Gruol D J, Bourgeois S
Regulatory Biology Laboratory, The Salk Institute for Biological Studies, San Diego, California 92186-5800, USA.
Cancer Res. 1997 Feb 15;57(4):720-7.
P-glycoprotein expression in lymphoid malignancies has the potential to compromise the efficacy of many therapeutic regimens using anthracyclines, glucocorticoids, and Vinca alkaloids. All three classes of drugs are transported by P-glycoproteins. We have explored the possibility that modified steroids could serve a dual purpose, as glucocorticoid receptor agonists and P-glycoprotein inhibitors. Substitution of such steroids for those currently in use would help to overcome the selective advantage held by cells expressing P-glycoproteins. 17-Deoxydexamethasone and dichlorisone were modified by the addition of a dimethylamino benzoate group at the 21-carbon atom of the steroids. The two resulting steroids, SA47 and SA450, were potent glucocorticoid receptor agonists also capable of inhibiting the human P-glycoprotein with an efficiency equal to that of verapamil. Thus, both compounds are examples of steroids that could potentially serve as beneficial substitutions for dexamethasone or prednisolone in the chemotherapy of lymphomas and leukemias.
P-糖蛋白在淋巴系统恶性肿瘤中的表达可能会影响许多使用蒽环类药物、糖皮质激素和长春花生物碱的治疗方案的疗效。这三类药物均由P-糖蛋白转运。我们探讨了修饰后的类固醇能否兼具双重作用，即作为糖皮质激素受体激动剂和P-糖蛋白抑制剂。用这类类固醇替代目前使用的类固醇，将有助于克服表达P-糖蛋白的细胞所具有的选择性优势。在类固醇的21碳原子上添加一个二甲基氨基苯甲酸基团，对17-脱氧地塞米松和二氯松进行修饰。由此得到的两种类固醇SA47和SA450是强效的糖皮质激素受体激动剂，同时还能够抑制人P-糖蛋白，其抑制效率与维拉帕米相当。因此，这两种化合物都是类固醇的实例，它们在淋巴瘤和白血病的化疗中可能有望作为地塞米松或泼尼松龙的有益替代物。
