十七碳烯丙基磷酰三甲基丙铵（erufosine）是一种潜在的无髓毒性骨髓瘤治疗药物。

Erucylphospho-N,N,N-trimethylpropylammonium (erufosine) is a potential antimyeloma drug devoid of myelotoxicity.

机构信息

Laboratory for Experimental Chemotherapy, Dept. of Pharmacology, Pharmacotherapy and Toxicology, Faculty of Pharmacy, Medical University of Sofia, Dunav 2, 1000 Sofia, Bulgaria.

出版信息

Cancer Chemother Pharmacol. 2011 Jan;67(1):13-25. doi: 10.1007/s00280-010-1273-5. Epub 2010 Feb 23.

DOI:10.1007/s00280-010-1273-5

PMID:20177898

Abstract

PURPOSE

Erufosine is an i.v. injectable alkylphosphocholine which is active against various haematological malignancies in vitro. In the present study, its effects on multiple myeloma (MM) cell lines and on murine and human hematopoietic progenitor cells (HPCs) were investigated.

METHODS

The following MM cell lines were used: RPMI-8226, U-266 and OPM-2. The cytotoxicity of erufosine against these cell lines was determined by the MTT-dye reduction assay. Bcl-2, Bcl-X(L) and pAkt expression levels, activation of caspases, as well as cleavage of PARP, were studied by Western blotting. Migration was evaluated by a modified Boyden-chamber assay. The haematologic toxicity of erufosine was assessed using clonogenicity assays with normal HPCs of murine or human origin.

RESULTS

Significant cytotoxic activity of erufosine against the MM cell lines was found. Comparison of the characteristics of erufosine-induced cell death in the three cell lines revealed a complex mode of action with apoptotic mechanisms prevailing in OPM-2 cells and non-apoptotic mechanisms prevailing in U-266 cells. The sensitivity of the MM cell lines to erufosine-induced apoptosis correlated inversely with the Bcl-X(L) expression level. Erufosine participated in synergistic interactions with various drugs. Furthermore, it showed potent migration-inhibiting activity in RPMI-8226 cells. Erufosine was not toxic to normal HPCs of murine or human origin and even stimulated progenitors from human umbilical cord blood to form granulocyte/macrophage colonies. Moreover, erufosine ameliorated the toxicity of bendamustine to murine HPCs.

CONCLUSIONS

Overall, the data presented reveal that erufosine could have potential as an antimyeloma drug and deserves further development.

摘要

目的

依鲁替尼是一种静脉注射用烷基膦胆碱，在体外对多种血液系统恶性肿瘤均有活性。本研究旨在观察其对多发性骨髓瘤（MM）细胞系及鼠和人造血祖细胞（HPC）的作用。

方法

采用 RPMI-8226、U-266 和 OPM-2 三种 MM 细胞系，通过 MTT 染料还原法检测依鲁替尼对这些细胞系的细胞毒性。采用 Western blot 法检测 Bcl-2、Bcl-X（L）和 pAkt 表达水平、半胱氨酸天冬氨酸蛋白酶（caspase）的激活以及聚（ADP-核糖）聚合酶（PARP）的裂解情况。通过改良 Boyden 室测定法评估迁移能力。采用克隆形成试验检测正常鼠源和人源 HPC 的血液学毒性。

结果

依鲁替尼对 MM 细胞系具有显著的细胞毒性。比较三种细胞系中依鲁替尼诱导的细胞死亡特征，发现其作用机制复杂，凋亡机制在 OPM-2 细胞中占主导地位，而非凋亡机制在 U-266 细胞中占主导地位。MM 细胞系对依鲁替尼诱导的细胞凋亡的敏感性与 Bcl-X（L）表达水平呈负相关。依鲁替尼与多种药物具有协同作用。此外，它对 RPMI-8226 细胞具有显著的迁移抑制活性。依鲁替尼对鼠源和人源 HPC 均无毒性，甚至能刺激人脐血来源的祖细胞形成粒细胞/巨噬细胞集落。此外，依鲁替尼能减轻苯达莫司汀对鼠 HPC 的毒性。