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Proc Natl Acad Sci U S A. 1995 Mar 28; 92(7): 2959–2963.

Interaction of the anthracycline 4'-iodo-4'-deoxydoxorubicin with amyloid fibrils: inhibition of amyloidogenesis.


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.

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  • Glenner GG. Amyloid deposits and amyloidosis. The beta-fibrilloses (first of two parts). N Engl J Med. 1980 Jun 5;302(23):1283–1292. [PubMed]
  • Sipe JD. Amyloidosis. Annu Rev Biochem. 1992;61:947–975. [PubMed]
  • Pras M, Schubert M, Zucker-Franklin D, Rimon A, Franklin EC. The characterization of soluble amyloid prepared in water. J Clin Invest. 1968 Apr;47(4):924–933. [PMC free article] [PubMed]
  • Burke MJ, Rougvie MA. Cross- protein structures. I. Insulin fibrils. Biochemistry. 1972 Jun 20;11(13):2435–2439. [PubMed]
  • Formelli F, Carsana R, Pollini C. Pharmacokinetics of 4'-deoxy-4'-iodo-doxorubicin in plasma and tissues of tumor-bearing mice compared with doxorubicin. Cancer Res. 1987 Oct 15;47(20):5401–5406. [PubMed]
  • Ganowiak K, Hultman P, Engström U, Gustavsson A, Westermark P. Fibrils from synthetic amyloid-related peptides enhance development of experimental AA-amyloidosis in mice. Biochem Biophys Res Commun. 1994 Feb 28;199(1):306–312. [PubMed]
  • Sipe JD, Gonnerman WA, Loose LD, Knapschaefer G, Xie WJ, Franzblau C. Direct binding enzyme-linked immunosorbent assay (ELISA) for serum amyloid A (SAA). J Immunol Methods. 1989 Dec 20;125(1-2):125–135. [PubMed]
  • Glenner GG, Eanes ED, Bladen HA, Linke RP, Termine JD. Beta-pleated sheet fibrils. A comparison of native amyloid with synthetic protein fibrils. J Histochem Cytochem. 1974 Dec;22(12):1141–1158. [PubMed]
  • Lansbury PT., Jr In pursuit of the molecular structure of amyloid plaque: new technology provides unexpected and critical information. Biochemistry. 1992 Aug 4;31(30):6865–6870. [PubMed]
  • Klunk WE, Pettegrew JW, Abraham DJ. Quantitative evaluation of congo red binding to amyloid-like proteins with a beta-pleated sheet conformation. J Histochem Cytochem. 1989 Aug;37(8):1273–1281. [PubMed]
  • Turnell WG, Finch JT. Binding of the dye congo red to the amyloid protein pig insulin reveals a novel homology amongst amyloid-forming peptide sequences. J Mol Biol. 1992 Oct 20;227(4):1205–1223. [PubMed]
  • Barbieri B, Giuliani FC, Bordoni T, Casazza AM, Geroni C, Bellini O, Suarato A, Gioia B, Penco S, Arcamone F. Chemical and biological characterization of 4'-iodo-4'-deoxydoxorubicin. Cancer Res. 1987 Aug 1;47(15):4001–4006. [PubMed]
  • Snell CR, Fasman GD. Kinetics and thermodynamics of the helix leads to transconformation of poly(L-lysine) and L-leucine copolymers. A compensation phenomenon. Biochemistry. 1973 Mar 13;12(6):1017–1025. [PubMed]
  • Beaven GH, Gratzer WB, Davies HG. Formation and structure of gels and fibrils from glucagon. Eur J Biochem. 1969 Nov;11(1):37–42. [PubMed]
  • Come JH, Fraser PE, Lansbury PT., Jr A kinetic model for amyloid formation in the prion diseases: importance of seeding. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):5959–5963. [PMC free article] [PubMed]
  • Jarrett JT, Berger EP, Lansbury PT., Jr The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer's disease. Biochemistry. 1993 May 11;32(18):4693–4697. [PubMed]
  • Shirahama T, Miura K, Ju ST, Kisilevsky R, Gruys E, Cohen AS. Amyloid enhancing factor-loaded macrophages in amyloid fibril formation. Lab Invest. 1990 Jan;62(1):61–68. [PubMed]
  • Niewold TA, Hol PR, van Andel AC, Lutz ET, Gruys E. Enhancement of amyloid induction by amyloid fibril fragments in hamster. Lab Invest. 1987 May;56(5):544–549. [PubMed]
  • Varga J, Flinn MS, Shirahama T, Rodgers OG, Cohen AS. The induction of accelerated murine amyloid with human splenic extract. Probable role of amyloid enhancing factor. Virchows Arch B Cell Pathol Incl Mol Pathol. 1986;51(3):177–185. [PubMed]
  • Ali-Khan Z, Quirion R, Robitaille Y, Alizadeh-Khiavi K, Du T. Evidence for increased amyloid enhancing factor activity in Alzheimer brain extract. Acta Neuropathol. 1988;77(1):82–90. [PubMed]
  • Jarrett JT, Lansbury PT., Jr Seeding "one-dimensional crystallization" of amyloid: a pathogenic mechanism in Alzheimer's disease and scrapie? Cell. 1993 Jun 18;73(6):1055–1058. [PubMed]

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