Genzyme Corporation, 49 New York Ave, Framingham, MA 01701-9322, USA.
Cancer Chemother Pharmacol. 2011 Dec;68(6):1537-46. doi: 10.1007/s00280-011-1658-0. Epub 2011 Apr 28.
To investigate the activity and myeloprotective properties of erufosine, a novel alkylphosphocholine (APC), on human malignant cells and normal bone marrow cells.
Human or mouse bone marrow cells were exposed to erufosine, miltefosine, perifosine, or edelfosine in CFU-GM assays. Human MDA-MB-231 breast carcinoma, Panc-1 pancreatic carcinoma, and RPMI8226 multiple myeloma cells were exposed to erufosine in colony formation assays. Colony formation of Panc-1 tumor cells and mouse bone marrow cells ex vivo were quantified following intravenous administration of erufosine to tumor-bearing mice. Western blotting methods were applied to human U87 glioblastoma cells exposed to erufosine to investigate Akt inhibition.
Erufosine was less toxic to human and mouse bone marrow cells than perifosine, miltefosine, and edelfosine and was equally toxic to human and mouse CFU-GM. The human cancer cells MDA-MB-231 breast, Panc-1 pancreatic, and RPMI8226 MM cells were more sensitive to erufosine in a colony formation assay than were human bone marrow cells generating an approximately tenfold differential in IC(90) values. Erufosine injected intravenously significantly reduced Panc-1 tumor cell colony formation ex vivo but not mouse bone marrow CFU-GM. Erufosine inhibited Akt phosphorylation in human U87 glioblastoma cells.
Erufosine offers potential as a novel therapeutic for cancer with a reduced toxicity profile to bone marrow cells compared with other agents in this class. Human cancer cells were more sensitive to erufosine than human or mouse bone marrow cells indicating a favorable therapeutic window for erufosine.
研究新型烷基磷酸胆碱（APC）依鲁替尼对人恶性细胞和正常骨髓细胞的活性和骨髓保护作用。
在 CFU-GM 测定中，将人或鼠骨髓细胞暴露于依鲁替尼、米替福新、培非司亭或埃德拉福辛中。在集落形成测定中，将人 MDA-MB-231 乳腺癌、Panc-1 胰腺癌细胞和 RPMI8226 多发性骨髓瘤细胞暴露于依鲁替尼中。在荷瘤小鼠静脉给予依鲁替尼后，定量检测 Panc-1 肿瘤细胞和鼠骨髓细胞的集落形成。应用 Western blot 方法研究人 U87 神经胶质瘤细胞中依鲁替尼对 Akt 抑制的作用。
与培非司亭、米替福新和埃德拉福辛相比，依鲁替尼对人及鼠骨髓细胞的毒性更小，对人及鼠 CFU-GM 的毒性相同。人乳腺癌细胞 MDA-MB-231、胰腺癌细胞 Panc-1 和多发性骨髓瘤细胞 RPMI8226 在集落形成测定中比人骨髓细胞对依鲁替尼更为敏感，IC90 值差异约为 10 倍。静脉内注射依鲁替尼可显著降低 Panc-1 肿瘤细胞的体外集落形成，但不降低鼠骨髓 CFU-GM。依鲁替尼可抑制人 U87 神经胶质瘤细胞中 Akt 的磷酸化。
与该类中的其他药物相比，依鲁替尼为具有降低骨髓细胞毒性的新型癌症治疗药物提供了潜力。人癌细胞对依鲁替尼的敏感性高于人或鼠骨髓细胞，这表明依鲁替尼具有良好的治疗窗口。
