Cellular Protection Against the Antitumor Drug Bleomycin

  • Dindial Ramotar
  • Huijie Wang
  • Chaunhua He
Part of the Cancer Drug Discovery and Development book series (CDD&D)


Bleomycin is a basic hydrosoluble antibiotic originally isolated as a copper complex from the culture medium of Streptomyces verticillis (1,2). Bleomycin comprises a family of 11 isomers differing only in the terminal amine moiety (see Fig. 1), and the most abundant form is bleomycin-A2 (2–5). By the late sixties, substantial evidence had accumulated showing that bleomycin can diminish the growth of experimentally induced tumors in mice and rats and dramatically decrease the size of human tumors (6–10). It has been postulated that bleomycin mediates the cell killing by directly attacking the DNA (11,12). This notion rapidly gained support from subsequent independent studies showing that bleomycin triggers the induction of lysogenic phage in bacteria, a result of DNA damage, and induces mitotic recombination and mutations in many model sys tems, including the budding yeast Saccharomyces cerevisiae, Aspergillus, and Drosophila (13–18). Later studies also showed that bleomycin can induce micro-nuclei formation and chromosome aberrations in human lymphocytes (19). The accumulated findings strongly suggest that bleomycin may mediate its effect as a chemotherapeutic agent by mutating the DNA (20–23). However, more recent studies showed that RNA is also a target for bleomycin, raising debate about the actual therapeutic cellular target (i.e., DNA vs RNA) (24).


Saccharomyces Cerevisiae Cellular Protection Drug Efflux Pump Methyl Methane Sulfonate Methyl Methane Sulfonate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Umezawa H. Bleomycin and other antitumor antibiotics of high molecular weight. Antimicrobial Agents Chemother 1965;5:1079–1085.Google Scholar
  2. 2.
    Umezawa H, Maeda K, Takeuchi T, et al. New antibiotics, bleomycin A and B. J Antibiot (Tokyo) 1966;19:200–209.Google Scholar
  3. 3.
    Umezawa H, Ishizuka M, Maeda K, et al. Studies on bleomycin. Cancer 1967;20:891–895.PubMedCrossRefGoogle Scholar
  4. 4.
    Umezawa H. Natural and artificial bleomycins: chemistry and antitumor activities. Pure Appl Chem 1971;28:665–680.PubMedCrossRefGoogle Scholar
  5. 5.
    Fisher LM, Kuroda R, Sakai TT. Interaction of bleomycin A2 with deoxyribonucleic acid: DNA unwinding and inhibition of bleomycin-induced DNA breakage by cationic thiazole amides related to bleomycin A2. Biochemistry 1985;24:3199–31207.PubMedCrossRefGoogle Scholar
  6. 6.
    Suzuki H, Nagai K, Yamaki H, et al. Mechanism of action of bleomycin. Studies with the growing culture of bacterial and tumor cells. J Antibiot (Tokyo) 1968;21:379–386.CrossRefGoogle Scholar
  7. 7.
    Kanno T, Nakazawa T, Sugimoto T. Study of bleomycin on brain tumors. 1. Inhibitory effect of bleomycin on cultured brain tumor cells. Seishin Igaku Kenkyusho Gyosekishu 1969;16:23–31 (in Japanese).PubMedGoogle Scholar
  8. 8.
    Terasima T, Umezawa H. Lethal effect of bleomycin on cultured mammalian cells. J Antibiot (Tokyo) 1970;23:300–304.CrossRefGoogle Scholar
  9. 9.
    Ichikawa T, Nakano I, Hirokawa I. Bleomycin treatment of the tumors of penis and scrotum. J Urol 1969;102:699–707.PubMedGoogle Scholar
  10. 10.
    Oka S, Sato K, Nakai Y, et al. Treatment of lung cancer with bleomycin. II. Sci Rep Res Inst Tohoku Univ[Med] 1970;17:77–91.Google Scholar
  11. 11.
    Terasima T, Yasukawa M, Umezawa H. Breaks and rejoining of DNA in cultured mammalian cells treated with bleomycin. Gann 1970;61:513–516.PubMedGoogle Scholar
  12. 12.
    Suzuki H, Nagai K, Akutsu E, et al. On the mechanism of action of bleomycin. Strand scission of DNA caused by bleomycin and its binding to DNA in vitro. J Antibiot (Tokyo) 1970;23:473–480.CrossRefGoogle Scholar
  13. 13.
    Haidle CW, Weiss KK, Mace ML Jr. Induction of bacteriophage by bleomycin. Biochem Biophys Res Commun 1972;48:1179–1184.PubMedCrossRefGoogle Scholar
  14. 14.
    Ferguson LR, Turner PM. “Petite” mutagenesis by anticancer drugs in Saccharomyces cerevisiae. Eur J Cancer Clin Oncol 1988;24:591–596.PubMedCrossRefGoogle Scholar
  15. 15.
    Koy JF, Pleninger P, Wall L, et al. Genetic changes and bioassays in bleomycin- and phleomycin-treated cells, and their relationship to chromosomal breaks. Mutat Res 1995;336:19–27.PubMedCrossRefGoogle Scholar
  16. 16.
    Demopoulos NA, Stamatis ND, Yannopoulos G. Induction of somatic and male crossing-over by bleomycin in Drosophila melanogaster. Mutat Res 1980;78:347–351.PubMedCrossRefGoogle Scholar
  17. 17.
    Demopoulos NA, Kappas A, Pelecanos M. Recombinogenic and mutagenic effects of the antitumor antibiotic bleomycin in Aspergillus nidulans. Mutat Res 1982;102:51–57.PubMedCrossRefGoogle Scholar
  18. 18.
    Cederberg H, Ramel C. Modifications of the effect of bleomycin in the somatic mutation and recombination test in Drosophila melanogaster. Mutat Res 1989;214:69–80.PubMedCrossRefGoogle Scholar
  19. 19.
    Hoffmann GR, Colyer SP, Littlefield LG. Induction of micronuclei by bleomycin in GO human lymphocytes: I. Dose-response and distribution. Environ Mol Mutagen 1993;21: 130–135.PubMedCrossRefGoogle Scholar
  20. 20.
    Burger RM, Peisach J, Horwitz SB. Activated bleomycin. A transient complex of drug, iron, and oxygen that degrades DNA. J Biol Chem 1981;256:11,636–11,644.Google Scholar
  21. 21.
    Burger RM, Peisach J, Horwitz SB. Stoichiometry of DNA strand scission and aldehyde formation by bleomycin. J Biol Chem 1982;257:8612–8614.PubMedGoogle Scholar
  22. 22.
    Hecht SM. DNA strand scission by activated bleomycin group antibiotics. Fed Proc 1986;45:2784–2791.PubMedGoogle Scholar
  23. 23.
    Kane SA, Hecht SM. Polynucleotide recognition and degradation by bleomycin. Prog Nucleic Acid Res Mol Biol 1994;49:313–352.PubMedCrossRefGoogle Scholar
  24. 24.
    Hecht SM. Bleomycin: new perspectives on the mechanism of action. J Nat Prod 2000;63:158–168.PubMedCrossRefGoogle Scholar
  25. 25.
    Wharam MD, Phillips TL, Kane L, et al. Response of a murine solid tumor to in vivo combined chemotherapy and irradiation. Radiology 1973;109:451–455.PubMedGoogle Scholar
  26. 26.
    Jani JP, Mistry JS, Morris G, et al. In vivo circumvention of human colon carcinoma resistance to bleomycin. Cancer Res 1992;52:2931–2937.PubMedGoogle Scholar
  27. 27.
    Povirk LF, Austin MJ. Genotoxicity of bleomycin. Mutat Res 1991;257:127–143.PubMedCrossRefGoogle Scholar
  28. 28.
    Lazo JS, Sebti SM, Schellens JH. Bleomycin. Cancer Chemother Biol Response Modif 1996;16:39–47.PubMedGoogle Scholar
  29. 29.
    Dorr RT. Bleomycin pharmacology: mechanism of action and resistance, and clinical pharmacokinetics. Semin Oncol 1992;19:3–8.PubMedGoogle Scholar
  30. 30.
    Sikic BI. Biochemical and cellular determinants of bleomycin cytotoxicity. Cancer Surveys 1986;5:81–91.PubMedGoogle Scholar
  31. 31.
    Harrison JH Jr, Lazo JS. High dose continuous infusion of bleomycin in mice: a new model for drug-induced pulmonary fibrosis. J Pharmacol Exp Ther 1987;243:1185–1194.PubMedGoogle Scholar
  32. 32.
    Ekimoto H, Takahashi K, Matsuda A, et al. Lipid peroxidation by bleomycin-iron complexes in vitro. J Antibiot (Tokyo). 1985;38:1077–1082.CrossRefGoogle Scholar
  33. 33.
    Wang Q, Wang Y, Hyde DM, et al. Effect of antibody against integrin alpha4 on bleomycin-induced pulmonary fibrosis in mice. Biochem Pharmacol 2000;60:1949–1958.PubMedCrossRefGoogle Scholar
  34. 34.
    Miyaki M, Ono T, Hori S, et al. Binding of bleomycin to DNA in bleomycin-sensitive and -resistant rat ascites hepatoma cells. Cancer Res 1975;35:2015–2019.PubMedGoogle Scholar
  35. 35.
    Akiyama S, Ikezaki K, Kuramochi H, et al. Bleomycin-resistant cells contain increased bleomycin-hydrolase activities. Biochem Biophys Res Commun 1981;101:55–60.PubMedCrossRefGoogle Scholar
  36. 36.
    Morris G, Mistry JS, Jani JP, et al. Neutralization of bleomycin hydrolase by an epitope-specific antibody. Mol Pharmacol 1992;42:57–62.PubMedGoogle Scholar
  37. 37.
    Sebti SM, Jani JP, Mistry JS, et al. Metabolic inactivation: a mechanism of human tumor resistance to bleomycin. Cancer Res 1991;51:227–232.PubMedGoogle Scholar
  38. 38.
    Urade M, Ogura T, Mima T, et al. Establishment of human squamous carcinoma cell lines highly and minimally sensitive to bleomycin and analysis of factors involved in the sensitivity. Cancer 1992;69:2589–2597.PubMedCrossRefGoogle Scholar
  39. 39.
    Pron G, Belehradek J Jr, Mir LM. Identification of a plasma membrane protein that specifically binds bleomycin. Biochem Biophys Res Commun 1993;194:333–337.PubMedCrossRefGoogle Scholar
  40. 40.
    Pron G, Belehradek J Jr, Orlowski S, et al. Involvement of membrane bleomycin-binding sites in bleomycin cytotoxicity. Biochem Pharmacol 1994;48:301–310.PubMedCrossRefGoogle Scholar
  41. 41.
    Pron G, Mahrour N, Orlowski S, et al. Internalisation of the bleomycin molecules responsible for bleomycin toxicity: a receptor-mediated endocytosis mechanism. Biochem Pharmacol 1999;57:45–56.PubMedCrossRefGoogle Scholar
  42. 42.
    Poddevin B, Orlowski S, Belehradek J Jr, et al. Very high cytotoxicity of bleomycin introduced into the cytosol of cells in culture. Biochem Pharmacol 1991;(42 Suppl):S67–S75.PubMedCrossRefGoogle Scholar
  43. 43.
    Tounekti O, Pron G, Belehradek J Jr et al. Bleomycin, an apoptosis-mimetic drug that induces two types of cell death depending on the number of molecules internalized. Cancer Res 1993;53:5462–5469.PubMedGoogle Scholar
  44. 44.
    Tounekti O, Belehradek J Jr, Mir LM. [Bleomycin is an antineoplastic agent capable of mimicking apoptosis]. Bull Cancer 1994;81:1043–1049.PubMedGoogle Scholar
  45. 45.
    Tounekti O, Kenani A, Foray N, et al. The ratio of single- to double-strand DNA breaks and their absolute values determine cell death pathway. Br J Cancer 2001;84:1272–1279.PubMedCrossRefGoogle Scholar
  46. 46.
    Oppenheimer NJ, Rodriguez LO, Hecht SM. Metal binding to modified bleomycins. Zinc and ferrous complexes with an acetylated bleomycin. Biochemistry 1980; 19: 4096–4103.PubMedCrossRefGoogle Scholar
  47. 47.
    Ehrenfeld GM, Rodriguez LO, Hecht SM, et al. Copper(I)-bleomycin: structurally unique complex that mediates oxidative DNA strand scission. Biochemistry 1985;24:81–92.PubMedCrossRefGoogle Scholar
  48. 48.
    Ehrenfeld GM, Shipley JB, Heimbrook DC, et al. Copper-dependent cleavage of DNA by bleomycin. Biochemistry 1987;26:931–942.PubMedCrossRefGoogle Scholar
  49. 49.
    Levy MJ, Hecht SM. Copper(II) facilitates bleomycin-mediated unwinding of plasmid DNA. Biochemistry 1988;27:2647–2650.PubMedCrossRefGoogle Scholar
  50. 50.
    Petering DH, Mao Q, Li W, et al. Metallobleomycin-DNA interactions: structures and reactions related to bleomycin-induced DNA damage. Met Ions Biol Syst 1996;33:619–648.PubMedGoogle Scholar
  51. 51.
    Hoehn ST, Junker HD, Bunt RC, et al. Solution structure of co(iii)-bleomycin-OOH bound to a phosphoglycolate lesion containing oligonucleotide: implications for bleomycin-induced double-strand DNA cleavage. Biochemistry 2001;40:5894–5905.PubMedCrossRefGoogle Scholar
  52. 52.
    Oppenheimer NJ, Chang C, Rodriguez LO, et al. Copper(I). bleomycin. A structurally unique oxidation-reduction active complex. J Biol Chem 1981;256:1514–1517.PubMedGoogle Scholar
  53. 53.
    Sausville EA, Peisach J, Horwitz SB. A role for ferrous ion and oxygen in the degradation of DNA by bleomycin. Biochem Biophys Res Commun 1976;73:814–822.PubMedCrossRefGoogle Scholar
  54. 54.
    Sausville EA, Stein RW, Peisach J, et al. Properties and products of the degradation of DNA by bleomycin and iron(II). Biochemistry 1978;17:2746–2754.PubMedCrossRefGoogle Scholar
  55. 55.
    Sausville EA, Peisach J, Horwitz SB. Effect of chelating agents and metal ions on the degradation of DNA by bleomycin. Biochemistry 1978;17:2740–2746.PubMedCrossRefGoogle Scholar
  56. 56.
    Kane S A, Natrajan A, Hecht SM. On the role of the bithiazole moiety in sequence-selective DNA cleavage by Fe-bleomycin. J Biol Chem 1994;269:10,899–10,904.Google Scholar
  57. 57.
    Abraham AT, Zhou X, Hecht SM. DNA cleavage by Fe(II). bleomycin conjugated to a solid support. J Am Chem Soc 1999;121:1982–1983.CrossRefGoogle Scholar
  58. 58.
    Leitheiser CJ, Rishel MJ, Wu X, et al. Solid-phase synthesis of bleomycin group antibiotics. Elaboration of deglycobleomycin A(5). Org Lett 2000;2:3397–3399.PubMedCrossRefGoogle Scholar
  59. 59.
    Burger RM. Cleavage of nucleic acids by bleomycin. Chem Rev 1998;98:1153–1169.PubMedCrossRefGoogle Scholar
  60. 60.
    Burger RM, Peisach J, Blumberg WE, et al. Iron-bleomycin interactions with oxygen and oxygen analogues. Effects on spectra and drug activity. J Biol Chem 1979;254:10,906–10,912.Google Scholar
  61. 61.
    Povirk LF, Wubter W, Kohnlein W, et al. DNA double-strand breaks and alkali-labile bonds produced by bleomycin. Nucleic Acids Res 1977;4:3573–3580.PubMedCrossRefGoogle Scholar
  62. 62.
    Ekimoto H, Kuramochi H, Takahashi K, et al. Kinetics of the reaction of bleomycin-Fe(II)-02 complex with DNA. J Antibiot (Tokyo) 1980;33:426–434.CrossRefGoogle Scholar
  63. 63.
    Burger RM, Berkowitz AR, Peisach J, et al. Origin of malondialdehyde from DNA degraded by Fe(II) x bleomycin. J Biol Chem 1980;255:11,832–11,838.Google Scholar
  64. 64.
    Burger RM, Peisach J, Horwitz SB. Mechanism of bleomycin action: in vitro studies. Life Sci 1981;28:715–727.PubMedCrossRefGoogle Scholar
  65. 65.
    Worth L Jr, Frank BL, Christner DF, et al. Isotope effects on the cleavage of DNA by bleomycin: mechanism and modulation. Biochemistry 1993;32:2601–2609.PubMedCrossRefGoogle Scholar
  66. 66.
    Giloni L, Takeshita M, Johnson F, et al. Bleomycin-induced strand-scission of DNA. Mechanism of deoxyribose cleavage. J Biol Chem 1981;256:8608–8615.PubMedGoogle Scholar
  67. 67.
    Dedon PC, Plastaras JP, Rouzer CA, et al. Indirect mutagenesis by oxidative DNA damage: formation of the pyrimidopurinone adduct of deoxyguanosine by base propenal. Proc Natl Acad Sci USA 1998;95:11,113–11,116.CrossRefGoogle Scholar
  68. 68.
    Chaudhary AK, Nokubo M, Reddy GR, et al. Detection of endogenous malondialdehyde -deoxyguanosine adducts in human liver. Science 1994;265:1580–1582.PubMedCrossRefGoogle Scholar
  69. 69.
    Fink SP, Reddy GR, Marnett LJ. Mutagenicity in Escherichia coli of the major DNA adduct derived from the endogenous mutagen malondialdehyde. Proc Natl Acad Sci USA 1997;94:8652–8657.PubMedCrossRefGoogle Scholar
  70. 70.
    Mao H, Schnetz-Boutaud NC, Weisenseel JP, et al. Duplex DNA catalyzes the chemical rearrangement of a malondialdehyde deoxyguanosine adduct. Proc Natl Acad Sci USA 1999;96:6615–6620.PubMedCrossRefGoogle Scholar
  71. 71.
    Absalon MJ, Wu W, Kozarich JW, et al. Sequence-specific double-strand cleavage of DNA by Fe-bleomycin. 2. Mechanism and dynamics. Biochemistry 1995;34:2076–2086.PubMedCrossRefGoogle Scholar
  72. 72.
    Dedon PC, Goldberg IH. Free-radical mechanisms involved in the formation of sequence-dependent bistranded DNA lesions by the antitumor antibiotics bleomycin, neocarzinostatin, and calicheamicin. Chem Res Toxicol 1992;5:311–332.PubMedCrossRefGoogle Scholar
  73. 73.
    Steighner RJ, Povirk LF. Bleomycin-induced DNA lesions at mutational hot spots: implications for the mechanism of double-strand cleavage. Proc Natl Acad Sci USA 1990;87: 8350–8354.PubMedCrossRefGoogle Scholar
  74. 74.
    Onishi T, Iwata H, Takagi Y. Effects of reducing and oxidizing agents on the action of bleomycin. J Biochem (Tokyo) 1975;77:745–752.Google Scholar
  75. 75.
    Burger RM, Peisach J, Horwitz SB. Effects of 02 on the reactions of activated bleomycin. J Biol Chem 1982;257:3372–3375.PubMedGoogle Scholar
  76. 76.
    Burger RM, Blanchard JS, Horwitz SB, et al. The redox state of activated bleomycin. J Biol Chem 1985;260:15,406–15,409.Google Scholar
  77. 77.
    Templin J, Berry L, Lyman S, et al. Properties of redox-inactivated bleomycins. In vitro DNA damage and inhibition of Ehrlich cell proliferation. Biochem Pharmacol 1992;43: 615–623.PubMedCrossRefGoogle Scholar
  78. 78.
    Absalon MJ, Kozarich JW, Stubbe J. Sequence-specific double-strand cleavage of DNA by Fe-bleomycin. 1. The detection of sequence-specific double-strand breaks using hairpin oligonucleotides. Biochemistry 1995;34:2065–2075.PubMedCrossRefGoogle Scholar
  79. 79.
    Povirk LF. Catalytic release of deoxyribonucleic acid bases by oxidation and reduction of an iron.bleomycin complex. Biochemistry 1979;18:3989–3995.PubMedCrossRefGoogle Scholar
  80. 80.
    Kuroda R, Shinomiya M, Otsuka M. Origin of sequence specific cleavage of DNA by bleomycins. Nucleic Acids Symp Ser 1992;27:9–10.PubMedGoogle Scholar
  81. 81.
    Nightingale KP, Fox KR. DNA structure influences sequence specific cleavage by bleomycin. Nucleic Acids Res 1993;21:2549–2555.PubMedCrossRefGoogle Scholar
  82. 82.
    Kuroda R, Satoh H, Shinomiya M, et al. Novel DNA photocleaving agents with high DNA sequence specificity related to the antibiotic bleomycin A2. Nucleic Acids Res 1995;23:1524–1530.PubMedCrossRefGoogle Scholar
  83. 83.
    Kane S A, Hecht SM, Sun JS, et al. Specific cleavage of a DNA triple helix by Fellbleomycin. Biochemistry 1995;34:16,715–16,724.CrossRefGoogle Scholar
  84. 84.
    Mascharak PK, Sugiura Y, Kuwahara J, et al. Alteration and activation of sequence-specific cleavage of DNA by bleomycin in the presence of the antitumor drug cis-diamminedichloro-platinum(II). Proc Natl Acad Sci USA 1983;80:6795–6798.PubMedCrossRefGoogle Scholar
  85. 85.
    Hertzberg RP, Caranfa MJ, Hecht SM. DNA methylation diminishes bleomycin-mediated strand scission. Biochemistry 1985;24:5286–5289.PubMedCrossRefGoogle Scholar
  86. 86.
    Hertzberg RP, Caranfa MJ, Hecht SM. Degradation of structurally modified DNAs by bleomycin group antibiotics. Biochemistry 1988;27:3164–3174.PubMedCrossRefGoogle Scholar
  87. 87.
    Bennett RA, Swerdlow PS, Povirk LF. Spontaneous cleavage of bleomycin-induced abasic sites in chromatin and their mutagenicity in mammalian shuttle vectors. Biochemistry 1993;32:3188–3195.PubMedCrossRefGoogle Scholar
  88. 88.
    Dar ME, Jorgensen TJ. Deletions at short direct repeats and base substitutions are characteristic mutations for bleomycin-induced double- and single-strand breaks, respectively, in a human shuttle vector system. Nucleic Acids Res 1995;23:3224–3230.PubMedCrossRefGoogle Scholar
  89. 89.
    Pavon V, Esteve I, Guerrero R, et al. Induced mutagenesis by bleomycin in the purple sulfur bacterium Thiocapsa roseopersicina. Curr Microbiol 1995;30:117–120.PubMedCrossRefGoogle Scholar
  90. 90.
    Steighner RJ, Povirk LF. Effect of in vitro cleavage of apurinic/apyrimidinic sites on bleomycin-induced mutagenesis of repackaged lambda phage. Mutat Res 1990;240:93–100.PubMedCrossRefGoogle Scholar
  91. 91.
    Tates AD, van Dam FJ, Natarajan AT, et al. Frequencies of HPRT mutants and micronuclei in lymphocytes of cancer patients under chemotherapy: a prospective study. Mutat Res 1994;307:293–306.PubMedCrossRefGoogle Scholar
  92. 92.
    Carter BJ, de Vroom E, Long EC, et al. Site-specific cleavage of RNA by Fe(II).bleomycin. Proc Natl Acad Sci USA 1990;87:9373–9377.PubMedCrossRefGoogle Scholar
  93. 93.
    Huttenhofer A, Hudson S, Noller HF, et al. Cleavage of tRNA by Fe(II)-bleomycin. J Biol Chem 1992;267:24,471–24,45.Google Scholar
  94. 94.
    Holmes CE, Hecht SM. Febleomycin cleaves a transfer RNA precursor and its “transfer DNA” analog at the same major site. J Biol Chem 1993;268:25,909–25,913.Google Scholar
  95. 95.
    Hecht SM. RNA degradation by bleomycin, a naturally occurring bioconjugate. Bioconjug Chem 1994;5:513–526.PubMedCrossRefGoogle Scholar
  96. 96.
    Keck MV, Hecht SM. Sequence-specific hydrolysis of yeast tRNA(Phe) mediated by metal-free bleomycin. Biochemistry 1995;34:12,029–12,037.CrossRefGoogle Scholar
  97. 97.
    Morgan MA, Hecht SM. Iron(II) bleomycin-mediated degradation of a DNA-RNA hetero-duplex. Biochemistry 1994;33:10,286–10,293.CrossRefGoogle Scholar
  98. 98.
    Holmes CE, Carter BJ, Hecht SM. Characterization of iron (II).bleomycin-mediated RNA strand scission. Biochemistry 1993;32:4293–4307.PubMedCrossRefGoogle Scholar
  99. 99.
    Holmes CE, Duff RJ, van der Marel GA, et al. On the chemistry of RNA degradation by Febleomycin. Bioorg Med Chem 1997;5:1235–1248.PubMedCrossRefGoogle Scholar
  100. 100.
    Moore CW, Del Valle R, McKoy J, et al. Lesions and preferential initial localization of [,S-methyl-3H]bleomycin A2 on Saccharomyces cerevisiae cell walls and membranes. Antimicrob Agents Chemother 1992;36:2497–2505.PubMedCrossRefGoogle Scholar
  101. 101.
    Beaudouin R, Lim ST, Steide JA, et al. Bleomycin affects cell wall anchorage of mannoproteins in Saccharomyces cerevisiae. Antimicrob Agents Chemother 1993;37: 1264–1269.PubMedCrossRefGoogle Scholar
  102. 102.
    Lim ST, Jue CK, Moore CW, et al. Oxidative cell wall damage mediated by bleomycin-Fe(II) in Saccharomyces cerevisiae. J Bacteriol 1995;177:3534–3539.PubMedGoogle Scholar
  103. 103.
    Hay J, Shahzeidi S, Laurent G. Mechanisms of bleomycin-induced lung damage. Arch Toxicol 1991;65:81–94.PubMedCrossRefGoogle Scholar
  104. 104.
    Arndt D, Zeisig R, Bechtel D, et al. Liposomal bleomycin: increased therapeutic activity and decreased pulmonary toxicity in mice. Drug Deliv 2001;8:1–7.PubMedCrossRefGoogle Scholar
  105. 105.
    Ramotar D. The apurinic-apyrimidinic endonuclease IV family of DNA repair enzymes. Biochem Cell Biol 1997;75:327–336.PubMedGoogle Scholar
  106. 106.
    Genilloud O, Garrido MC, Moreno F. The transposon Tn5 carries a bleomycin-resistance determinant. Gene 1984;32:225–233.PubMedCrossRefGoogle Scholar
  107. 107.
    Collis CM, Hall RM. Identification of a Tn5 determinant conferring resistance to phleomycins, bleomycins, and tallysomycins. Plasmid 1985;14:143–151.PubMedCrossRefGoogle Scholar
  108. 108.
    Blot M, Meyer J, Arber W. Bleomycin-resistance gene derived from the transposon Tn5 confers selective advantage to Escherichia coli K-12. Proc Natl Acad Sci USA 1991;88: 9112–9116.PubMedCrossRefGoogle Scholar
  109. 109.
    Semon D, Movva NR, Smith TF, et al. Plasmid-determined bleomycin resistance in Staphylococcus aureus. Plasmid 1987;17:46–53.CrossRefGoogle Scholar
  110. 110.
    Drocourt D, Calmels T, Reynes JP, et al. Cassettes of the Streptoalloteichus hindustanus ble gene for transformation of lower and higher eukaryotes to phleomycin resistance. Nucleic Acids Res 1990; 18:4009.PubMedCrossRefGoogle Scholar
  111. 111.
    Gennimata D, Davies J, Tsiftsoglou AS. Bleomycin resistance in Staphylococcus aureus clinical isolates. J Antimicrob Chemother 1996;37:65–75.PubMedCrossRefGoogle Scholar
  112. 112.
    Gatignol A, Baron M, Tiraby G. Phleomycin resistance encoded by the ble gene from transposon Tn 5 as a dominant selectable marker in Saccharomyces cerevisiae. Mol Gen Genet 1987;207:342–348.PubMedCrossRefGoogle Scholar
  113. 113.
    Dumas P, Bergdoll M, Cagnon C, Crystal structure and site-directed mutagenesis of a bleomycin resistance protein and their significance for drug sequestering. EMBO J 1994;13:2483–2492.PubMedGoogle Scholar
  114. 114.
    Hayes JD, Wolf CR. Molecular mechanisms of drug resistance. Biochem J 1990;272: 281–295.PubMedGoogle Scholar
  115. 115.
    Maruyama M, Kumagai T, Matoba Y, et al. Crystal structures of the transposon Tn5-carried bleomycin resistance determinant uncomplexed and complexed with bleomycin. J Biol Chem 2001;276:9992–9999.PubMedCrossRefGoogle Scholar
  116. 116.
    Blot M, Heitman J, Arber W. Tn5-mediated bleomycin resistance in Escherichia coli requires the expression of host genes. Mol Microbiol 1993;8:1017–1024.PubMedCrossRefGoogle Scholar
  117. 117.
    Calcutt MJ, Schmidt FJ. Bleomycin biosynthesis: structure of the resistance genes of the producer organism. Ann NY Acad Sci 1994;721:133–137.PubMedCrossRefGoogle Scholar
  118. 118.
    Sugiyama M, Kumagai T, Matsuo H, et al. Overproduction of the bleomycin-binding proteins from bleomycin-producing Streptomyces verticillus and a methicillin-resistant Staphylococcus aureus in Escherichia coli and their immunological characterisation. FEBS Lett 1995;362:80–84.PubMedCrossRefGoogle Scholar
  119. 119.
    Umezawa H, Hori S, Sawa T, Yoshioka T, et al. A bleomycin-inactivating enzyme in mouse liver. J Antibiot (Tokyo) 1974;27:419–424.CrossRefGoogle Scholar
  120. 120.
    Sebti SM, Lazo JS. Metabolic inactivation of bleomycin analogs by bleomycin hydrolase. Pharmacol Ther 1988;38:321–329.PubMedCrossRefGoogle Scholar
  121. 121.
    Nishimura C, Suzuki H, Tanaka N, et al. Bleomycin hydrolase is a unique thiol aminopep-tidase. Biochem Biophys Res Commun 1989;163:788–796.PubMedCrossRefGoogle Scholar
  122. 122.
    Lazo JS, Humphreys CJ. Lack of metabolism as the biochemical basis of bleomycin-induced pulmonary toxicity. Proc Natl Acad Sci USA 1983;80:3064–3068.PubMedCrossRefGoogle Scholar
  123. 123.
    Ferrando AA, Velasco G, Campo E, et al. Cloning and expression analysis of human bleomycin hydrolase, a cysteine proteinase involved in chemotherapy resistance. Cancer Res 1996;56:1746–1750.PubMedGoogle Scholar
  124. 124.
    Jani JP, Mistry JS, Morris G, et al. In vivo sensitization of human lung carcinoma to bleomycin by the cysteine proteinase inhibitor E-64. Oncol Res 1992;4:59–63.PubMedGoogle Scholar
  125. 125.
    Enenkel C, Wolf DH. BLH1 codes for a yeast thiol aminopeptidase, the equivalent of mammalian bleomycin hydrolase. J Biol Chem 1993;268:7036–7043.PubMedGoogle Scholar
  126. 126.
    Magdolen U, Muller G, Magdolen V, et al. A yeast gene (BLH1) encodes a polypeptide with high homology to vertebrate bleomycin hydrolase, a family member of thiol proteinases. Biochim Biophys Acta 1993; 1171:299–303.PubMedCrossRefGoogle Scholar
  127. 127.
    Bromme D, Rossi AB, Smeekens SP, et al. Human bleomycin hydrolase: molecular cloning, sequencing, functional expression, and enzymatic characterization. Biochemistry 1996;35: 6706–6714.PubMedCrossRefGoogle Scholar
  128. 128.
    O’Farrell PA, Gonzalez F, Zheng W, et al. Crystal structure of human bleomycin hydrolase, a self-compartmentalizing cysteine protease. Structure Fold Des 1999;7:619–627.PubMedCrossRefGoogle Scholar
  129. 129.
    Pei Z, Calmels TP, Creutz CE, et al. Yeast cysteine proteinase gene yep 1 induces resistance to bleomycin in mammalian cells. Mol Pharmacol 1995;48:676–681.PubMedGoogle Scholar
  130. 130.
    Masson J Y, Ramotar D. The Saccharomyces cerevisiae IMP2 gene encodes a transcriptional activator that mediates protection against DNA damage caused by bleomycin and other oxidants. Mol Cell Biol 1996;16:2091–2100.PubMedGoogle Scholar
  131. 131.
    Zheng W, Xu HE, Johnston SA. The cysteine-peptidase bleomycin hydrolase is a member of the galactose regulon in yeast. J Biol Chem 1997;272:30,350–30,305.Google Scholar
  132. 132.
    Xu HE, Johnston SA. Yeast bleomycin hydrolase is a DNA-binding cysteine protease. Identification, purification, biochemical characterization. J Biol Chem 1994;269:21,177–21,183.Google Scholar
  133. 133.
    Joshua-Tor L, Xu HE, Johnston S A, et al. Crystal structure of a conserved protease that binds DNA: the bleomycin hydrolase, Gall. Science 1995;269:945–950.PubMedCrossRefGoogle Scholar
  134. 134.
    Zheng W, Johnston SA, Joshua-Tor L. The unusual active site of Gal6/bleomycin hydrolase can act as a carboxypeptidase, aminopeptidase, and peptide ligase. Cell 1998;93:103–109.PubMedCrossRefGoogle Scholar
  135. 135.
    Koldamova RP, Lefterov IM, DiSabella MT, et al. Human bleomycin hydrolase binds ribo-somal proteins. Biochemistry 1999;38:7111–7117.PubMedCrossRefGoogle Scholar
  136. 136.
    Schwartz DR, Homanics GE, Hoyt DG, et al. The neutral cysteine protease bleomycin hydrolase is essential for epidermal integrity and bleomycin resistance. Proc Natl Acad Sci USA 1999;96:4680–4685.PubMedCrossRefGoogle Scholar
  137. 137.
    Demple B, Harrison L. Repair of oxidative damage to DNA: enzymology and biology. Annu Rev Biochem 1994;63:915–948.PubMedCrossRefGoogle Scholar
  138. 138.
    Ramotar D, Popoff SC, Demple B. Complementation of DNA repair-deficient Escherichia coli by the yeast Apnl apurinic/apyrimidinic endonuclease gene. Mol Microbiol 1991;5:149–155.PubMedCrossRefGoogle Scholar
  139. 139.
    Demple B, Johnson A, Fung D. Exonuclease III and endonuclease IV remove 3’ blocks from DNA synthesis primers in H2O2-damaged Escherichia coli. Proc Natl Acad Sci USA 1986;83:7731–7735.PubMedCrossRefGoogle Scholar
  140. 140.
    Levin JD, Johnson AW, Demple B. Homogeneous Escherichia coli endonuclease IV. Characterization of an enzyme that recognizes oxidative damage in DNA. J Biol Chem 1988;263:8066–8071.PubMedGoogle Scholar
  141. 141.
    Levin JD, Demple B. In vitro detection of endonuclease IV-specific DNA damage formed by bleomycin in vivo. Nucleic Acids Res 1996;24:885–889.PubMedCrossRefGoogle Scholar
  142. 142.
    Cunningham RP, Saporito SM, Spitzer SG, et al. Endonuclease IV (nfo) mutant of Escherichia coli. J Bacteriol 1986;168:1120–1127.Google Scholar
  143. 143.
    Popoff SC, Spira AI, Johnson AW, et al. Yeast structural gene (APN1) for the major apurinic endonuclease: homology to Escherichia coli endonuclease IV. Proc Natl Acad Sci USA 1990;87:4193–4197.PubMedCrossRefGoogle Scholar
  144. 144.
    Ramotar D, Popoff SC, Gralla EB, et al. Cellular role of yeast Apn 1 apurinic endonuclease/ 3’-diesterase: repair of oxidative and alkylation DNA damage and control of spontaneous mutation. Mol Cell Biol 1991;11:4537–4544.PubMedGoogle Scholar
  145. 145.
    Sander M, Ramotar D. Partial purification of Pdel from Saccharomyces cerevisiae: enzymatic redundancy for the repair of 3’-terminal DNA lesions and abasic sites in yeast. Biochemistry 1997;36:6100–6106.PubMedCrossRefGoogle Scholar
  146. 146.
    Bennett RA. The Saccharomyces cerevisiae ETH1 gene, an inducible homolog of exonu-clease III that provides resistance to DNA-damaging agents and limits spontaneous mutagenesis. Mol Cell Biol 1999;19:1800–1809.PubMedGoogle Scholar
  147. 147.
    Johnson RE, Torres-Ramos CA, Izumi T, et al. Identification of APN2, the Saccharomyces cerevisiae homolog of the major human AP endonuclease HAP1, and its role in the repair of abasic sites. Genes Dev 1998;12:3137–3143.PubMedCrossRefGoogle Scholar
  148. 148.
    Jilani A, Ramotar D, Slack C, et al. Molecular cloning of the human gene, PNKP, encoding a polynucleotide kinase 3’-phosphatase and evidence for its role in repair of DNA strand breaks caused by oxidative damage. J Biol Chem 1999;274:24,176–24,186.CrossRefGoogle Scholar
  149. 149.
    Yang X, Tellier P, Masson JY, et al. Characterization of amino acid substitutions that severely alter the DNA repair functions of Escherichia coli endonuclease IV. Biochemistry 1999;38:3615–3623.PubMedCrossRefGoogle Scholar
  150. 150.
    Vance JR, Wilson TE. Uncoupling of 3’-phosphatase and 5’-kinase functions in budding yeast. Characterization of Saccharomyces cerevisiae DNA 3’-phosphatase (TPP1). J Biol Chem 2001;276:15,073–15,081.CrossRefGoogle Scholar
  151. 151.
    Abe H, Wada M, Kohno K, et al. Altered drug sensitivities to anticancer agents in radiation-sensitive DNA repair deficient yeast mutants. Anticancer Res 1994;14:1807–1810.PubMedGoogle Scholar
  152. 152.
    Keszenman DJ, Salvo VA, Nunes E. Effects of bleomycin on growth kinetics and survival of Saccharomyces cerevisiae: a model of repair pathways. J Bacteriol 1992; 174: 3125–3132.PubMedGoogle Scholar
  153. 153.
    Resnick MA, Martin P. The repair of double-strand breaks in the nuclear DNA of Saccharomyces cerevisiae and its genetic control. Mol Gen Genet 1976;143:119–129.PubMedCrossRefGoogle Scholar
  154. 154.
    Jentsch S, McGrath JP, Varshavsky A. The yeast DNA repair gene RAD6 encodes a ubiquitin-conjugating enzyme. Nature 1987;329:131–134.PubMedCrossRefGoogle Scholar
  155. 155.
    Madura K, Prakash S, Prakash L. Expression of the Saccharomyces cerevisiae DNA repair gene RAD6 that encodes a ubiquitin conjugating enzyme, increases in response to DNA damage and in meiosis but remains constant during the mitotic cell cycle. Nucleic Acids Res 1990;18:771–778.PubMedCrossRefGoogle Scholar
  156. 156.
    He CH, Masson JY, Ramotar D. A Saccharomyces cerevisiae phleomycin-sensitive mutant, phl40, is defective in the RAD6 DNA repair gene. Can J Microbiol 1996;42:1263–1266.PubMedCrossRefGoogle Scholar
  157. 157.
    Mages GJ, Feldmann HM, Winnacker EL. Involvement of the Saccharomyces cerevisiae HDF1 gene in DNA double-strand break repair and recombination. J Biol Chem 1996;271: 7910–7915.PubMedCrossRefGoogle Scholar
  158. 158.
    Feldmann H, Driller L, Meier B, et al. HDF2, the second subunit of the Ku homologue from Saccharomyces cerevisiae. J Biol Chem 1996;271:27,765–27,769.Google Scholar
  159. 159.
    Downs JA, Lowndes NF, Jackson SP. A role for Saccharomyces cerevisiae histone H2A in DNA repair. Nature 2000;408:1001–1004.PubMedCrossRefGoogle Scholar
  160. 160.
    Botstein D, Chervitz SA, Cherry JM. Yeast as a model organism [comment]. Science 1997;277:1259–1260.PubMedCrossRefGoogle Scholar
  161. 161.
    Phizicky EM, Fields S. Protein-protein interactions: methods for detection and analysis. Microbiol Rev 1995;59:94–123.PubMedGoogle Scholar
  162. 162.
    Winzeler EA, Davis RW. Functional analysis of the yeast genome. Curr Opin Genet Dev 1997;7:771–776.PubMedCrossRefGoogle Scholar
  163. 163.
    Winzeler EA, Shoemaker DD, Astromoff A, et al. Functional characterization of the S. cerevisiae genome by gene deletion and parallel analysis. Science 1999;285:901–906.PubMedCrossRefGoogle Scholar
  164. 164.
    Goldstein AL, McCusker JH, Knop M, et al. Three new dominant drug resistance cassettes for gene disruption in Saccharomyces cerevisiae. Yeast 1999;15:1541–1553.PubMedCrossRefGoogle Scholar
  165. 165.
    Lashkari DA, DeRisi JL, McCusker JH, et al. Yeast microarrays for genome wide parallel genetic and gene expression analysis. Proc Natl Acad Sci USA 1997;94:13,057–13,062.Google Scholar
  166. 166.
    Mayer G, Launhardt H, Munder T. Application of the green fluorescent protein as a reporter for Acel-based, two-hybrid studies. Biotechniques 1999;27:86–88, 92–94.PubMedGoogle Scholar
  167. 167.
    Pereira RIS. The use of baker’s yeast in the generation of asymmetric centers to produce chiral drugs and others compounds. Crit Rev Biotechnol 1998;18:25–83.CrossRefGoogle Scholar
  168. 168.
    Andrade MA, Sander C, Valencia A. Updated catalogue of homologues to human disease-related proteins in the yeast genome. FEBS Lett 1998;426:7–16.PubMedCrossRefGoogle Scholar
  169. 169.
    Bassett DE Jr, Basrai MA, Connelly C, et al. Exploiting the complete yeast genome sequence. Curr Opin Genet Dev 1996;6:763–766.PubMedCrossRefGoogle Scholar
  170. 170.
    Foury F. Human genetic diseases: a cross-talk between man and yeast. Gene 1997;195:1–10.PubMedCrossRefGoogle Scholar
  171. 171.
    Carney JP. Chromosomal breakage syndromes. Curr Opin Immunol 1999; 11:443–447.PubMedCrossRefGoogle Scholar
  172. 172.
    Modrich P, Lahue R. Mismatch repair in replication fidelity, genetic recombination, and cancer biology. Annu Rev Biochem 1996;65:101–133.PubMedCrossRefGoogle Scholar
  173. 173.
    Neff NF, Ellis NA, Ye TZ, et al. The DNA helicase activity of BLM is necessary for the correction of the genomic instability of bloom syndrome cells. MolBiol Cell 1999; 10:665–676.PubMedGoogle Scholar
  174. 174.
    Vermeulen W, de Boer J, Citterio E, et al. Mammalian nucleotide excision repair and syndromes. Biochem Soc Trans 1997;25:309–315.PubMedGoogle Scholar
  175. 175.
    Moore CW. Further characterizations of bleomycin-sensitive (blm) mutants of Saccharomyces cerevisiae with implications for a radiomimetic model. JBacteriol 1991; 173:3605–3608.Google Scholar
  176. 176.
    Burns N, Grimwade B, Ross-Macdonald PB, et al. Large-scale analysis of gene expression, protein localization, and gene disruption in Saccharomyces cerevisiae. Genes Dev 1994;8:1087–1105.Google Scholar
  177. 177.
    He CH, Masson JY, Ramotar D. Functional mitochondria are essential for Saccharomyces cerevisiae cellular resistance to bleomycin. Curr Genet 1996;30:279–283.PubMedCrossRefGoogle Scholar
  178. 178.
    He CH, Ramotar D. An allele of the yeast RPB7 gene, encoding an essential subunit of RNA polymerase II, reduces cellular resistance to the antitumor drug bleomycin. Biochem Cell Biol 1999;77:375–382.PubMedCrossRefGoogle Scholar
  179. 179.
    Donnini C, Lodi T, Ferrero I, et al. Allelism of IMP1 and GAL2 genes of Saccharomyces cerevisiae. J Bacteriol 1992;174:3411–3415.Google Scholar
  180. 180.
    Ramotar D, Masson JY. A Saccharomyces cerevisiae mutant defines a new locus essential for resistance to the antitumour drug bleomycin. Can J Microbiol 1996;42:835–843.PubMedCrossRefGoogle Scholar
  181. 181.
    Lodi T, Goffrini P, Ferrero I, et al. IMP2, a gene involved in the expression of glucose-repressible genes in Saccharomyces cerevisiae. Microbiology 1995;141:2201–2209.Google Scholar
  182. 182.
    Masson JY, Ramotar D. The transcriptional activator Imp2p maintains ion homeostasis in Saccharomyces cerevisiae. Genetics 1998;149:893–901.Google Scholar
  183. 183.
    Colwill K, Pawson T, Andrews B, et al. The Clk/Sty protein kinase phosphorylates SR splicing factors and regulates their intranuclear distribution. EMBO J 1996;15:265–275.PubMedGoogle Scholar
  184. 184.
    Rossi F, Labourier E, Forne T, et al. Specific phosphorylation of SR proteins by mammalian DNA topoisomerase I. Nature 1996;381:80–82.PubMedCrossRefGoogle Scholar
  185. 185.
    Kobe B, Deisenhofer J. The leucine-rich repeat: a versatile binding motif. Trends Biochem Sci 1994;19:415–421.PubMedCrossRefGoogle Scholar
  186. 186.
    Kobe B, Deisenhofer J. A structural basis of the interactions between leucine-rich repeats and protein ligands. Nature 1995;374:183–186.PubMedCrossRefGoogle Scholar
  187. 187.
    Benson JD, Benson M, Howley PM, Struhl K. Association of distinct yeast Not2 functional domains with components of Gcn5 histone acetylase and Ccr4 transcriptional regulatory complexes. EMBO J 1998;17:6714–6722.PubMedCrossRefGoogle Scholar
  188. 188.
    Giaccia AJ, Kastan MB. The complexity of p53 modulation: emerging patterns from divergent signals. Genes Dev 1998;12:2973–2983.PubMedCrossRefGoogle Scholar
  189. 189.
    Prives C, Hall PA. The p53 pathway. J Pathol 1999;187:112–126.PubMedCrossRefGoogle Scholar
  190. 190.
    Polyak K, Xia Y, Zweier JL, et al. A model for p53-induced apoptosis. [see comments]. Nature 1997;389:300–305.PubMedCrossRefGoogle Scholar
  191. 191.
    Alarco AM, Balan I, Talibi D, et al. API-mediated multidrug resistance in Saccharomyces cerevisiae requires FLR1 encoding a transporter of the major facilitator superfamily. J Biol Chem 1997;272:19,304–19,313.CrossRefGoogle Scholar
  192. 192.
    Coleman ST, Tseng E, Moye-Rowley WS. Saccharomyces cerevisiae basic region-leucine zipper protein regulatory networks converge at the ATR1 structural gene. J Biol Chem 1997;272:23,224–23,230.Google Scholar
  193. 193.
    Decottignies A, Lambert L, Catty P, et al. Identification and characterization of SNQ2, a new multidrug ATP binding cassette transporter of the yeast plasma membrane. J Biol Chem 1995;270:18,150–18,157.Google Scholar
  194. 194.
    Katzmann DJ, Hallstrom TC, Mahe Y, et al. Multiple Pdrlp/Pdr3p binding sites are essential for normal expression of the ATP binding cassette transporter protein-encoding gene PDR5. J Biol Chem 1996;271:23,049–23,054.Google Scholar
  195. 195.
    Katzmann DJ, Epping EA, Moye-Rowley WS. Mutational disruption of plasma membrane trafficking of Saccharomyces cerevisiae Yorlp, a homologue of mammalian multidrug resistance protein. Mol Cell Biol 1999;19:2998–3009.PubMedGoogle Scholar
  196. 196.
    Oskouian B, Saba JD. YAP1 confers resistance to the fatty acid synthase inhibitor cerulenin through the transporter Flrlp in Saccharomyces cerevisiae. Mol Gen Genet 1999;261:346–353.PubMedCrossRefGoogle Scholar
  197. 197.
    Wemmie J A, Moye-Rowley WS. Mutational analysis of the Saccharomyces cerevisiae ATP-binding cassette transporter protein Ycflp. Mol Microbiol 1997;25:683–694.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2004

Authors and Affiliations

  • Dindial Ramotar
  • Huijie Wang
  • Chaunhua He

There are no affiliations available

Personalised recommendations