Nandy P, Periclou A P, Avramis V I
Department of Pediatrics, School of Medicine, University of Southern California, Childrens Hospital Los Angeles, CA 90027, USA.
Anticancer Res. 1998 Mar-Apr;18(2A):727-37.
The only effective drug against ALL that inhibits protein synthesis is Asparaginase (ASNase). The drug depletes asparagine (Asn) in serum and cells and since the leukemic T-cells (thymic origin cells) lack asparagine synthetase, the amino acid starvation leads to apoptosis. When PEG-ASNase is combined with antimetabolite drugs such as ara-C, or combinations of 6-MP followed by ara-C, it augments the cytotoxic effect synergistically against human T-leukemia cells.
Synergism studies with two- or three-drug combination regimens in the human leukemia cell lines, CEM/0 and CEM/ara-C/7A have been investigated along with its effect in inducing apoptosis.
The IC50 (approximately Dm) values of ara-C were 0.032 microM and 0.11 microM, and that of PEG-ASNase were 0.002 IU/ml and 1.52 IU/ml against CEM/0 and CEM/ara-C/7A cells, respectively. Thus, CEM/ara-C/7A cell line that is partially resistant to ara-C exhibited 681-fold cross-resistant to PEG-ASNase as compared to CEM/0. The concurrent drug exposure of ara-C and PEG-ASNase for 48 hours resulted in IC50 values of 0.56 nM for ara-C and 0.56 mIU/ml for PEG-ASNase respectively, in CEM/0 cells which represents a 57.4-fold synergism compared to ara-C alone. In the CEM/ara-C/7A cell line, the co-incubation with these two drugs resulted in IC50 value of 0.015 microM for ara-C and 0.015 IU/ml for PEG-ASNase respectively, or a 7.25-fold synergism as compared to ara-C and 101.1-fold synergism in comparison with PEG-ASNase alone. Pre-clinical studies involving three-drug combination consisting of 6-MP, ara-C and PEG-ASNase in a sequence-specific manner showed a 15.6-fold synergism against CEM/0 cell line over the two-drug combination of 6-MP followed by ara-C or approximately 160-fold syneryism over ara-C alone.
The two-drug combination of ara-C and PEG-ASNase or the three-drug combination of 6-MP, ara-C and PEG-ASNase in the ara-C sensitive and resistant cell line showed significant drug synergism and CEM/ara-C/7A cells exhibited collateral sensitivity to PEG-ASNase. The three-drug combination also induced dose-dependent apoptotic DNA fragmentation which was higher than the two-drug combination of 6-MP and ara-C. We also conclude that the sequence specific use of PEG-ASNase in combination with the nucleoside analog drugs may benefit leukemia patients in early relapse.
唯一一种有效抑制蛋白质合成来治疗急性淋巴细胞白血病（ALL）的药物是天冬酰胺酶（ASNase）。该药物会消耗血清和细胞中的天冬酰胺（Asn），由于白血病T细胞（胸腺起源细胞）缺乏天冬酰胺合成酶，氨基酸饥饿会导致细胞凋亡。当聚乙二醇化天冬酰胺酶（PEG - ASNase）与抗代谢药物如阿糖胞苷（ara - C）联合使用，或与6 - 巯基嘌呤（6 - MP）后接阿糖胞苷的联合用药方案联合使用时，它对人T白血病细胞具有协同增强的细胞毒性作用。
研究了在人白血病细胞系CEM/0和CEM/ara - C/7A中两种或三种药物联合治疗方案的协同作用及其诱导细胞凋亡的效果。
ara - C对CEM/0和CEM/ara - C/7A细胞的半数抑制浓度（IC50，约为Dm）值分别为0.032微摩尔/升和0.11微摩尔/升，PEG - ASNase对这两种细胞的IC50值分别为0.002国际单位/毫升和1.52国际单位/毫升。因此，对ara - C部分耐药的CEM/ara - C/7A细胞系与CEM/0相比，对PEG - ASNase表现出681倍的交叉耐药性。在CEM/0细胞中，ara - C和PEG - ASNase同时暴露48小时后，ara - C的IC50值为0.56纳摩尔/升，PEG - ASNase的IC50值为0.56毫国际单位/毫升，与单独使用ara - C相比，显示出57.4倍的协同作用。在CEM/ara - C/7A细胞系中，这两种药物共同孵育后，ara - C的IC50值为0.015微摩尔/升，PEG - ASNase的IC50值为0.015国际单位/毫升，与ara - C单独使用相比有7.25倍的协同作用，与单独使用PEG - ASNase相比有101.1倍的协同作用。涉及按特定顺序使用6 - MP、ara - C和PEG - ASNase的三药联合的临床前研究表明，与6 - MP后接ara - C的两药联合相比，对CEM/0细胞系有15.6倍的协同作用，或与单独使用ara - C相比有大约160倍的协同作用。
在对ara - C敏感和耐药的细胞系中，ara - C与PEG - ASNase的两药联合或6 - MP、ara - C和PEG - ASNase的三药联合显示出显著的药物协同作用，并且CEM/ara - C/7A细胞对PEG - ASNase表现出间接敏感性。三药联合还诱导了剂量依赖性的凋亡DNA片段化，其程度高于6 - MP和ara - C的两药联合。我们还得出结论，PEG - ASNase与核苷类似物药物按特定顺序联合使用可能使早期复发的白血病患者受益。
