.6
通讯作者：
DARZYNKIEWICZ, Z
中科院分区：
文献类型：
--
作者：
LI, X;GONG, JP;DARZYNKIEWICZ, Z
对110余例不同类型白血病（ALL、AML、CML急变期、APL）患者化疗前和化疗中外周血和骨髓单个白血病细胞进行了原位DNA链断裂检测。在外源性末端脱氧核苷酸转移酶催化的反应中，用地高辛或生物素缀合的dUTP标记DNA链断裂，并用双变量流式细胞术分析细胞的DNA复染。治疗前DNA链断裂的细胞比例（最有可能反映自发性细胞凋亡）从0.1%到16%不等，但在大多数情况下低于3%。给药不同种类的药物，包括DNA拓扑异构酶I（拓扑替康）和II（米托蒽醌，VP-16）抑制剂，抗代谢药（阿糖胞苷）或微管毒药（紫杉醇），都引发了细胞的出现广泛的DNA断裂，典型的凋亡，高达80%。以DNA链断裂细胞的最大百分比测量的反应峰值，在个体患者之间变化多达10倍，通常在DNA拓扑异构酶抑制剂初始给药后8至24小时之间观察到，并且在对紫杉醇或阿糖胞苷的反应期间稍晚（48-72小时）。因此，数据显示，在诱导细胞凋亡方面，可以通过本方法方便地测量对用各种药物治疗的响应。在正在进行的前瞻性研究中，对每种类型白血病的治疗前和治疗期间凋亡指数的预后价值进行了评估。
The apoptosis-associated DNA strand breaks were detected in situ, in individual leukemic cells in peripheral blood and bone marrow of over 110 patients with different types of leukemia (ALL, AML, CML in blastic crisis, APL), prior to and during routine chemotherapy. The DNA strand breaks were labeled with digoxigenin- or biotin-conjugated dUTP in the reaction catalyzed by exogenous terminal deoxynucleotidyl transferase, and the cells, counterstained for DNA, were analyzed by bivariate flow cytometry. The proportion of cells with DNA strand breaks prior to therapy, most likely reflecting spontaneous apoptosis, varied from 0.1 to 16%, but in the large majority of cases was below 3%. Administration of drugs of different classes, which included DNA topoisomerase I (Topotecan) and II (mitoxantrone, VP-16) inhibitors, antimetabolite (ara-C) or microtubule poison (Taxol), all triggered the appearance of cells with extensive DNA breakage, typical of apoptosis, to up to 80%. The peak of the response, measured as maximal percent of cells with DNA strand breaks, which varied between individual patients by as much as factor 10, was generally seen between 8 to 24 h after the initial administration of DNA topoisomerase inhibitors, and somewhat later (48-72 h) during the response to Taxol or ara-C. Thus, the data show that the response to treatment with a variety of drugs, in terms of induction of apoptosis, can be conveniently measured by the present method. The prognostic value of the apoptotic index, before, as well as during treatment, is being estimated for each type of leukemia, in the ongoing prospective studies.