G. Merlini et al., INTERACTION OF THE ANTHRACYCLINE 4'-IODO-4'-DEOXYDOXORUBICIN WITH AMYLOID FIBRILS - INHIBITION OF AMYLOIDOGENESIS, Proceedings of the National Academy of Sciences of the United Statesof America, 92(7), 1995, pp. 2959-2963
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.