Avramis V I, Nandy P, Kwock R, Solorzano M M, Mukherjee S K, Danenberg P, Cohen L J
Division of Hematology/Oncology, Childrens Hospital Los Angeles, CA 90027, USA. vavramis%
Anticancer Res. 1998 Jul-Aug;18(4A):2327-38.
Combinations of nucleoside analog drugs, such as F-araA and ara-C, combined with Topoisomerase II inhibitors, such as anthracyclines, are synergistic against human leukemic T-cells and induce apoptotic cell death. Similarly, nucleoside analog drugs followed by mitotic inhibitors also have a synergistic effect. Sequence specific combinations of F-araA followed by ara-C and Taxotere (docetaxel) in CEM/0 cells showed a 2- to 3-fold synergism over the two drug (F-araA + ara-C) combinations and 2- to 4-fold synergism over Taxotere alone. This synergism was evident due to enhanced cellular apoptosis. In the CEM/ara-C/7A cell line, which is partially resistant to ara-C, the synergy observed with the triple drug combination was 9-fold greater than the F-araA plus araC combination, and 3-fold greater than Taxotere alone, making this three-drug regimen collaterally sensitive to ara-C. This study describes the mechanisms of the synergistic effect in regards to apoptosis achieved by three-drug regimens comprised of two nucleoside analog drugs and a mitotic inhibitor in comparison with the combination of two nucleotide analog drugs. The study also demonstrates that the possible biochemical mechanism of cellular toxicity and drug synergism is attributed to induction of apoptosis following drug treatment and the onset of the apoptotic cascade is primarily regulated by p21/WAF-I, which is transcriptionally activated by p53 following DNA damage. The anti-apoptotic protein, bcl-2, seemed to have no effect in inhibiting apoptosis following treatment with the two or three drug regimens in this in vitro leukemia model. The three-drug combination induced greater cellular apoptosis than the two-drug combination or Taxotere monotherapy. We conclude that the greater drug synergism observed in human leukemic cells, sensitive or resistant to ara-C, by Fludarabine + ara-C + Taxotere can be explained by the greater oligonucleosomal DNA fragmentation indicative of increased cellular apoptosis. The mechanism of this increased cytotoxic action is due to the upregulation of p53 and p21/WAF-1 with a down regulation of bcl-2. These studies are encouraging, and testing this three drug regimen in a clinical setting may result in improved antileukemic therapies.
核苷类似物药物（如氟阿糖腺苷和阿糖胞苷）与拓扑异构酶II抑制剂（如蒽环类药物）联合使用，对人白血病T细胞具有协同作用，并诱导凋亡性细胞死亡。同样，核苷类似物药物之后使用有丝分裂抑制剂也具有协同作用。在CEM/0细胞中，先使用氟阿糖腺苷再使用阿糖胞苷以及多西他赛的序列特异性组合，相较于两种药物（氟阿糖腺苷 + 阿糖胞苷）组合显示出2至3倍的协同作用，相较于单独使用多西他赛显示出2至4倍的协同作用。这种协同作用因细胞凋亡增强而明显。在对阿糖胞苷部分耐药的CEM/ara-C/7A细胞系中，三联药物组合观察到的协同作用比氟阿糖腺苷加阿糖胞苷组合大9倍，比单独使用多西他赛大3倍，使得这种三联药物方案对阿糖胞苷具有旁敏感性。本研究描述了由两种核苷类似物药物和一种有丝分裂抑制剂组成的三联药物方案与两种核苷酸类似物药物组合相比，在凋亡方面协同作用的机制。该研究还表明，细胞毒性和药物协同作用的可能生化机制归因于药物治疗后凋亡的诱导，且凋亡级联反应的启动主要由p21/WAF-1调节，p21/WAF-1在DNA损伤后由p53转录激活。在这个体外白血病模型中，抗凋亡蛋白bcl-2在两种或三种药物方案治疗后似乎对抑制凋亡没有作用。三联药物组合诱导的细胞凋亡比两种药物组合或多西他赛单药治疗更多。我们得出结论，在对阿糖胞苷敏感或耐药的人白血病细胞中，氟达拉滨 + 阿糖胞苷 + 多西他赛观察到的更大药物协同作用可以通过更大程度的寡核小体DNA片段化来解释，这表明细胞凋亡增加。这种细胞毒性作用增加的机制是由于p53和p21/WAF-1上调以及bcl-2下调。这些研究令人鼓舞，在临床环境中测试这种三联药物方案可能会改善抗白血病治疗。
