目标:迄今为止,T细胞急性淋巴细胞白血病(T-ALL)的治疗选择仍然非常有限.本研究评估了单一疗法和联合疗法(包括选择性BCL-2抑制剂)对T-ALL细胞系的疗效。也就是Jurkat,CCRF-CEM,还有Loucy.
方法:Loucy是一种早期T前体ALL(ETP-ALL)细胞系,其特征是未成熟的表型,而Jurkat和CCRF-CEM是晚期T细胞祖细胞ALL(LTP-ALL)细胞系。用维奈托克进行单一疗法,阿糖胞苷,苯达莫司汀,或氮杂胞苷,而维奈托克加阿糖胞苷联合治疗,维奈托克加苯达莫司汀,或维奈托克加氮杂胞苷。48小时后使用台盼蓝和3-(4,5-二甲基噻唑-2-基)-5-(3-羧基甲氧基苯基)-2-(4-磺基苯基)-2H-四唑(MTS)进行细胞活力测定。通过使用SynergyFinderPlus和drcR包进行评估抗癌药物之间协同相互作用的统计分析。
结果:在阿糖胞苷中加入维奈托克,苯达莫司汀,或阿扎胞苷达到了累加效果,在Jurkat和CCRF-CEM中,Loewe的协同得分范围为-10至10。相反,维奈托克和阿糖胞苷的组合显示出累加效应(Loewe协同评分:MTS和台盼蓝测定的8.45和5.82,分别),而维奈托克加苯达莫司汀或阿扎胞苷在Loucy中表现出协同作用(MTS分析显示Loewe协同评分>10)。值得注意的是,Bliss/Loewe评分显示,维奈托克和苯达莫司汀的组合是最协同的,得分为13.832±0.55。
结论:维奈托克和苯达莫司汀的组合在抑制ETP-ALL细胞增殖方面表现出最大的协同作用。需要进一步的研究来确定维奈托克和苯达莫司汀在高危T-ALL中的协同作用机制。
OBJECTIVE: To date, therapeutic options for T-cell acute lymphoblastic leukemia (T-ALL) remain very limited. This study evaluated the efficacy of monotherapies and combination therapies including a selective BCL-2 inhibitor for T-ALL cell lines, namely Jurkat, CCRF-CEM, and Loucy.
METHODS: Loucy is an early T-precursor ALL (ETP-ALL) cell line characterized by an immature phenotype, whereas Jurkat and CCRF-CEM are late T-cell progenitor ALL (LTP-ALL) cell lines. Monotherapy was conducted with venetoclax, cytarabine,
bendamustine, or azacytidine, whereas combination therapy was performed with venetoclax plus cytarabine, venetoclax plus
bendamustine, or venetoclax plus azacytidine. Cell viability assay was conducted after 48 h using Trypan blue and the 3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS). Statistical analysis for evaluating synergistic interactions between anticancer drugs was performed by using the SynergyFinder Plus and drc R package.
RESULTS: Adding venetoclax to cytarabine,
bendamustine, or azacitidine achieved an additive effect, with Loewe synergic scores ranging from -10 to 10 in Jurkat and CCRF-CEM. Conversely, the combination of venetoclax and cytarabine displayed an additive effect (Loewe synergic score: 8.45 and 5.82 with MTS and Trypan blue assays, respectively), whereas venetoclax plus bendamustine or azacitidine exhibited a synergistic effect (Loewe synergic score >10 with MTS assay) in Loucy. Remarkably, the Bliss/Loewe score revealed that the combination of venetoclax and
bendamustine was the most synergistic, yielding a score of 13.832±0.55.
CONCLUSIONS: The combination of venetoclax and
bendamustine demonstrated the greatest synergistic effect in suppressing ETP-ALL cell proliferation. Further studies are warranted to determine the mechanisms for the synergism between venetoclax and bendamustine in high-risk T-ALL.