Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Department of Oncology and Hemato-oncology, Università degli Studi di Milano, Milan, Italy.
Br J Cancer. 2019 Oct;121(7):567-577. doi: 10.1038/s41416-019-0557-8. Epub 2019 Sep 2.
Anthracycline-containing regimens, namely cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or CHOEP (CHOP + etoposide), represent the current standard of care for patients with newly diagnosed peripheral T-cell lymphomas (PTCLs), although responses are unsatisfactory. In this study, we investigated the pathways able to mitigate the sensitivity to CHOP-based regimens in preclinical models of T-cell lymphoma (TCL) to select agents for the development of CHOP-based drug combinations.
We performed gene expression profiling of malignant T-cell lines exposed to CHOEP; flow cytometry was employed to study the effects of drug combinations on cell viability, cell cycle distribution, apoptosis and mitochondrial membrane depolarisation. Western blot analyses were performed to study cell signalling downstream of the T-cell receptor and apoptosis. The in vivo effect of the drug combination was tested in xenograft models.
We highlighted a modulation of tyrosine kinases belonging to the T-cell receptor pathway upon chemotherapy that provided the rationale for combining the tyrosine kinase inhibitor dasatinib with CHOEP. Dasatinib improves CHOEP activity and reduces viability in vitro. Furthermore, combination treatment results in tumour growth inhibition in in vivo xenograft mouse models.
Our data provide the rationale for clinical testing of the dasatinib-CHOEP combination in patients with T-cell lymphoma.
含蒽环类药物的方案，即环磷酰胺、多柔比星、长春新碱和泼尼松（CHOP）或 CHOP+依托泊苷（CHOEP），是新诊断的外周 T 细胞淋巴瘤（PTCL）患者的当前标准治疗方法，尽管反应并不令人满意。在这项研究中，我们研究了能够减轻 T 细胞淋巴瘤（TCL）临床前模型中对 CHOP 为基础的方案的敏感性的途径，以选择用于开发基于 CHOP 的药物组合的药物。
我们对暴露于 CHOEP 的恶性 T 细胞系进行了基因表达谱分析；采用流式细胞术研究药物组合对细胞活力、细胞周期分布、凋亡和线粒体膜去极化的影响。进行 Western blot 分析以研究 T 细胞受体和凋亡下游的细胞信号转导。在异种移植模型中测试了药物组合的体内效果。
我们在化疗后强调了属于 T 细胞受体途径的酪氨酸激酶的调节，这为将酪氨酸激酶抑制剂 dasatinib 与 CHOEP 联合使用提供了依据。Dasatinib 增强了 CHOEP 的活性并降低了体外细胞活力。此外，联合治疗导致体内异种移植小鼠模型中的肿瘤生长抑制。
我们的数据为在 T 细胞淋巴瘤患者中测试 dasatinib-CHOP 联合治疗提供了依据。
