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(American Journal of Pathology. 2000;156:1919-1925.)
© 2000 American Society for Investigative Pathology

Regular Articles

4'-Iodo-4'-Deoxydoxorubicin Disrupts the Fibrillar Structure of Transthyretin Amyloid

Joana Almeida Palha^*, Dario Ballinari, Nadia Amboldi, Isabel Cardoso^*§, Rui Fernandes^*, Vittorio Bellotti^¶, Giampaolo Merlini^¶ and Maria João Saraiva^*§

From the Amyloid Unit,^*
Instituto de Biologia Molecular e Celular, Porto e Instituto Superior de Ciências da Saúde,
Paredes, Portugal; Pharmacia and Upjohn,
Discovery Research Oncology, Nerviano, Italy; the Instituto de Ciência Biomédicas Abel Salazar,^§
Universidade do Porto, Portugal; and the Biotechnology Research Laboratories,^¶
University Hospital IRCCS Policlinico San Matteo and the Department of Biochemistry, University of Pavia, Italy

Transthyretin (TTR) is a tetrameric protein synthesized mainly by the liver and the choroid plexus, from where it is secreted into the plasma and the cerebrospinal fluid, respectively. Some forms of polyneuropathy, vitreopathy, and cardiomyopathy are caused by the deposition of normal and/or mutant TTR molecules in the form of amyloid fibrils. Familial amyloidotic polyneuropathy is the most common form of TTR amyloidosis related to the V30M variant. It is still unclear the process by which soluble proteins deposit as amyloid. The treatment of amyloid-related disorders might attempt the stabilization of the soluble protein precursor to retard or inhibit its deposition as amyloid; or aim at the resorption of the deposited amyloid. The anthracycline 4'-iodo-4'-deoxydoxorubicin (I-DOX) has been shown to reduce the amyloid load in immunoglobulin light-chain amyloidosis. We investigated 1) whether I-DOX has affinity for TTR amyloid in tissues, 2) determined the I-DOX binding constants to TTR synthetic fibrils, and 3) determined the nature of the effect of I-DOX on TTR fibrils. We report that 1) I-DOX co-localizes with amyloid deposits in tissue sections of patients with familial amyloidotic polyneuropathy; 2) I-DOX strongly interacts with TTR amyloid fibrils and presents two binding sites with k_d of 1.5 x 10^-11 mol/L and 5.6 x 10^-10 mol/L, respectively; and 3) I-DOX disrupts the fibrillar structure of TTR amyloid into amorphous material, as assessed by electron microscopy but does not solubilize the fibrils as confirmed by filter assays. These data support the hypothesis that I-DOX and less toxic derivatives can prove efficient in the treatment of TTR-related amyloidosis.

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