Merlini G, Ascari E, Amboldi N, Bellotti V, Arbustini E, Perfetti V, Ferrari M, Zorzoli I, Marinone M G, Garini P
Institute of Clinical Medicine II, University Hospital S. Matteo, Pavia, Italy.
Proc Natl Acad Sci U S A. 1995 Mar 28;92(7):2959-63. doi: 10.1073/pnas.92.7.2959.
All types of amyloidosis are structurally characterized by the cross beta-pleated sheet conformation of the fibrils, irrespective of their biochemical composition. The clinical observation that the anthracycline 4'-iodo-4'-deoxy-doxorubicin (IDOX) can induce amyloid resorption in patients with immunoglobulin light chain amyloidosis was the starting point for this investigation of its possible mechanism of action. IDOX binds strongly to all five types of natural amyloid fibrils tested: immunoglobulin light chains, amyloid A, transthyretin (methionine-30 variant), beta-protein (Alzheimer), and beta 2-microglobulin. Quantitative binding studies showed that IDOX, but not doxorubicin, binds strongly to amyloid fibrils. This binding is saturable and involves two apparently distinct binding sites with Kd values of 5.9 x 10(-11) M and 3.4 x 10(-9) M. IDOX inhibited in vitro insulin amyloid fibrillogenesis. In vivo studies using the experimental amyloid murine model confirmed the specific targeting of IDOX to amyloid deposits. Preincubation of amyloid enhancing factor with IDOX significantly reduced the formation of amyloid deposits. It is hypothesized that IDOX exerts its beneficial effects through the inhibition of fibril growth, thus increasing the solubility of existing amyloid deposits and facilitating their clearance. IDOX may represent the progenitor of a class of amyloid-binding agents that could have both diagnostic and therapeutic potential in all types of amyloidoses.
所有类型的淀粉样变性在结构上的特征都是原纤维具有交叉β-折叠片层构象，无论其生化组成如何。临床观察发现，蒽环类药物4'-碘-4'-脱氧阿霉素（IDOX）可诱导免疫球蛋白轻链淀粉样变性患者的淀粉样物质吸收，这是本次对其可能作用机制研究的起点。IDOX与所测试的所有五种天然淀粉样原纤维都有强烈结合：免疫球蛋白轻链、淀粉样蛋白A、转甲状腺素蛋白（甲硫氨酸-30变体）、β-蛋白（阿尔茨海默病相关）和β2-微球蛋白。定量结合研究表明，IDOX而非阿霉素能与淀粉样原纤维强烈结合。这种结合是可饱和的，涉及两个明显不同的结合位点，解离常数（Kd）值分别为5.9×10⁻¹¹ M和3.4×10⁻⁹ M。IDOX在体外抑制胰岛素淀粉样纤维形成。使用实验性淀粉样小鼠模型的体内研究证实了IDOX对淀粉样沉积物的特异性靶向作用。淀粉样增强因子与IDOX预孵育可显著减少淀粉样沉积物的形成。据推测，IDOX通过抑制纤维生长发挥其有益作用，从而增加现有淀粉样沉积物的溶解度并促进其清除。IDOX可能代表一类淀粉样结合剂的先驱，这类结合剂在所有类型的淀粉样变性中可能都具有诊断和治疗潜力。
