PDF(Pubmed)
Abstract：
Acute promyelocytic leukemia (APL) is characterized by rearrangements of the retinoic acid receptor, RARα, which makes all-trans retinoic acid (ATRA) highly effective in the treatment of this disease, inducing promyelocytes differentiation. Current therapy, based on ATRA in combination with arsenic trioxide, with or without chemotherapy, provides high rates of event-free survival and overall survival. However, a decline in the drug activity, due to increased ATRA metabolism and RARα mutations, is often observed over long-term treatments. Furthermore, dedifferentiation can occur providing relapse of the disease. In this study we evaluated fenretinide, a semisynthetic ATRA derivative, encapsulated in nanomicelles (nano-fenretinide) as an alternative treatment to ATRA in APL. Nano-fenretinide was prepared by fenretinide encapsulation in a self-assembling phospholipid mixture. Physico-chemical characterization was carried out by dinamic light scattering and spectrophotometry. The biological activity was evaluated by MTT assay, flow cytometry and confocal laser-scanning fluorescence microscopy. Nano-fenretinide induced apoptosis in acute promyelocytic leukemia cells (HL60) by an early increase of reactive oxygen species and a mitochondrial potential decrease. The fenretinide concentration that induced 90-100% decrease in cell viability was about 2.0 µM at 24 h, a concentration easily achievable in vivo when nano-fenretinide is administered by oral or intravenous route, as demonstrated in previous studies. Nano-fenretinide was effective, albeit at slightly higher concentrations, also in doxorubicin-resistant HL60 cells, while a comparison with TK6 lymphoblasts indicated a lack of toxicity on normal cells. The results indicate that nano-fenretinide can be considered an alternative therapy to ATRA in acute promyelocytic leukemia when decreased efficacy, resistance or recurrence of disease emerge after protracted treatments with ATRA.
摘要：
急性早幼粒细胞白血病（APL）的特征是视黄酸受体的重排，RARα,这使得全反式维甲酸（ATRA）在治疗这种疾病方面非常有效，诱导早幼粒细胞分化。目前的治疗,基于ATRA与三氧化二砷的组合，有或没有化疗，提供高的无事件生存率和总生存率。然而,药物活性下降，由于增加的ATRA代谢和RARα突变，在长期治疗中经常观察到。此外，去分化可以发生，提供疾病的复发。在这项研究中，我们评估了fenretinide，半合成ATRA衍生物，封装在纳米胶束（nano-fenretinide）中，作为APL中ATRA的替代治疗。通过将fenretinide封装在自组装磷脂混合物中制备纳米fenretinide。通过dinamic光散射和分光光度法进行了物理化学表征。通过MTT法评价其生物活性,流式细胞术和共聚焦激光扫描荧光显微镜。纳米芬维汀通过早期增加活性氧和线粒体电位降低而诱导急性早幼粒细胞白血病细胞（HL60）凋亡。在24小时时，引起细胞活力降低90-100％的芬维内酯浓度约为2.0µM，当通过口服或静脉途径给药纳米芬列汀时，体内容易达到的浓度，正如以前的研究所证明的那样。纳米芬列奈德是有效的，尽管浓度略高，也在多柔比星抗性HL60细胞中，而与TK6淋巴母细胞的比较表明对正常细胞缺乏毒性。结果表明，当急性早幼粒细胞白血病疗效下降时，纳米芬维宁可被认为是ATRA的替代疗法。用ATRA长期治疗后出现耐药性或疾病复发。
