Advertisement

Nature of Activated Bleomycin

  • Richard M. Burger
Chapter
Part of the Structure and Bonding book series (STRUCTURE, volume 97)

Abstract

Activated bleomycin is the drug species seen to be kinetically competent to initiate DNA degradation in the reaction of bleomycin, Fe(II), and O2. It also forms in reactions of bleomycin with Fe(III) and peroxide, or bleomycin with superoxide and either Fe(III) or Fe(II). Efforts to characterize this transient species proceeded by kinetic and spectroscopic strategies. Activated bleomycin now appears to be a drug-ferric-peroxide complex, but this may not be the proximate active drug species. Assuming that activated bleomycin peroxide cleavage yields a reactive product analogous to peroxidase compound I explains many characteristics of bleomycin-mediated DNA degradation reactions. DNA degradation is responsible for the cytotoxic and antitumor activities of this clinically useful antibiotic.

Keywords

Iron Oxygen Peroxide Superoxide DNA Antitumor Antibiotic 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Umezawa H, Maeda K, Takeuchi T, Okami Y (1966) J Antibiot (Tokyo) Ser A 19: 200Google Scholar
  2. 2.
    Umezawa H, Suhara Y, Takita T, Maeda K (1966) J Antibiot (Tokyo) Ser A 19: 210Google Scholar
  3. 3.
    Lazo JS, Chabner BA (1996) Bleomycin. In: Chabner BA, Longo DL (eds) Cancer chemotherapy and biotherapy: principals and practice. Lippincott-Raven, Philadelphia, PA, p 379Google Scholar
  4. 4.
    Munn SE, Higgins E, Marshall M, Clement M (1996) Br J Dermatol 135: 969CrossRefGoogle Scholar
  5. 5.
    Drocourt D, Calmels T, Reynes J-P, Baron M, Tiraby G (1990) Nucl Acids Res 18: 4009CrossRefGoogle Scholar
  6. 6.
    Suzuki H, Nagai K, Yamaki H, Tanaka N, Umezawa H (1968) J Antibiot (Tokyo) 21: 379Google Scholar
  7. 7.
    Onishi T, Shimada K, Takagi Y (1973) Biochem Biophys Acta 312: 248Google Scholar
  8. 8.
    Gudas LJ, Pardee AB (1976) J Mol Biol 101: 459CrossRefGoogle Scholar
  9. 9.
    Moore CW (1978) Mutation Res 58: 41CrossRefGoogle Scholar
  10. 10.
    Murray V, Martin RF (1985) J Biol Chem 260: 10, 389Google Scholar
  11. 11.
    Povirk LF, Goldberg IH (1987) Biochimie 69: 815CrossRefGoogle Scholar
  12. 12.
    Umezawa K, Haresaku M, Muramatsu M, Matsushima T (1987) Biomed Pharmacother 41: 214Google Scholar
  13. 13.
    Povirk (1996) Mutation Res 355: 71Google Scholar
  14. 14.
    Levin JD, Demple B (1996) Nucleic Acids Res 24: 885CrossRefGoogle Scholar
  15. 15.
    Nagai N, Yamaki H, Suzuki H, Tanaka N, Umezawa H (1969) Biochim Biophys Acta 179: 165Google Scholar
  16. 16.
    Burger RM (1998) Chem Rev 98: 1153CrossRefGoogle Scholar
  17. 17.
    Nagai K, Suzuki H, Tanaka N, Umezawa H (1969) J Antibiot (Tokyo) 22: 624Google Scholar
  18. 18.
    Carter BJ, de Vroom E, van der Marel GA, van Boom JH, Hecht SM (1990) Proc Natl Acad Sci USA 87: 9373CrossRefGoogle Scholar
  19. 19.
    Lim ST, Jue CK, Moore CW, Lipke PN (1995) J Bacteriol 177: 3534Google Scholar
  20. 20.
    Sausville EA, Peisach J, Horwitz SB (1976) Biochem Biophys Res Commun 73: 814CrossRefGoogle Scholar
  21. 21.
    Kuramochi H, Takahashi K, Takita T, Umezawa H (1981) J Antibiot (Tokyo) 34: 578Google Scholar
  22. 22.
    Burger RM, Peisach J, Horwitz SB (1981) J Biol Chem 256: 11,636Google Scholar
  23. 23.
    Sam JW, Tang X-J, Peisach J (1994) J Am Chem Soc 116: 5250CrossRefGoogle Scholar
  24. 24.
    Burger RM, Tian G, Drlica K (1995) J Am Chem Soc 117: 1167CrossRefGoogle Scholar
  25. 25.
    Burger RM, Kent TA, Horwitz SB, Münck E, Peisach J (1983) J Biol Chem 258: 1559Google Scholar
  26. 26.
    Barr JR, Van Atta RB, Natrajan A, Hecht SM, van der Marel GA, van Boom JH (1990) J Am Chem Soc 112: 4058CrossRefGoogle Scholar
  27. 27.
    Maeda K, Kosaka H, Yagishita K, Umezawa H (1956) J Antibiot (Ser A) 9: 82Google Scholar
  28. 28.
    Kawaguchi H, Tsukuira H, Tomita K, Konishi M, Saito K, Kobaru S, Numata K, Fujisawa K, Miyaski T, Hatori M, Koshiyama H (1977) J Antibiot (Tokyo) 30: 779Google Scholar
  29. 29.
    Claussen CA, Long EC (1999) Chem Rev 99: 2797CrossRefGoogle Scholar
  30. 30.
    Xu RX, Nettesheim D, Otvos JD, Petering DH (1994) Biochemistry 33: 907CrossRefGoogle Scholar
  31. 31.
    Caceres-Cortes J, Sugiyama H, Ikudome K, Saito I, Wang AH-J (1997) Eur J Biochem 244: 818CrossRefGoogle Scholar
  32. 32.
    Wu W, Vanderwall DE, Turner CJ, Kozarich JW, Stubbe J (1996) J Am Chem Soc 118: 1281CrossRefGoogle Scholar
  33. 33.
    Povirk LF, Wübker W, Köhnlein W, Hutchinson F (1977) Nucleic Acids Res 4: 3573CrossRefGoogle Scholar
  34. 34.
    Povirk LF, Köhnlein W, Hutchinson F (1978) Biochim Biophys Acta 521: 126Google Scholar
  35. 35.
    Burger RM, Berkowitz AR, Peisach J, Horwitz SB (1980) J Biol Chem 255: 11,832Google Scholar
  36. 36.
    Giloni L, Takeshita M, Johnson F, Iden C, Grollman AP (1981) J Biol Chem 256: 8608Google Scholar
  37. 37.
    Sugiyama H, Kilkuskie RE, Hecht SM, van der Marel GA, van Boom JH (1985) J Am Chem Soc 107: 7765CrossRefGoogle Scholar
  38. 38.
    Wu JC, Kozarich JW, Stubbe JA (1983) J Biol Chem 258: 4694Google Scholar
  39. 39.
    Absalon MJ, Kozarich JW, Stubbe J (1992) Nucleic Acids Res 20: 4179CrossRefGoogle Scholar
  40. 40.
    Haidle CW, Weiss KK, Kuo MT (1972) Mol Pharmacol 8: 531Google Scholar
  41. 41.
    Wu JC, Stubbe JA, Kozarich JW (1985) Biochemistry 24: 7569CrossRefGoogle Scholar
  42. 42.
    Sugiyama H, Xu C, Murugesan N, Hecht SM (1985) J Am Chem Soc 107: 4104CrossRefGoogle Scholar
  43. 43.
    Sugiyama H, Xu C, Murugesan N, Hecht SM, van der Marel GA, van Boom JH (1988) Biochemistry 27: 58CrossRefGoogle Scholar
  44. 44.
    Burger RM, Peisach J, Horwitz SB (1982) J Biol Chem 257: 3372Google Scholar
  45. 45.
    McGall GH, Rabow LE, Stubbe J, Kozarich JW (1987) J Am Chem Soc 109: 2836CrossRefGoogle Scholar
  46. 46.
    Albertini JP, Garnier-Suillerot A, Tosi L (1982) Biochem Biophys Res Commun 104: 557CrossRefGoogle Scholar
  47. 47.
    Sausville EA, Peisach J, Horwitz SB (1978) Biochemistry 17: 2740CrossRefGoogle Scholar
  48. 48.
    Burger RM, Horwitz SB, Peisach J, Wittenberg JB (1979) J Biol Chem 254: 12,299Google Scholar
  49. 49.
    Burger RM, Peisach J, Blumberg WE, Horwitz SB (1979) J Biol Chem 254: 10,906Google Scholar
  50. 50.
    Sugiura Y, Kikuchi T (1978) J Antibiot (Tokyo) 31: 1310Google Scholar
  51. 51.
    Dabrowiak JC, Greenaway FT, Santillo FS, Crooke ST (1979) Biochem Biophys Res Commun 91: 721CrossRefGoogle Scholar
  52. 52.
    Fulmer P, Petering DH (1994) Biochemistry 33: 5319CrossRefGoogle Scholar
  53. 53.
    Melnyk D, Horwitz SB, Peisach J (1981) Biochemistry 20: 5327CrossRefGoogle Scholar
  54. 54.
    Burger RM, Peisach J, Horwitz SB (1978) J Biol Chem 253: 4830Google Scholar
  55. 55.
    Ishida R, Takahashi T (1975) Biochem Biophys Res Commun 66: 1432CrossRefGoogle Scholar
  56. 56.
    Bickers DR, Dixit R, Mukhtar H (1984) Biochim Biophys Acta 781: 265Google Scholar
  57. 57.
    Sausville EA, Stein RW, Peisach J, Horwitz SB (1978) Biochemistry 17: 2746CrossRefGoogle Scholar
  58. 58.
    Lown JW (1979) Contribution of the Superoxide anion-hydroxyl radical pathway to the cleavage of DNA by bleomycin. In: Hecht SM (ed) Bleomycin: chemical, biochemical, and biological aspects. Springer, Berlin Heidelberg New York, p 184Google Scholar
  59. 59.
    Yamanaka N, Kato T, Nishida K, Ota K (1978) Cancer Res 38: 3900Google Scholar
  60. 60.
    Trush MA (1983) Chem-Biol Interactions 45: 65CrossRefGoogle Scholar
  61. 61.
    Ciriolo MR, Magliozzo RS, Peisach J (1987) J Biol Chem 262: 6290Google Scholar
  62. 62.
    Ciriolo MR, Peisach J, Magliozzo RS (1989) J Biol Chem 264: 1443Google Scholar
  63. 63.
    Sam JW, Tang X-J, Magliozzo RS, Peisach J (1995) J Am Chem Soc 117: 1012CrossRefGoogle Scholar
  64. 64.
    Lippai I, Magliozzo RS, Peisach J (1999) J Am Chem Soc 121: 780CrossRefGoogle Scholar
  65. 65.
    Petering DH, Byrnes RW, Antholione WE (1990) Chem Biol Interact 73: 133CrossRefGoogle Scholar
  66. 66.
    Chang C-H, Meares CF (1982) Biochemistry 21: 6332CrossRefGoogle Scholar
  67. 67.
    Haasnoot CAG, Pandit UK, Kruk C, Hilbers CW (1984) J Biomolec Struct Dyn 2: 449Google Scholar
  68. 68.
    Akkerman MAJ, Haasnoot CAG, Hilbers CW (1988) Eur J Biochem 173: 211CrossRefGoogle Scholar
  69. 69.
    Akkerman MAJ, Neijman EJWF, Wijmenga SS, Hilbers CW, Bermel W (1990) J Am Chem Soc 112: 7462CrossRefGoogle Scholar
  70. 70.
    Wu W, Vanderwall DE, Lui SM, Tang X-J, Turner CJ, Kozarich JW, Stubbe J (1996) J Am Chem Soc 118: 1268CrossRefGoogle Scholar
  71. 71.
    Manderville RA, Ellena JF, Hecht SM (1994) J Am Chem Soc 116: 10,851CrossRefGoogle Scholar
  72. 72.
    Manderville RA, Ellena JF, Hecht SM (1995) J Am Chem Soc 117: 7891CrossRefGoogle Scholar
  73. 73.
    Caceres-Cortes J, Sugiyama H, Ikudome K, Saito I, Wang AH-J (1997) Biochemistry 36: 9995CrossRefGoogle Scholar
  74. 74.
    Lehmann TE, Ming L-J, Rosen ME, Que L Jr (1997) Biochemsitry 36: 2807CrossRefGoogle Scholar
  75. 75.
    Veselov A, Sun H, Sienkiewicz A, Taylor H, Burger RM, Scholes CP (1995) J Am Chem Soc 117: 7508CrossRefGoogle Scholar
  76. 76.
    Veselov A, Burger RM, Scholes CP (1998) J Am Chem Soc 120: 1030CrossRefGoogle Scholar
  77. 77.
    Takahashi S, Sam JW, Peisach J, Rousseau DL (1994) J Am Chem Soc 116: 4408CrossRefGoogle Scholar
  78. 78.
    Burger RM, Blanchard JS, Horwitz SB, Peisach J (1985) J Biol Chem 260: 15,406Google Scholar
  79. 79.
    Roberts JE, Hoffman BM, Rutter R, Hager LP (1981) J Am Chem Soc 103: 7654CrossRefGoogle Scholar
  80. 80.
    Lumpkin O, Dixon WT (1971) J Chem Phys 71: 3550CrossRefGoogle Scholar
  81. 81.
    Westre TE, Loeb KE, Zaleski JM, Hedman B, Hodgson KO, Solomon EI (1995) J Am Chem Soc 117: 1309CrossRefGoogle Scholar
  82. 82.
    Padbury G, Sligar S (1987) Fed Proc 46: 2265Google Scholar
  83. 83.
    Natrajan A, Hecht SM, Van der Marel GA, Van Boom JH (1990) J Am Chem Soc 112: 4532CrossRefGoogle Scholar
  84. 84.
    Rabow LE, Stubbe J, Kozarich JW (1990) J Am Chem Soc 112: 3196CrossRefGoogle Scholar
  85. 85.
    McGall GH, Rabow LE, Ashley RG, Wu SH, Kozarich JW, Stubbe J (1992) J Am Chem Soc 114: 4958CrossRefGoogle Scholar
  86. 86.
    Rabow LE, McGall GH, Stubbe J, Kozarich JW (1990) J Am Chem Soc 112: 3203CrossRefGoogle Scholar
  87. 87.
    Absalon MJ, Wu W, Kozarich JW, Stubbe J (1995) Biochemistry 34: 2076CrossRefGoogle Scholar
  88. 88.
    Sugiyama H, Sera T, Dannoue Y, Marumoto R, Saito I (1991) J Am Chem Soc 113: 2290CrossRefGoogle Scholar
  89. 89.
    Sugiyama H, Ohmori K, Saito I (1994) J Am Chem Soc 116: 10,326CrossRefGoogle Scholar
  90. 90.
    Bigeleisen J (1949) J Chem Phys 17: 675CrossRefGoogle Scholar
  91. 91.
    Fry A (1970) Heavy atom isotope effects in organic reaction mechanism studies. In: Collins CJ, Bowman NS (eds) Isotope effects in chemical reactions. Van Nostrand Reinhold, New York, p 364Google Scholar
  92. 92.
    Klinman JP (1978) Adv Enzymol 46: 415Google Scholar
  93. 93.
    Rashid R, Langfinger D, Wagner R, Schuchmann H-P, von Sonntag C (1999) Int J Radiat 75: 101CrossRefGoogle Scholar
  94. 94.
    Takeshita M, Grollman AP (1979) A molecular basis for the interaction of bleomycin with DNA. In: Hecht SM (ed) Bleomycin: chemical, biochemical, and biological aspects. Springer, Berlin Heidelberg New York, p 207Google Scholar
  95. 95.
    Burger RM, Drlica K (1996) Bleomycin reaction pathways: kinetic approaches. In: Meunier B (ed) DNA and RNA cleavers and chemotherapy of cancer and viral disease. Kluwer, Dordrecht, Netherlands, p 91Google Scholar
  96. 96.
    Burger RM, Projan SJ, Horwitz SB, Peisach J (1986) J Biol Chem 261: 15,955Google Scholar
  97. 97.
    Burger RM, Drlica K, Birdsall B (1994) J Biol Chem 269: 25,978Google Scholar
  98. 98.
    Solomon EI, Brunold TC, Davis MI, Kemsley JN, Lee S-K, Lehnert N, Neese F, Skulan AJ, Yang Y-S, Zhou J (2000) Chem Rev 100: 235CrossRefGoogle Scholar
  99. 99.
    Boger DL, Ramsey TM, Cai H, Hoehn ST, Kozarich JW, Stubbe J ( 1998) J Am Chem Soc 120: 53CrossRefGoogle Scholar

Copyright information

© Springer Verlag Berlin Heidelberg 2000

Authors and Affiliations

  • Richard M. Burger
    • 1
  1. 1.Public Health Research InstituteNew YorkUSA

Personalised recommendations