Advertisement

The polyamine oxidase inactivator MDL 72527

Chapter
Part of the Progress in Drug Research book series (PDR, volume 59)

Summary

Polyamine oxidase is a FAD-dependent amine oxidase, which is constitutively expressed in nearly all tissues of the vertebrate organism. In 1985, N1N4-bis(2,3-butadienyl)-1,4-butanediamine (MDL 72527) was designed as a selective enzyme-activated irreversible inhibitor of polyamine oxidase (EC 1.5.3.11). It inactivates, at micromolar concentration and time-dependently, the enzyme in cells, as well as in all organs of experimental animals, without inhibiting other enzymes of polyamine metabolism. MDL 72527 served during nearly two decades as a unique tool in the elucidation of the physiological roles of polyamine oxidase. The compound has anticancer and contragestational effects, and it improves the anticancer effect of the ornithine decarboxylase inactivator (D,L)-2-(difluoromethyl)ornithine (DFMO). Profound depletion of the polyamine pools of tumour cells and effects on different components of the immune defence system are responsible for the anticancer effects of MDL 72527/DFMO combinations. Recently a direct cytotoxic effect of MDL 72527 at concentrations above those required for polyamine oxidase inactivation was observed. The induction of apoptosis by MDL 72527 was ascribed to its lysosomotropic properties. Therapeutic potentials of the apoptotic effect of MDL 72527 need to be explored. Polyamine oxidase is the last enzyme of the polyamine interconversion pathway that awaits the detailed elucidation of its structure and regulation. MDL 72527 should be useful as a lead in the development of inactivators which are selective for the isoforms of polyamine oxidase. Isozyme-selective inhibitors will give more profound insights into and reveal a diversity of specific functions of polyamine oxidase.

Key words

Polyamines putrescine spermidine spermine polyamine oxidase metabolism MDL 72527 enzyme inhibitors cells cancer therapy leukaemia brain damage 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    S.S. Cohen: A guide to the polyamines, Oxford University Press, New York 1998.Google Scholar
  2. 2.
    L.J. Marton and A.E. Pegg: Annu. Rev. Pharmacol. Toxicol.3555 (1995).PubMedCrossRefGoogle Scholar
  3. 3.
    D.L. Kramer, in: K. Nishioka (ed.): Polyamines in cancer: Basic mechanisms and clinical approaches, Landes/Springer, New York, Austin 1996, 151–189.Google Scholar
  4. 4.
    F. Douaud, N. Le Roch, J. Renault, R. Havouis, M. Vaultier, J.P. Moulinoux and N. Seiler: Anti-Cancer Drug Design12621 (1997).PubMedGoogle Scholar
  5. 5.
    E. Höltta: Biochemistry1691 (1977).PubMedCrossRefGoogle Scholar
  6. 6.
    J.G. Hirsch: J. Exp. Med.97345 (1953).PubMedCrossRefGoogle Scholar
  7. 7.
    H. Tabor and C.W. Tabor: Adv. Enzymol.36203 (1972).PubMedGoogle Scholar
  8. 8.
    H. Blaschko: Rev. Physiol. Biochem. Pharmacol.7083 (1974).PubMedCrossRefGoogle Scholar
  9. 9.
    E.A. Zeller, J. Barsky, J.R. Fouts, W.F. Kirchheimer and L.S. Van Orden: Experientia8349 (1952).CrossRefGoogle Scholar
  10. 10.
    N. Seiler, in: D.R. Morris and L.J. Marton (eds.): Polyamines in biology and medicine, Marcel Dekker, New York 1981, 127–149.Google Scholar
  11. 11.
    P. Bey, F.N. Bolkenius, N. Seiler and P. Casara: J. Med. Chem.281 (1985).PubMedCrossRefGoogle Scholar
  12. 12.
    H. Antrup and N. Seiler: Neurochem. Res.5123 (1980).PubMedCrossRefGoogle Scholar
  13. 13.
    F.N. Bolkenius and N. Seiler: Int. J. Biochem.13287 (1981).PubMedCrossRefGoogle Scholar
  14. 14.
    I. Matsui and A.E. Pegg: Biochem. Biophys. Res. Commun.921009 (1980).PubMedCrossRefGoogle Scholar
  15. 15.
    N. Seiler, F.N. Bolkenius, B. Knödgen and K. Haegele: Biochim. Biophys. Acta6761 (1980).CrossRefGoogle Scholar
  16. 16.
    N. Seiler: Can. J. Physiol. Pharmacol.652024 (1987).PubMedCrossRefGoogle Scholar
  17. 17.
    R.A. Casero Jr. and A.E. Pegg: FASEB J.7653 (1993).Google Scholar
  18. 18.
    J.D. Taylor, A.A. Wykes, Y.C. Gladish and W.B. Martin: Nature (Lond.)187941 (1960).CrossRefGoogle Scholar
  19. 19.
    R. Rando and A. Eigner: Mol. Pharmacol.131005 (1977).PubMedGoogle Scholar
  20. 20.
    A. Krantz, B. Kokel, Y.P. Sachdeva, J. Salach, A. Claesson and C. Sahlberg, in: T. Kalman (ed.): Drug action and design: Mechanism-based enzyme inhibitors, Elsevier/North Holland, New York 1979, 145–174.Google Scholar
  21. 21.
    N. Seiler, F.N. Bolkenius, P. Bey, P.S. Mamont and C. Danzin, in: L. Selmeci, M.E. Brosnan and N. Seiler (eds.): Recent progress in polyamine research, Akadémiai Kiado, Budapest 1985, 305–319.Google Scholar
  22. 22.
    F.N. Bolkenius and N. Seiler, in: M. Sandler and H.J. Smith (eds.): Design of enzyme inhibitors as drugs, Oxford University Press, Oxford 1989, 245–256.Google Scholar
  23. 23.
    D.M.L. Morgan, in: S. Bardocz, A. White and G. Hajos (eds.): COST 917, Biologically active amines in food, Vol. II. Office for Official Publications of the European Communities, Luxembourg 1998, 48–63.Google Scholar
  24. 24.
    T. Tsukada, S. Furusako, S. Maekawa, H. Hibasami and K. Nakashima: Int. J. Biochem.20695 (1988).PubMedCrossRefGoogle Scholar
  25. 25.
    Y. Wang, W. Devereux, P.M. Woster, T.M. Stewart, A. Hacker and R.A. Casero Jr.: Cancer Res.615370 (2001).PubMedGoogle Scholar
  26. 26.
    W.W. Just, F.U. Hartl, H. Schimassek, F.N. Bolkenius and N. Seiler: Int. Conf. on Polyamines, Budapest, Abstr. No. 106 (1984).Google Scholar
  27. 27.
    N. Seiler, F.N. Bolkenius, B. Knödgen and P. Mamont: Biochim. Biophys. Acta615480-(1980).PubMedCrossRefGoogle Scholar
  28. 28.
    R.P. Libby and C.W. Porter: Biochem. Biophys. Res. Commun.144528 (1987).PubMedCrossRefGoogle Scholar
  29. 29.
    F.N. Bolkenius and N. Seiler, in: A. Perin, A. Scalabrino, M.E. Sessa and M.E. Ferioli (eds.): Perspectives in polyamine research, Wichtig Editore, Milano 1988, 21–24.Google Scholar
  30. 30.
    F.N. Bolkenius and N. Seiler: Biol. Chem. Hoppe-Seyler 370, 525 (1989).PubMedCrossRefGoogle Scholar
  31. 31.
    A.J. Bitonti, J.A. Dumont, T.L. Bush, D.M. Stemerick, M.L. Edwards and P.P. McCann: J. Biol. Chem.265382 (1990).PubMedGoogle Scholar
  32. 32.
    N.J. Prakash, T.L. Bowfin, M.L. Edwards, P.S. Sunkara and A. Sjoerdssma: Anticancer Res.101281 (1990).PubMedGoogle Scholar
  33. 33.
    F.N. Bolkenius, P. Bey and N. Seiler: Biochim. Biophys. Acta83869 (1985).PubMedCrossRefGoogle Scholar
  34. 34.
    S. Macaione, F. Cangemi, C. Fabiano, G. Crisafulli, T. Aronica and R. Ientile: Ital. J. Biochem.42151 (1993).PubMedGoogle Scholar
  35. 35.
    M.A. Desiderio and L. Bardella: Hepatology19728 (1994).PubMedCrossRefGoogle Scholar
  36. 36.
    N. Seiler and F.N. Bolkenius: Neurochem. Res.10529 (1985).PubMedCrossRefGoogle Scholar
  37. 37.
    W.W. Shin, W.F. Fong, S.F. Pang and P.C.L. Wong: J. Neurochem.441056 (1985).PubMedCrossRefGoogle Scholar
  38. 38.
    F.N. Bolkenius and N. Seiler: Int. J. Devl. Neuroscience4217 (1986).CrossRefGoogle Scholar
  39. 39.
    T. Shinki, H. Tanata, T. Kadofuku, T. Sato and T. Suda: Gastroenterology961494 (1989).PubMedGoogle Scholar
  40. 40.
    N. Seiler, J. Koch-Weser, B. Knödgen, W. Richards, C. Tardif, F.N. Bolkenius, P. Schechter, G. Tell, P. Mamont, J. Fozard et al. (eds.): Advances in polyamine research, Vol. 3, Raven Press, New York 1981, 197.Google Scholar
  41. 41.
    N. Seiler, F.N. Bolkenius and B. Knödgen: Biochem. J.225219 (1985).PubMedGoogle Scholar
  42. 42.
    N. Seiler, in: R.H. Dowling, U.R. Fölsch and C. Löser (eds.): Polyamines in the gastrointestinal tract, Kluwer Academic Publishers, Dordrecht 1992, 65–85.Google Scholar
  43. 43.
    J. Hessels, H. Ferwerda, A.W. Kingma and F.A. Muskiet: Biochem. J.266843 (1990).PubMedGoogle Scholar
  44. 44.
    P. Bey, in: N. Seiler, M.J. Jung and J. Koch-Weser (eds.): Enzyme-activated irreversible inhibitors, Elsevier/North Holland, Amsterdam 1978, 27–41.Google Scholar
  45. 45.
    P.S. Mamont, M.C. Duchesne, A.M. Joder-Ohlenbusch and J. Grove, in: N. Seiler, M.J. Jung and J. Koch-Weser (eds.): Enzyme-activated irreversible inhibitors, Elsevier/North Holland, Amsterdam 1978, 43–54.Google Scholar
  46. 46.
    P.S. Sunkara, S.B. Baylin and G.D. Luk, in: P.P. McCann, A.E. Pegg and A. Sjoerdsma (eds.): Inhibition of polyamine metabolism, Academic Press, Orlando 1987, 49–77.Google Scholar
  47. 47.
    N. Seiler, C. Danzin, N.J. Prakash and J. Koch-Weser, in: N. Seiler, M.J. Jung and J. Koch-Weser J (eds.): Enzyme-activated irreversible inhibitors, Elsevier/North Holland, Amsterdam 1978, 55–71.Google Scholar
  48. 48.
    P.J. Schechter, J.L.R. Barlow and A. Sjoerdsma, in: P.P. McCann, A.E. Pegg and A. Sjoerdsma (eds.): Inhibition of polyamine metabolism, Academic Press, Orlando 1987, 345–364.Google Scholar
  49. 49.
    F.N. Bolkenius and N. Seiler: Biochim. Biophys. Acta923125 (1987).PubMedCrossRefGoogle Scholar
  50. 50.
    N. Seiler and F. Dezeure: Int. J. Biochem.22211 (1990).PubMedCrossRefGoogle Scholar
  51. 51.
    W.E. Hull, W. Kunz, R.E. Port and N. Seiler: NMR in Biomedicine111 (1988).PubMedCrossRefGoogle Scholar
  52. 52.
    E.S. Redgate, A.G. Grudziak, M. Deutsch and S.S. Boggs: J. Neurooncol.42123 (1999).PubMedCrossRefGoogle Scholar
  53. 53.
    B. Duranton, V. Holl, Y. Schneider, S. Carnesecchi, F. Gossé, F. Raul and N. Seiler: Cell Biol. Toxicol.in press. Google Scholar
  54. 54.
    A.G. Halline, P.K. Dudeja, R.F. Jacoby, X. Llor, B.B. Teng, L.N. Chowdhury, N.O. Davidson and T.A. Brasitus: Carcinogenesis112127 (1990).PubMedCrossRefGoogle Scholar
  55. 55.
    P.K. Mehrotra, S. Kitchlu and S. Farheen: Contraception5755 (1998).PubMedCrossRefGoogle Scholar
  56. 56.
    J.R. Fozard, in: P.P. McCann, A.E. Pegg and A. Sjoerdsma (eds.): Inhibition of polyamine metabolism, Academic Press, Orlando 1987, 187–202.Google Scholar
  57. 57.
    N. Claverie, J. Wagner, B. Knödgen and N. Seiler: Anticancer Res.7765 (1987).PubMedGoogle Scholar
  58. 58.
    S. Sarhan, B. Knödgen and N. Seiler: Anticancer Res.9215(1989).PubMedGoogle Scholar
  59. 59.
    N. Seiler, S. Sarhan, C. Grauffel, R. Jones, B. Knödgen and J.P. Moulinoux: Cancer Res.505077 (1990).PubMedGoogle Scholar
  60. 60.
    J. Hessels, A.W. Kingma, F.A. Muskiet, S. Sarhan and N. Seiler: Int. J. Cancer48697 (1991).PubMedCrossRefGoogle Scholar
  61. 61.
    J.P. Moulinoux, F. Darcel, V. Quemener, R. Havouis and N. Seiler: Anticancer Res.11175 (1991).PubMedGoogle Scholar
  62. 62.
    S. Sarhan, M. Weibel and N. Seiler: Anticancer Res.11987 (1991)PubMedGoogle Scholar
  63. 63.
    J.P. Moulinoux, V. Quemener, B. Cipolla, F. Guille, R. Havouis, C. Martin, B. Lobel and N. Seiler: J. Urol.1461408 (1991).PubMedGoogle Scholar
  64. 64.
    V. Quemener, J.P. Moulinoux, R. Havouis and N. Seiler: Anticancer Res.121447 (1992).PubMedGoogle Scholar
  65. 65.
    B. Cipolla, Y. Blanchard, L. Chamaillard, V. Quemener, R. Havouis and J.P. Moulinoux: Urol. Res.2493 (1996).PubMedCrossRefGoogle Scholar
  66. 66.
    S. Sarhan, B. Knödgen and N. Seiler: Anticancer Res.12457 (1992).PubMedGoogle Scholar
  67. 67.
    L. Chamaillard, V. Quemener, R. Havouis and J.P. Moulinoux: Anticancer Res.131027 (1993).PubMedGoogle Scholar
  68. 68.
    L. Chamaillard, V. Catros-Quemener, J.G. Delcros, J.Y. Bansard, R. Havouis, D. Desury, A. Commeurec, N. Genetet and J.P. Moulinoux: Br. J. Cancer76365 (1997).PubMedCrossRefGoogle Scholar
  69. 69.
    T.L. Bowlin, J.N. Prakash, M.L. Edwards and A. Sjoerdsma: Cancer Res.5162 (1991).PubMedGoogle Scholar
  70. 70.
    N. Seiler and C.L. Atanassov, in: E. Jucker (ed.): Progress in drug research, Vol. 43, Birkhäuser, Basel 1994, 87–141.Google Scholar
  71. 71.
    N. Talai and E. Flescher: J. Autoimmunity1309 (1988).CrossRefGoogle Scholar
  72. 72.
    E. Flescher, T.L. Bowlin and N. Talal: J. Immunol.142907 (1989).PubMedGoogle Scholar
  73. 73.
    E. Flescher, T.L. Bowlin and N. Talal: Clin. Exp. Immunol.87435 (1992).PubMedCrossRefGoogle Scholar
  74. 74.
    N. Seiler, J.P. Moulinoux, R. Havouis and L. Toujas: Biochem. Cell Biol.73275 (1995).PubMedCrossRefGoogle Scholar
  75. 75.
    D.M.L. Morgan, J. Ferulga and A.C. Allison, in: J. Gaugas (ed.): Polyamines in biomedical research, Wiley, Chichester 1980, 303–308.Google Scholar
  76. 76.
    U. Bachrach: Ann. N.Y. Acad. Sci.171939 (1970).CrossRefGoogle Scholar
  77. 77.
    D.M.L. Morgan, in: U. Bachrach and Y.M. Heimer (eds.): The physiology of polyamines, Vol. 1, CRC Press, Boca Raton 1988, 203–229.Google Scholar
  78. 78.
    R.E. Parchment, in: K. Nishioka (ed.): Polyamines in cancer: Basic mechanisms and clinical approaches, Springer/Landes, New York, Austin 1996, 99–150.Google Scholar
  79. 79.
    G. Houen: Acta Pathol. Microbiol. Immunol. Scand.1Suppl. 96, 5 (1999).Google Scholar
  80. 80.
    N. Seiler, B. Knödgen, M.W. Gittos, W.Y. Chan, G. Griesmann and O.M. Rennert: Biochem. J.200123 (1981).PubMedGoogle Scholar
  81. 81.
    N. Seiler, B. Knödgen and K. Haegele: Biochem.J. 208, 189 (1982).PubMedGoogle Scholar
  82. 82.
    R.H. Hu and A.E. Pegg: Biochem. J.328307 (1997).PubMedGoogle Scholar
  83. 83.
    Y. Chen, D.L. Kramer, P. Diegelman, S. Vujcic and C.W. Porter: Cancer Res.616437 (2001).PubMedGoogle Scholar
  84. 84.
    H.C. Ha, P.M. Woster, J.D. Yager and R.A. Casero Jr.: Proc. Natl. Acad. Sci. USA9411557 (1997).PubMedCrossRefGoogle Scholar
  85. 85.
    L. Alhonen, J.J. Parkkinen, T. Keinanen, R. Sinervirta, K.H. Herzig and J. Jänne: Proc. Natl. Acad. Sci. USA978290 (2000).PubMedCrossRefGoogle Scholar
  86. 86.
    K. Otani, Y. Yano, T. Hasuma, T. Arakawa, K. Kobayashi; I. Matsui-Yuasa and S. Otani: Am. J. Physiol.274G299 (1998).PubMedGoogle Scholar
  87. 87.
    Y. Hayashi, Y. Morizumi, T. Hattori and J. Tanaka: Brain Res.828184 (1999).PubMedCrossRefGoogle Scholar
  88. 88.
    M. Baudry and I. Najm: Neurosci. Lett.171151 (1994).PubMedCrossRefGoogle Scholar
  89. 89.
    A. Dogan, A.M. Rao, M.K. Baskaya, J. Hatcher, C. Temiz, V.L. Rao and R.J. Dempsey: J. Neurosurg.901078 (1999).PubMedCrossRefGoogle Scholar
  90. 90.
    A. Dogan, A.M. Rao, J. Hatcher, V.L. Rao, M.K. Baskaya and R.J. Dempsey: J. Neurochem.72765 (1999).PubMedCrossRefGoogle Scholar
  91. 91.
    A.M. Rao, J.F. Hatcher, A. Dogan and R.J. Dempsey: J. Neurochem.741106 (2000).PubMedCrossRefGoogle Scholar
  92. 92.
    T.D. Johnson, in: E. Jucker (ed.): Progress in drug research, Vol. 50, Birkhäuser, Basel 1998, 193–258CrossRefGoogle Scholar
  93. 93.
    W. Liu, R. Liu, S.S. Schreiber and M. Baudry: J. Neurochem.79976 (2001).PubMedCrossRefGoogle Scholar
  94. 94.
    W. Schuler: Experientia7230 (1952).CrossRefGoogle Scholar
  95. 95.
    G.A. Zimmerman, M. Meistrell III, O. Bloom, K.M. Cockcroft, M. Bianchi, D. Risucci, J. Broome, A. Farmer, H. Cerami, H. Vlassra et al.: Proc. Natl. Acad. Sci. USA923744 (1995).PubMedCrossRefGoogle Scholar
  96. 96.
    K.M. Cockcroft, M. Meistrell III, G.A. Zimmerman, D. Risucci, O. Bloom, A. Cerami and K.J. Tracey: Stroke271393 (1996).CrossRefGoogle Scholar
  97. 97.
    S. Ivanova, G.I. Botchkina, Y. Al-Abed, M. Meistrell III, F. Batliwalla, J.M. Dubinsky, C. Iadecola, H. Wang, P.K. Gregersen, J.W. Eaton et al.: J. Exp. Med.188327(1998).PubMedCrossRefGoogle Scholar
  98. 98.
    M.A. Desiderio, I. Zini, P. Davalli, M. Zoli, A. Corti, K. Fuxe and L.G. Agnati: J. Neurochem.51225 (1988).CrossRefGoogle Scholar
  99. 99.
    W.P. Burkard, K.F. Gey and A. Pletscher: J. Neurochem.10183 (1963).PubMedCrossRefGoogle Scholar
  100. 100.
    P. Ou and S.P. Wolff: Biochem. Pharmacol.461139 (1993).PubMedCrossRefGoogle Scholar
  101. 101.
    R. Bryk, A. Lubeskie and D.J. Wolff: Arch. Biochem. Biophys.369243 (1999).PubMedCrossRefGoogle Scholar
  102. 102.
    C. Gorlach, T. Hortobagyi, S. Hortobagyi and Z. Benyo: Restor. Neurol. Neurosci.1771 (2000).PubMedGoogle Scholar
  103. 103.
    M.L. Morgan and G. Illei, in: S. Bardocz, A. White and G. Hajos (eds):COST 917, Biologically active amines in food, Vol. II. Office for Official Publications of the European Communities, Luxembourg 1998, 95–100.Google Scholar
  104. 104.
    N. Seiler: Neurochem. Res.25471 (2000).PubMedCrossRefGoogle Scholar
  105. 105.
    S. Sachan, V. Quemener, J.P. Moulinoux, B. Knödgen and N. Seiler: Int. J. Biochem.23617 (1991).Google Scholar
  106. 106.
    J.P. Moulinoux, V. Quemener and N.A. Khan: Cell. Mol. Biol.37773 (1991).PubMedGoogle Scholar
  107. 107.
    N. Seiler, in: E. Jucker (ed.): Progress in drug research, Vol. 37, Birkhäuser, Basel 1991, 107–159.Google Scholar
  108. 108.
    J. Blankenship: Arch. Biochem. Biophys.18920 (1978).PubMedCrossRefGoogle Scholar
  109. 109.
    P. Libby: Methods Enzymol.94329 (1983).PubMedCrossRefGoogle Scholar
  110. 110.
    G. Brunton, M.H. Grant and H.M. Wallace: Biochem. J.280193 (1991).PubMedGoogle Scholar
  111. 111.
    N. Seiler, B. Duranton, F. Gosse and F. Raul: Cell Biol. Toxicol.16117 (2000).PubMedCrossRefGoogle Scholar
  112. 112.
    N. Seiler, B. Duranton, F. Vincent, F. Gossé, J. Renault and F. Raul: Int. J. Biochem. Cell Biol.32703 (2000).PubMedCrossRefGoogle Scholar
  113. 113.
    N. Seiler, L. Badolo, B. Duranton, F. Vincent, Y. Schneider, F. Gossé and F. Raul: Int. J. Biochem. Cell Biol.321055 (2000).PubMedCrossRefGoogle Scholar
  114. 114.
    N. Seiler, F. Douaud, J. Renault, J.G. Delcros, R. Havouis, P. Uriac and J.P. Moulinoux: Int. J. Biochem. Cell Biol.30393(1998).PubMedCrossRefGoogle Scholar
  115. 115.
    H. Dai, D.L. Kramer, C. Yang, K.G. Murti, C.W. Porter and J.L. Cleveland: Cancer Res.594944 (1999).PubMedGoogle Scholar
  116. 116.
    C.W. Porter, J. Stanek, J. Black, M. Vaughan, B. Ganis and A. Pleshkewych: Cancer Res.501929 (1990).PubMedGoogle Scholar
  117. 117.
    V. Quemener, J.P. Moulinoux, J. Lucas, N. Khan, E Darcel, L.A. Martin, R. Primault and N. Seiler: Biol. Cell77195 (1993).PubMedCrossRefGoogle Scholar
  118. 118.
    V. Quemener, J.P. Moulinoux, N. Khan and N. Seiler: Biol. Cell70133 (1990).PubMedCrossRefGoogle Scholar
  119. 119.
    R. Kitz and B. Wilson B: J. Biol. Chem.2373245 (1962).Google Scholar
  120. 120.
    P. Skehan, R. Storeng, D. Scudiero, A. Monks, J. McMahon, D. Vistica, J.P. Warren, H. Boekesch, S. Kerney and M.R. Boyd: J. Natl. Cancer Inst.821107 (1990).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel AG 2002

Authors and Affiliations

  1. 1.Laboratory of Nutritional Oncology INSERM U-392Institut de Recherche Contre les Cancers de l’Appareil Digestif (IRCAD)StrasbourgFrance

Personalised recommendations