Japan Medical Affairs, Japan Oncology Business Unit, Takeda Pharmaceutical Company Limited, 1-1 Nihonbashi Honcho 2-chome, Chuo-ku, Tokyo, 103-8668, Japan.
Integrated Biology, Integrated & Translational Science, Axcelead Drug Discovery Partners, Inc., 26-1, Muraoka-Higashi 2-chome Fujisawa, Kanagawa, 251-0012, Japan.
Cancer Chemother Pharmacol. 2024 Feb;93(2):137-149. doi: 10.1007/s00280-023-04609-5. Epub 2023 Nov 3.
Peripheral T-cell lymphoma (PTCL) is an aggressive disease with a poor prognosis. Brentuximab vedotin (BV), an anti-CD30 monoclonal antibody linked to a microtubule-disrupting agent, has been approved for the treatment of PTCL. We evaluated a new effective combination partner of BV using non-clinical approaches that could potentially identify agents capable of improving survival times for patients with PTCL.
A high-throughput screening test was used to select the most synergistic partner of BV from 14 candidate drugs that were under development or available in clinical practice for PTCL. HH cells, originating from an aggressive cutaneous T-cell lymphoma, were used as an experimental model of PTCL. Apoptotic effects of the synergistic partner of BV were further investigated in vitro and in vivo using HH-cell xenograft mice.
Chidamide (tucidinostat), a novel histone deacetylase inhibitor, was found to have the greatest synergistic effect with BV on HH cells. The combined effects of chidamide and BV were demonstrated in a study of HH-cell xenograft mice; mean tumor size following combined treatment was 22% of that observed in the control group, compared with 71% and 58% following chidamide and BV monotherapy, respectively. Further investigations in vitro and in vivo revealed that the levels of an anti-apoptotic protein, Bcl-2, and a rate-limiting factor of DNA replication, CDC45, were reduced in HH cells treated with chidamide combined with BV compared with the control group.
The use of chidamide in conjunction with BV may positively affect and enhance T-cellular apoptotic pathways without offsetting each other.
外周 T 细胞淋巴瘤（PTCL）是一种侵袭性疾病，预后不良。 Brentuximab vedotin（BV），一种与微管破坏剂连接的抗 CD30 单克隆抗体，已被批准用于治疗 PTCL。我们使用非临床方法评估了 BV 的一种新的有效联合伙伴，这可能有助于鉴定能够提高 PTCL 患者生存时间的药物。
使用高通量筛选试验从 14 种候选药物中选择与 BV 最协同的伙伴，这些候选药物正在开发中或在临床上用于治疗 PTCL。HH 细胞来源于侵袭性皮肤 T 细胞淋巴瘤，被用作 PTCL 的实验模型。在体外和体内使用 HH 细胞异种移植小鼠进一步研究了 BV 协同伙伴的凋亡作用。
发现新型组蛋白去乙酰化酶抑制剂西达本胺（tucidinostat）与 BV 对 HH 细胞具有最大的协同作用。在 HH 细胞异种移植小鼠的研究中证明了西达本胺和 BV 的联合作用；联合治疗后平均肿瘤大小为对照组的 22%，而西达本胺和 BV 单药治疗后分别为 71%和 58%。进一步的体外和体内研究表明，与对照组相比，用西达本胺联合 BV 处理的 HH 细胞中抗凋亡蛋白 Bcl-2 和 DNA 复制的限速因子 CDC45 的水平降低。
与 BV 联合使用西达本胺可能会积极影响并增强 T 细胞凋亡途径，而不会相互抵消。
