INTERACTION OF THE ANTHRACYCLINE 4'-IODO-4'-DEOXYDOXORUBICIN WITH AMYLOID FIBRILS - INHIBITION OF AMYLOIDOGENESIS

All types of amyloidosis are structurally characterized by the cross b eta-pleated sheet conformation of the fibrils, irrespective of their b iochemical composition, The clinical observation that the anthracyclin e 4'-iodo-4'-deoxydoxorubicin (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: i mmunoglobulin light chains, amyloid A, transthyretin (methionine-30 va riant), beta-protein (Alzheimer), and beta(2)-microglobulin. Quantitat ive binding studies showed that IDOX, but not doxorubicin, binds stron gly to amyloid fibrils. This binding is saturable and involves two app arently distinct binding sites with K-d values of 5.9 x 10(-11) M and 3.4 x 10(-9) M. IDOX inhibited in vitro insulin amyloid fibrillogenesi s, In vivo studies using the experimental amyloid murine model confirm ed the specific targeting of IDOX to amyloid deposits, Preincubation o f amyloid enhancing factor with IDOX significantly reduced the formati on of amyloid deposits. It is hypothesized that IDOX exerts its benefi cial effects through the inhibition of fibril growth, thus increasing the solubility of existing amyloid deposits and facilitating their cle arance, IDOX may represent the progenitor of a class of amyloid-bindin g agents that could have both diagnostic and therapeutic potential in all types of amyloidoses.