Archives of Toxicology

, Volume 65, Issue 2, pp 81–94 | Cite as

Mechanisms of bleomycin-induced lung damage

  • John Hay
  • Shahriar Shahzeidi
  • Geoffrey Laurent


Bleomycins are a family of compounds produced byStreptomyces verticillis. They have potent tumour killing properties which have given them an important place in cancer chemotherapy. They cause little marrow suppression, but pulmonary toxicity is a major adverse effect. The mechanisms of cell toxicity are well described based on in vitro experiments on DNA. The bleomycin molecule has two main structural components; a bithiazole component which partially intercalates into the DNA helix, parting the strands, as well as pyrimidine and imidazole structures, which bind iron and oxygen forming an activated complex capable of releasing damaging oxidants in close proximity to the polynucleotide chains of DNA. This may lead to chain scission or structural modifications leading to release of free bases or their propenal derivatives. The mechanisms are well described based on in vitro experiments on DNA, but how they relate to intact cells in whole animals is more tenuous. Bleomycin is able to cause cell damage independent from its effect on DNA by inducing lipid peroxidation. This may be particularly important in the lung and in part account for its ability to cause alveolar cell damage and subsequent pulmonary inflammation. The lung injury seen following bleomycin comprises an interstitial oedema with an influx of inflammatory and immune cells. This may lead to the development of pulmonary fibrosis, characterized by enhanced production and deposition of collagen and other matrix components. Several polypeptide mediators capable of stimulating fibroblasts replication or excessive collagen deposition have been implicated in this, but the precise role of these in bleomycin-induced fibrosis is yet to be demonstrated. Current therapy for bleomycin-induced lung damage is inadequate, with corticosteroids most often used. Given the mechanism of action described above, antioxidants and iron chelators might be beneficial. Although, studies to date are equivocal and there is insufficient evidence to promote their use clinically. Novel drugs are currently being developed and it is hoped these may be more useful.

Key words

Bleomycin Lung damage 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Adamson IYR, Bowden DH (1979) Bleomycin-induced injury and metaplasia of alveolar type 2 cells. Am J Pathol 96: 531–538PubMedGoogle Scholar
  2. Agostini MJ, Bernacki RJ, Beerman TA (1984) Synergistic interactions of ethidium bromide and bleomycin on cellular DNA and growth inhibition. Biochem Biophys Res Commun 120: 156–163CrossRefPubMedGoogle Scholar
  3. Albertini JP, Garnier-Suillerot A (1984) Iron-bleomycin-deoxyribonucleic acid system. Evidence of DNA interaction with the α-amino group of the aminoalanine moiety. Biochemistry 23: 47–53CrossRefPubMedGoogle Scholar
  4. Alberts DS, Chen H-SG, Liu R, Himmelstein KJ, Mayersohn M, Perrier D, Gross J, Moon T, Broughton A, Salmon SE (1978) Bleomycin pharmacokinetics in man. Cancer Chemother Pharmacol 1: 177–181CrossRefPubMedGoogle Scholar
  5. Antholine WE, Hyde JS, Sealy RC, Petering DH (1984) Structure of cupric bleomycin. J Biol Chem 259: 4437–4440PubMedGoogle Scholar
  6. Antonelli G, Dianzani F, Damme JV, Amicucci P, Marco FD, Gefaro A (1988) A macrophage-derived factor different from interleukin-1 and able to induce interferon- and lymphoproliferation in resting T lymphocytes. Cell Immunol 113: 376–386CrossRefPubMedGoogle Scholar
  7. Assoian RK, Grotendorst GR, Miller DM, Sporn MB (1984) Cellular transformation by coordinated action of three peptide growth factors from human platelets. Nature (Lond) 309: 804–806CrossRefGoogle Scholar
  8. Baggiolini MJ, Schnyder J, Bretz U, Dewald B, Ruch W (1980) Cellular mechanisms of proteinase release from inflammatory cells and the degradation of extracellular proteins. In: Protein degradation in health and disease. Ciba Foundation Symposium 75, Excerpta Medica, New York, pp 105–118Google Scholar
  9. Baird A, Durkin T (1986) Inhibition of endothelial cell proliferation by TGFβ: Interaction with acidic and basic fibroblast growth factors. Biochem Biophys Res Commun 138: 476–482CrossRefPubMedGoogle Scholar
  10. Barlogie B, Drewinko B, Schumann J, Freireich EJ (1976) Pulse cytopotometric analysis of cell pertubation with bleomycin in vitro. Cancer Res 31: 1182–1187Google Scholar
  11. Barranco SC, Luce JK, Romsdahl MM, Humphrey RM (1973) Bleomycin as a possible synchronising agent for human tumour cell in vivo. Cancer Res 33: 882–887PubMedGoogle Scholar
  12. Bauer KA, Skarin AT, Balikian JP, Garnick MB, Rosenthal DS, Canellos GP (1983) Pulmonary complications associated with combination chemotherapy programs containing bleomycin. Am J Med 74: 557–763CrossRefPubMedGoogle Scholar
  13. Bedrossian CWM, Luna MA, Mackay B, Lichtiger B (1973) Ultrastructure of pulmonary bleomycin toxicity. Cancer 32: 44–51PubMedGoogle Scholar
  14. Bellamy EA, Husband JE, Blaquiere RM, Law MR (1985) Bleomycin related lung damage: CT evidence. Radiology 156: 155–158PubMedGoogle Scholar
  15. Bennett JM, Reich SD (1979) Drugs five years later. Bleomycin. Ann Int Med 90: 945–948Google Scholar
  16. Bernier J, Kenani A, Houssin R, Helbecque N, Lohez M, Heoquet B, Henichart J (1986) Molecular interactions between bleomycin and amsacrine in the presence of cupric ions. J Inorg Biochem 27: 271–285CrossRefPubMedGoogle Scholar
  17. Berry DE, Chang L, Hecht SM (1985a) DNA damage and growth inhibition in cultured human cells by bleomycin congeners. Biochemistry 24: 3207–3213CrossRefPubMedGoogle Scholar
  18. Berry DE, Kilkuskie RE, Hecht SM (1986b) DNA damage induced by bleomycin in the presence of dibucaine is not predictive of cell growth inhibition. Biochemistry 24: 3214–3219CrossRefGoogle Scholar
  19. Blum RH et al. (1973) A clinical review of bleomycin. Cancer 31: 903–914PubMedGoogle Scholar
  20. Broughton A, Strong J (1976) Radioimmunoassay of bleomycin. Cancer Res 35: 1418–1421Google Scholar
  21. Burger RM, Peisach J, Blumberg WE, Horwitz SB (1979) Iron-bleomycin interactions with oxygen and oxygen analogues. J Biol Chem 21: 10906–10912Google Scholar
  22. Burger RM, Peisach J, Horwitz SB (1981) Activated bleomycin. A transient complex of drug, iron and oxygen that degrades DNA. J Biol Chem 256: 11636–11644PubMedGoogle Scholar
  23. Burger RM, Peisach J, Horwitz SB (1982) Stoichiometry of DNA strand scission and aldehyde formation by bleomycin. J Biol Chem 257: 8612–8614PubMedGoogle Scholar
  24. Burger RM, Freedman JH, Horwitz SB, Peisach J (1984) DNA degradation of manganese (II)-bleomycin plus peroxide. Inorg Chem 23: 2215–2217CrossRefGoogle Scholar
  25. Burger RM, Blanchard JS, Horwitz SB, Peisach J (1985) The redox state of activated bleomycin. J Biol Chem 260: 15406–15409PubMedGoogle Scholar
  26. Catane R, Schwade JG, Turisi AT, Webbe BC, Muggin FM (1979) Pulmonary toxicity after irradiation and bleomycin. Int J Radiat Oncol Biol Phys 1513–1518Google Scholar
  27. Chandler DB, Hyde DM, Giri SN (1983) Morphometric estimates of infiltrative cellular changes during the development of bleomycin-induced pulmonary fibrosis in hamsters. Am J Pathol 112: 170–177PubMedGoogle Scholar
  28. Chandler DB, Fulmer JD (1985) The effect of deferoxamine on bleomycin-induced lung fibrosis in the hamster. Am Rev Respir Dis 131: 596–598PubMedGoogle Scholar
  29. Chang CH, Meares CF (1984) Cobalt-bleomycins and deoxyribonucleic acid: Sequence dependent interactions, action spectrum for nicking, and indifference to oxygen. Biochemistry 23: 2268–2274CrossRefPubMedGoogle Scholar
  30. Clark JG, Overton JE, Marino BA, Uitto J, Starcher BC (1980) Collagen biosynthesis in bleomycin-induced pulmonary fibrosis in hamsters. J Lab Clin Med 96: 943–953PubMedGoogle Scholar
  31. Collis CH (1980) Lung damage from cytotoxic drugs. Cancer Chemother Pharmacol 4: 17–27CrossRefPubMedGoogle Scholar
  32. Comis RL (1978) Bleomycin pulmonary toxicity. In: Carter SK, Umezawa H, Crooke ST (eds) Bleomycin status and new developments. Academic Press, New York, pp 279–291Google Scholar
  33. Cooper KR, Hong WK (1981) Prospective study of the pulmonary toxicity of continuously infused bleomycin. Cancer Treat Rep 65: 419–425PubMedGoogle Scholar
  34. Crapo JD, Tierney DF (1974) Superoxide dismutase and oxygen toxicity. Am J Physiol 226: 1401–1407PubMedGoogle Scholar
  35. Crooke ST, Einhorn LH, D'Aoust JC, Prestayko AW (1978) The effects of prior exposure to bleomycin on the incidence of pulmonary toxicities in a group of patients with disseminated testicular carcinomas. Med Pediatr Oncol 5: 93–98PubMedGoogle Scholar
  36. Cross CE, Warren D, Gerriets JE, Wilson DW, Halliwell B, Last JA (1985) Desferrioxamine injection does not affect bleomycin-induced lung fibrosis in rats. J Lab Clin Invest 106: 433–438Google Scholar
  37. Dalgleish AG, Woods RL, Levi JA (1984) Bleomycin pulmonary toxicity; its relationship to renal mysfunction. Med Pediatr Oncol 12: 313–317PubMedGoogle Scholar
  38. Dayer JM, Passwell HJ, Schneeberger EE, Krane SM (1980) Intercutions among rheumatoid synovial cells and monocyte-macrophages: production of collagenase-stimulating factor by human monocytes exposed to concanavalin A or immunoglobulin Fc fragments. J Immunol 124: 1712–1720PubMedGoogle Scholar
  39. Dayer JM, Beutler B, Cerami A (1985) Cachectin/tumor necrosis factor stimulates collagenase and prostaglandin E2 production by human synovial cells and dermal fibroblasts. J Exp Med 162: 2163–2168CrossRefPubMedGoogle Scholar
  40. DeLena M, Guzzon A, Monfardini S, Bonadonna G (1972) Clinical, radiologic and histopathologic studies on pulmonary toxicity induced by treatment with bleomycin. Cancer Chemother Rep 56: 343–355Google Scholar
  41. De-Petro G, Barlati S, Vartio T, Vaheri A (1983) Transformation-enhancing activity in plasma of tumour patients: Relationship with fibronectis fragments. Int J Cancer 31(2): 157–162PubMedGoogle Scholar
  42. DiCorleto PE (1984) Cultured endothelial cells produce multiple growth factors for connective tissue cells. Exp Cell Res 153: 167–172CrossRefPubMedGoogle Scholar
  43. Dingle JT, Saklatvala J, Hembry R, Tyler J, Fell HB, Jubb R (1979) A cartilage catabolic factor from synovium. Biochem J 184: 177–180PubMedGoogle Scholar
  44. Ehrenfeld GM, Murugesan N, Hecht SM (1984) Activation of oxygen and mediation of DNA degradation by manganese-bleomycin. Inorg Chem 23: 1496–1498CrossRefGoogle Scholar
  45. Ehrenfeld GM, Rodriguez LO, Hecht SM, Chang C, Basus VJ, Oppenheimer J (1985) Copper(I)-bleomycin: Structurally unique complex that mediates oxidative DNA strand scission. Biochemistry 24: 81–92CrossRefPubMedGoogle Scholar
  46. Einhorn L, Krause M, Hornback N, Furnas B (1976) Enchanced pulmonary toxicity with bleomycin and radiotherapy in oat cell lung cancer. Cancer 37: 2414–2416PubMedGoogle Scholar
  47. Ekimoto H, Takahashi K, Matsuda A, Takita T, Umezawa H (1985) Lipid peroxidation by bleomycin-rion complexes in vitro. J Antibiot 38: 1077–1082PubMedGoogle Scholar
  48. Fisher LM, Kuroda R, Sakai TT (1985) Interaction of bleomycin A2 with deoxyribonucleic acid: DNA unwinding and inhibition of bleomycin induced DNA breakage by cationic thiazol amides related to bleomycin A2. Biochemistry 24: 3199–3207CrossRefPubMedGoogle Scholar
  49. Frater-Schroder M, Miller G, Birchmeier W, Bohleu P (1986) TGFβ inhibits endothelial cell proliferation. Biochem Biophys Res Commun 137: 295–302CrossRefPubMedGoogle Scholar
  50. Giloni L, Takeshita M, Johnson F, Iden C, Grollman AP (1981) Bleomycin induced strand scission of DNA. Mechanism of deoxyribose cleavage. J Biol Chem 256: 8608–8615Google Scholar
  51. Ginsberg SJ, Comis RL (1982) The pulmonary toxicity of antineoplastic agents. Semin Oncol 9: 34–51PubMedGoogle Scholar
  52. Giri SN (1986) Pharmacokinetics, subcellular distribution and covalent binding of [3H] bleomycin in hamsters after intratracheal administration. Exp Mol Pathol 45: 207–220CrossRefPubMedGoogle Scholar
  53. Giri SN, Schwartz LW, Hollinger MA, Freywald MF, Schiedt MJ, Zuckerman JE (1980) Biochemical and structural alterations of hamster lungs in response to intratracheal administration of bleomycin. Exp Mol Pathol 33: 1–14CrossRefPubMedGoogle Scholar
  54. Goldstein RH, Lucey EC, Franzblau C, Snider GL (1979) Failure of mechanical properties of parallel changes in lung connective tissue composition in bleomycin-induced pulmonary fibrosis in hamsters. Am Rev Respir Dis 120: 67–73PubMedGoogle Scholar
  55. Goldiner PL, Carlon GC, Cvitovic E, Schweizer O, Howland WS (1978) Factors influencing postoperative morbidity and mortality in patients treated with bleomycin. Br Med J 1: 1664–1667PubMedGoogle Scholar
  56. Gray AJ, Reeves JT, Harrison NK, Winlove P, Laurent GJ (1990) Growth factors for human fibroblasts in the solute remaining after clot formation. J Cell Sci (in press)Google Scholar
  57. Grotendorst GR (1984) Alteration of the chemotactic response of NIH/3T3 cells of PDGF by growth factors, transformation and tumor promoters. Cell 36: 279–285CrossRefPubMedGoogle Scholar
  58. Grotendorst GR, Seppa HEJ, Kleinman HK, Martin GR (1981) Attachment of smooth muscle cells of collagen and their migration toward platelet-derived growth factor. Proc Natl Acad Sci 78: 3669–3672PubMedGoogle Scholar
  59. Gutteridge JMC, Richmond R, Halliwell B (1979) Inhibition of iron-catalysed formation of hydroxyl radicals from Superoxide and lipid peroxidation by desferioxamine. Biochem J 184: 469–472PubMedGoogle Scholar
  60. Haas CD, Coltman CA, Gottlieb JA, Haut A, Luce JK, Talley RW, Samal B, Wilson HE (1976) Phase II evaluation of bleomycin. Cancer 38: 8–12PubMedGoogle Scholar
  61. Halliwell B (1985) Use of desferrioxamine as a probe for iron-dependent formation of hydroxyl radicals. Evidence for a direct reaction between Desferal and the Superoxide radical. Biochem Pharmacol 1985; 34: 229–233CrossRefPubMedGoogle Scholar
  62. Hay JG, Haslam PL, Dewer A, Addis B, Laurent GJ (1987a) The development of acute lung injury following the combination of intravenous bleomycin and exposure to hyperoxia in rats. Thorax 42: 374–382PubMedGoogle Scholar
  63. Hay JG, Haslam PL, Staple LH, Laurent GJ (1987 b) Role of iron and oxygen in bleomycin-induced pulmonary edema. In: Alturaa BM, Davis E (eds) Advances in microcirculation 13: 239–255Google Scholar
  64. Hay JG, Haslam PL, Turner-Warwick M, Laurent GJ (1987c) The effect of iron and desferrioxamine on the lung injury induced by intravenous bleomycin and hyperoxia. Free Rad Res Commun 4: 109–114Google Scholar
  65. Hecht SM (1986) DNA strand scission by activated bleomycin group antibiotics. Fed Proc 45: 2784–2791PubMedGoogle Scholar
  66. Henichart JP, Bernier JL, Lemay P, Houssin R, Catteau JP (1984) Subcellular distribution of spin-labelled bithiazoles and bleomycin in living KB cells: an ESR study, Cancer Biochem Biophys 7: 239–244PubMedGoogle Scholar
  67. Hewitt SD, Hider RC, Serpong P, Morris CJ, Blake DR (1989) Investigation of the anti-inflammatory properties of hydroxypyridones. Ann Rheum Dis 48: 383–388Google Scholar
  68. Hider RC (1984) Siderophore mediated absorption of iron. Struct Bond 58: 25–87Google Scholar
  69. Holoye PY, Luna MA, MacKay B, Bedrossian CWM (1978) Bleomycin hypersensitivity pneumonitis. Ann Int Med 88: 47–49PubMedGoogle Scholar
  70. Hou D, Hoch H, Johnston GJ, Tsou KC, Farkas RJ, Miller EE (1984) Distribution and stability of [111In] bleomycin and its fractions in tumour-bearing mice. Int J Nucl Med Biol 11: 129–139CrossRefPubMedGoogle Scholar
  71. Iacovino JR, Leitner J, Abbas AK, Lokich JJ, Snider GL (1976) Fatal pulmonary reaction from low does of bleomycin. JAMA 235: 1253–1255CrossRefPubMedGoogle Scholar
  72. Itaka Y, Nakamura H, Nakatani T, Muraoka Y, Fujii A, Takita T, Umezawa H (1978) Chemistry of bleomycin. The X-ray structure determination of P3A Cu(II) complex. J Antibiot 31: 1070–1072PubMedGoogle Scholar
  73. James H, Harrison JR, Lazo JS (1987) High dose continuous infusion of bleomycin in mice: A new model for drug-induced pulmonary fibrosis. J Pharmacol Exp Ther 243(3): 1185–1194PubMedGoogle Scholar
  74. Jamieson DD, Kerr DR, Unsworth I (1987) Interaction of N-acetyl cysteine and bleomycin on hyperbaric oxygen-induced lung damage in mice. Lung 165[4]: 239–247PubMedGoogle Scholar
  75. Jimenez SA, Freundlich B, Rosenbloom J (1984) Selective inhibition of human diploid fibroblast collagen synthesis by interferons. J Clin Invest 74[3]: 1112–1116PubMedGoogle Scholar
  76. Joelson R, Warnock M (1983) Pulmonary veno-occlusive disease after chemotherapy. Hum Pathol 13: 88–91Google Scholar
  77. Jones AW (1978) Bleomycin lung damage: the pathology and nature of the lesion. Br J Dis Chest 72: 321–326PubMedGoogle Scholar
  78. Kanofsky JR (1986) Singlet oxygen production by bleomycin. J Biol Chem 261: 13546–13550PubMedGoogle Scholar
  79. Kappus H, Mahmutoglu I (1986) Oxygen radical formation during redox cycling of bleomycin-Fe(III) catalyzed by NADPH-cytochrome P-450 reductase of liver microsomes and nuclei. Adv Exp Med Biol 197: 273–280PubMedGoogle Scholar
  80. Karlinsky JB (1982) Glycosaminoglucans in emphysematous and fibrotic hamster lungs. Am Rev Respir Dis 125: 85–88Google Scholar
  81. Kehrl JH, Wakefield LM, Roberts AB, Jakowlew S, Alvarez-Mon M, Derynck R, Sporn MB, Fauci AS (1986a) Production of TGFβ by human T-lymphocyte and its potential role in the regulation of T-cell growth. J Exp Med 163: 1037–1050CrossRefPubMedGoogle Scholar
  82. Kehrl JH, Roberts AB, Wakefield LM, Jakowlew S, Sporn MB, Fauci AS (1986b) Transforming growth factor β is an important immunomodullatory protein for human B lymphocytes. J Immunol 137: 3855–3860PubMedGoogle Scholar
  83. Kempf RA, Mitchell MS (1985) Effects of chemotherapeutic agents on the immune response. Cancer Invest 3: 23–33PubMedGoogle Scholar
  84. Khalil N, Bereznay O, Sporn M, Greenberg AH (1989) Macrophage production of TGFβ and fibroblast collagen synthesis in chronic pulmonary inflammation. J Exp Med 170: 727–737CrossRefPubMedGoogle Scholar
  85. Khansur T, Little D, Tavassoli M (1984) Fulminant and fatal angiodema caused by bleomycin treatment. Arch Int Med 144: 2267CrossRefGoogle Scholar
  86. Koenig WJ, Cross CE, Hesterberg TW, Last JA (1983) Mechanism of methylprednisolone prevention of bleomycin induced pulmonary fibrosis. Chest 5: 5S-7SGoogle Scholar
  87. Krakoff IH, Cvitkovic E, Currie V, Yeh S, Lamont C (1977) Clinical Pharmacology and therapeutic studies of bleomycin given by continuous infusion. Cancer 40: 2027PubMedGoogle Scholar
  88. Kuwahara J, Suzuki T, Sugiura Y (1985) Effective DNA cleavage by bleomycin-vanadium complex plus hydrogen peroxide. Biochem Biophys Res Comm 129: 368–374CrossRefPubMedGoogle Scholar
  89. Laurent GJ (1986) Lung collagen: more than Scaffolding. Thorax 41: 418–428PubMedGoogle Scholar
  90. Laurent GJ, McAnulty RJ (1983) Protein metabolism during bleomycin-induced pulmonary fibrosis in rabbits. Am Rev Respir Dis 128: 82–88PubMedGoogle Scholar
  91. Laurent GJ, McAnulty RJ, Corrin B, Cockerill P (1981) Biochemical and histological changes in pulmonary fibrosis induced in rabbits with intratracheal bleomycin. Eur J Clin Invest 11: 441–448PubMedGoogle Scholar
  92. Laurent GJ, Bishop JE, Gray A, Peacock A, Harrison NK, Winlove CP, Lever MJ, Reeves JT (1990) Deposition of arterial collagen in pulmonary hypertension. Putative role for growth factors derived from the circulation. In: Herget J, Widimsky J (eds) Progress in respiration research. Basel-Karger, Switzerland (in press)Google Scholar
  93. Lazo JS, Pham ET (1984) Pulmonary fate of [3H] bleomycin A2 in mice. J Pharmacol Exp Ther 228: 13–18PubMedGoogle Scholar
  94. Lazo JS, Humphreys CJ (1983) Lack of metabolism as the biochemical basis of bleomycin induced pulmonary toxicity. Proc Natl Acad Sci USA 80: 3064–3068PubMedGoogle Scholar
  95. Lazo JS, Merril WW, Pham ET, Lynch TJ, McCallister JD, Ingbar DH (1984) Bleomycin hydrolase activity in pulmonary cells. J Pharmacol Exp Ther 231: 583–588PubMedGoogle Scholar
  96. Lazo JS, Braun IB, Meandzija B, Kennedy KA, Pham ET, Smaldone LF (1985) Lidocaine potentiation of bleomycin cytotoxicity and DNA strand breakage in L1210 and human A-253 cells. Cancer Res 45: 2103–2109PubMedGoogle Scholar
  97. Levy RL, Chiarillo S (1980) Hyperpyrexia, allergic type reaction and death occurring with low dose bleomycin administration. Oncology 37: 316–317PubMedGoogle Scholar
  98. Lijnen HR, Collen D (1982) Interaction of plasminogen activators and inhibitors with plasminogen and fibrosis. Semin Thromb Hemost 8: 2–10PubMedGoogle Scholar
  99. Lown JW, Sondhi SM, Ong C, Skorobogaty A, Kishikawa H, Dabrowiak JC (1986) Deoxyribonucleic acid cleavage specificity of a series of acridine and acodazole iron porphyrins as functional bleomycin models. Biochemistry 25: 5111–5117CrossRefPubMedGoogle Scholar
  100. Luna MA, Bedrossian CWM, Lichtiger B, Salem PA (1972) Interstitial pneumonitis associated with bleomycin therapy. AJCP 58: 501–510PubMedGoogle Scholar
  101. Lyman S, Ujjani B, Renner K, Antholine W, Pertering DH, Whetstone JW, Knight JM (1986) Properties of the initial reaction of bleomycin and several of its metal complexes with Ehrlich cells. Cancer Res 46: 4472–4478PubMedGoogle Scholar
  102. Martinet Y, Bitterman PB, Mornex J-F, Grotendorst GR, Martin GR, Crystal RG (1986) Activated human monocytes express the c-sis proto-oncogene and release a mediator showing PDGF-like activity. Nature (Lond) 319: 158–160CrossRefGoogle Scholar
  103. Masui T, Wakefield LM, Lechner JF, Laveek MA, Sporn MB, Harris CC (1986) TGFβ is the primary differentation-inducing serum factor for normal human bronchial epithelial cells. Proc Natl Acad Sci USA 83: 2438–2442PubMedGoogle Scholar
  104. Matalon S, Harper WV, Goldinger JM, Nickerson PA, Olszowka J (1985) Modification of pulmonary oxygen toxicity by bleomycin treatment. J Appl Physiol 58: 1802–1809PubMedGoogle Scholar
  105. Mauviel A, Daireaux M, Redini F, Galera P, Loyau G, Pujol JP (1988) Tumor necrosis factor inhibits collagen and fibronecting synthesis in human derraml fibroblasts. FEBS Letts 236: 47–52CrossRefGoogle Scholar
  106. McCord JM, Fridovich I (1969) Superoxide dismutase. J Biol Chem 244: 6049–6055PubMedGoogle Scholar
  107. McCullough B, Collins JF, Grover FL (1978) Bleomycin-induced diffuse interstitial pulmonary fibrosis in baboons. J Clin Invest 61: 79–88PubMedGoogle Scholar
  108. Meikle MC, Heath JK, Reynolds JJ (1986) Advances in understanding cell interactions in tissue resorption. Relevance to the pathogenesis of periodontal diseases and a new hypothesis. J Oral Pathol 15: 239–250PubMedGoogle Scholar
  109. Metcalfe DD, Smith JA, Austen KF, Silbert JE (1980) Polydispersity of rat mast cell heparin. Implication for proteoglycan assembly. J Biol Chem 25[255]: 11753–11758Google Scholar
  110. Mirabelli CA, Ting A, Huang CH, Mong S, Crooke ST (1982) Bleomycin and talisomycin sequence specific strand scission of DNA: a mechanism of double strand cleavage. Cancer Res 42: 2779–2785PubMedGoogle Scholar
  111. Mizel SB, Dayer JM, Krane SM, Mergenhagen E (1981) Stimulation of rheumatoid synovial cell collagenase and prostaglandin production by partially purified lymphocyte-activating factor (interleukin-1). Proc Nat Acad Sci USA 78: 2472–2477Google Scholar
  112. Mizuno S, Ishida A (1982) Selective enhancement of bleomycin cytotoxicity in local anaesthetics. Biochem Biophys Res Commun 105: 425–431PubMedGoogle Scholar
  113. Mizuno S, Ishida A (1982) Potentiation of bleomycin cytotoxicity by membrane acting drugs and increased calcium ions. Biochem Biophys Res Commun 107: 1021–1027CrossRefPubMedGoogle Scholar
  114. Moses HL, Tucker RF, Leof EB, Coffey RJ, Halper J, Shipley GD (1985) Type beta transforming growth factor is a growth stimulator and a growth inhibitor in cancer cells. In: Feramisco J, Ozanne B, Stiles C (eds) Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, pp 65–71Google Scholar
  115. Moshere DF (1975) Cross-linking of cold-soluble globulin by fibrin-stabilizing factor. J Biol Chem 16: 6614–6612Google Scholar
  116. Muller WEG, Zahn RK, Maidhof A, Schroder HC, Bachman M, Umezawa H (1984) Synergistic effect of peplomycin in combination with bleomycin on L5178y mouse lymphoma cells in vivo. J Antibiot 37: 239–243PubMedGoogle Scholar
  117. Murphy G, Sellars A (1980) The extracellular regulation of collagen activity. In: Woolley DE, Evanson JM (eds) Collagenase in normal and pathological connective tissues. John Wiley and Sons, Chichester, England, pp 65–81Google Scholar
  118. Nagase H, Jackson RC, Brinckerhoff CE, Vater CA, Harris ED Jr (1981) A precursor form of latent collagenase produced in a cell-free system with mRNA from rabbit synovial cells. J Biol Chem 256: 11951–11954PubMedGoogle Scholar
  119. Norris DA, Clark RAF, Swigart LM, Huff JC, Clark J, Weston WL, Howell SE (1982) Fibronectin fragment(s) are chemotactic for human peripheral blood monocytes. J Immunol 129: 1612–1618PubMedGoogle Scholar
  120. Nugent KM, Glazier J, Monick MM, Hunninghake GW (1985) Stimulated human alveolar macrophages secrete interferon. Am Rev Respir Dis 131[5]: 714–718PubMedGoogle Scholar
  121. Nygard K, Smith-Erichsen N, Hatlevoll R, Refsum SB (1978) Pulmonary complications after bleomycin, irradiation and surgery for oesophageal cancer. Cancer 41: 17PubMedGoogle Scholar
  122. Oberley LW, Buettner GR (1979) The production of hydroxyl radical by bleomycin and iron(II). FEBS Lett 97: 47–49CrossRefGoogle Scholar
  123. Ohnuma T, Holland JF, Masuda H, Waligunda JA, Goldberg GA (1974) Microbiological assay of bleomycin: inactivation, tissue distribution and clearance. Cancer 33: 1230–1238PubMedGoogle Scholar
  124. Oppenheimer NJ, Rodriguez LO, Hecht SM (1979) Structural studies of the active complex of bleomycin. Proc Natl Acad Sci USA 76: 5616–5620PubMedGoogle Scholar
  125. Oppenheimer NJ, Chang C, Chang LH, Ehrenfeld G, Rodriguez LO, Hecht SM (1982) Degradation of DNA and formation of a structurally unique Fe(II) CO complex. J Biol Chem 257: 1606–1609PubMedGoogle Scholar
  126. Padmanabhan RV, Gudapaty R, Liener IE, Schwartz BA, Hoidal JR (1985) Protection against pulmonary oxygen toxicity in rats by the intratracheal administration of liposome encapsulated Superoxide dismutase or catalase. Am Rev Respir Dis 132: 164–167PubMedGoogle Scholar
  127. Pearlstein E (1976) Plasma membrane glucoprotein which mediates adhesion of fibroblasts to collagen. Nature (Lond) 262: 497–499CrossRefGoogle Scholar
  128. Peng YM, Alberts DS, Chen HSG, Mason N, Moon TE (1980) Antitumour activity and plasma kinetics of bleomycin by continuous and intermittent administration. Br J Cancer 41: 644–647PubMedGoogle Scholar
  129. Phan SH, Thrall RS, Williams C (1981) Bleomycin-induced pulmonary fibrosis. Am Rev Respir Dis 124: 428–434PubMedGoogle Scholar
  130. Postlethwaite AE, Keski-Oja J, Balian G, Kang AH (1981) Induction of fibroblast chemotaxis by fibronectin. J Exp Med 153: 494–499CrossRefPubMedGoogle Scholar
  131. Prestayko AW, Crooke ST (1978) Clinical pharmacology of bleomycin. In: Carter SK, Umezawa H, Crooke ST (eds) Bleomycin: Current status and new developments. Academic Press Inc New York, 117–130Google Scholar
  132. Reich E (1978) Activation of plasminogens: a general mechanism for producing localized extracellular proteolysis. In: Berlin RD, Herrman H, LePow IH, Tanzer JM (eds) Molecular basis of biological degradative processes. Academic Press, London, pp 155–170Google Scholar
  133. Reiser KM, Last JA (1981) Pulmonary fibrosis in experimental acute respiratory disease. Am Rev Respir Dis 123: 58–63PubMedGoogle Scholar
  134. Rifkin DB, Moscatelli D, Gross J, Jaffe EA (1984) Proteases, angiogenesis and invasion. In: Nicolson GL, Milas L (eds) Cancer invasion and metastasis: biologic and therapeutic aspects. Raven Press, New York, pp 187–200Google Scholar
  135. Riordan JW, Sakai TT (1983) Bleomycin analogues. Phenylthiazole models of the bithiazole moiety of bleomycin A2. J Med Chem 26: 884–891CrossRefPubMedGoogle Scholar
  136. Roll W, Sherry S, Wachman J (1954) The action of plasmin on synthetic pulstrates. J Biol Chem 208: 85PubMedGoogle Scholar
  137. Rose AG (1983) Pulmonary veno-occlusive disease due to bleomycin therapy for lymphoma. S Afr Med J 64: 636–638PubMedGoogle Scholar
  138. Rosenbaum RM, Wittner M, Lenger M (1969) Mitochondrial and other ultrastructural changes in great alveolar cells of oxygen-adapted and poisoned rats. Lab Invest 20: 516–528PubMedGoogle Scholar
  139. Rossi P, Karsenty G, Roberts AB, Roche NS, Sporn MB, de Crombrugghe B (1988) A nuclear factor 1 binding site mediated the Transcriptional activation of a type I collagen promoter by TGFβ. Cell 52[3]: 405–414PubMedGoogle Scholar
  140. Roy SN, Horwitz SB (1984) Characterisation of the association of radiolabelled BLM A2 with Hela cells. Cancer Res 44: 1541–1546PubMedGoogle Scholar
  141. Sakamoto S, Sakamoto M (1981) Effect of heparine on bone collagenase release and activity and an application of heparin-Sepharose affinity chromatography for in vitro study of bone resorption. In: Brown WV, Mann G, Roberts R, Lundblad L (eds) The chemistry and biology of heparin. Churchill Livingstone, London, pp 362–375Google Scholar
  142. Samuels ML, Lanzotti VJ, Holoyle PY, Boyce LE, Smith TL (1976) Combination chemotherapy in terminal tumours. Cancer Treat Rev 3: 185PubMedGoogle Scholar
  143. Sartoris DJ, Goodwin DA, Meares CF, DeRiemer LH, Fajardo LF (1984) Pharmacokinetics of indium-111 BLEDTA in man. Invest Radiol 19: 221–227PubMedGoogle Scholar
  144. Saus J, Quinones S, Otani Y, Nagase H, Harris JR, Kurkineu M (1988) The complete primary structure of human matrix metalloproteinase-3. J Biol Chem 263: 6742–6745PubMedGoogle Scholar
  145. Sausville EA, Peisach J, Horwitz SB (1976) A role for ferrous iron and oxygen in the degradation of DNA by bleomycin. Biochem Biophys Res Commun 73: 814–822PubMedGoogle Scholar
  146. Sausville EA, Peisach J, Horwitz SB (1978) Effect of chelating agents and metal ions on the degradation of DNA by bleomycin. Biochemistry 17: 2740–2745CrossRefPubMedGoogle Scholar
  147. Scheid W, Opperman B, Traut H (1984) The cytogenetic efficiency of the antitumour agents bleomycin and peplomycin is enhanced by the heart drug verapamil. Experientia 40: 746–747CrossRefPubMedGoogle Scholar
  148. Scheulen MD, Kapus H, Thyssen D, Schmidt CG (1981) Reduction cycling of Fe(III)-bleomycin by NADPH-cytochrome P-450 reductase. Biochem Pharmacol 30: 3385–3388CrossRefPubMedGoogle Scholar
  149. Seki T, Muraoka Y, Takahashi K, Horinishi H, Umezawa H (1985) Radioimmunoassays of bleomycin. J Antibiot 38: 1251–1256PubMedGoogle Scholar
  150. Sen P, Hittleman WN (1984) Kinetics and extent of repair of bleomycin induced chromosome damage in quiescent normal human fibroblasts and human mononuclear cells. Cancer Res 44: 591–596PubMedGoogle Scholar
  151. Seppa H, Grotendorst G, Seppa S, Schiffmann E, Martin GR (1982) Platelet-derived growth factor is chemotactic for fibroblasts. J Cell Biol 92[2]: 584–588CrossRefPubMedGoogle Scholar
  152. Stubbe J, Kozarich JW (1987) Mechanisms of bleomycin induced DNA degradation. Chem Rev 87: 1107–1136CrossRefGoogle Scholar
  153. Shazeidi S, Sarnstrand B, Jeffery PK, McAnulty RJ, Laurent GJ (1991) Oral N-acetylcysteine reduced bleomycin-induced collagen deposition in the lungs of mice. Eur Respir J (in press)Google Scholar
  154. Shipley GD, Pittelkow ME, Wille JJ, Scott RE, Moses HL (1986) Reversible inhibition of normal human prokerationcyte proliferation by TGFβ-growth inhibitor in serum free medium. Cancer Res 46: 2064–2071Google Scholar
  155. Snider GL, Hayes JA, Kortly AL (1978) Chronic interstitial pulmonary fibrosis produced in hamsters by endotracheal bleomycin: Pathology and Stereology. Am Rev Respir Dis 117: 1099–1108PubMedGoogle Scholar
  156. Sporn ME, Roberts AB, Anzanmo A, Wakefield LM, Roche NS, Stern DF (1985) Type β transforming growth factor β1 functional regulator of cellular growth. Proc Natl Acad Sci USA 82: 119–123PubMedGoogle Scholar
  157. Starcher BC, Kuhn C, Oerton JE (1978) Increased elastin and collagen content in the lungs of hamsters receiving an intratracheal injection of bleomycin. Am Rev Respir Dis 117: 299–305PubMedGoogle Scholar
  158. Sterling KM, DiPetrillo T, Cutoneo KC, Prestayko A (1982) Inhibition of collagen accumulation by glucocorticoids in rat lung after intratracheal bleomycin instillation. Cancer Res 42: 405–408PubMedGoogle Scholar
  159. Sugiura Y (1980) Bleomycin iron complexes. ESR study ligand effect, and implications for action mechanisms. J Am Chem Soc 102: 5208–5216CrossRefGoogle Scholar
  160. Sugiura Y, Suzuki T, Otuska M, Kobayashi S, Ohno M, Takita T, Umezawa H (1983) Synthetic analogues and biosynthetic intermediates of bleomycin. J Biol Chem 258: 1328–1336PubMedGoogle Scholar
  161. Suzuki H, Nagai K, Yamaki H, Umezawa H (1969) On the mechanism of action of bleomycin scission of DNA strand in vitro and in vivo. J Antibiot 22: 446–448PubMedGoogle Scholar
  162. Suzuki T, Kuwahara J, Sugiura Y (1984) DNA cleavages of bleomycin transition metal complexes induced by reductant, hydrogen peroxide and ultraviolet light. Nucleic Acids Res 15: 161–164Google Scholar
  163. Suzuki T, Kuwahara J, Sugirura Y (1985) Copper bleomycin has no significant DNA cleavage activity. Biochemistry 24: 4719–4721CrossRefPubMedGoogle Scholar
  164. Takahashi K, Yoshioka O, Matsuda A, Umezawa H (1977) Intracellular reduction of the cupric ion of bleomycin copper complex and transfer of the cuprous ion to a cellular protein. J Antibiot 30: 861–869PubMedGoogle Scholar
  165. Terasima T, Takabe Y, Katsumata T, Watanabe M, Umezawa H (1972) Effect of bleomycin on mammalian cell survival. J Natl Cancer Inst 49: 1093–1100PubMedGoogle Scholar
  166. Thrall RS, McCormick JR, Jack RM, McReynolds RA, Ward PA (1979) Bleomycin induced pulmonary fibrosis in the rat. Am J Pathol 95: 117–130PubMedGoogle Scholar
  167. Thrall RS, Barton RW, D'Amato DA, Sulavik SB (1982) Differential cellular analysis of bronchoalveolar lavage fluid obtained at various stages during the development of bleomycin induced pulmonary fibrosis in the rat. Am Rev Respir Dis 126: 488–492PubMedGoogle Scholar
  168. Tom WW, Montgomery MR (1979) Disposition of the pulmonary toxin bleomycin. Drug Metab Dispos 7: 90–93PubMedGoogle Scholar
  169. Uehara Y, Hori M, Umezawa H (1982) Specificity of transport of bleomycin and cobalt-bleomycin in L5178Y cells. Biochem Biophys Res Commun 104: 416–421PubMedGoogle Scholar
  170. Uesugi S, Shida T, Ikehara M, Kobayashi Y, Kyogoku Y (1984) Identification of oligonucleotide fragments produced in a strand scission reaction of d(C-G-C-G-C-G) duplex by bleomycin. Nuc Acid Res 12: 1581–1592Google Scholar
  171. Umezawa H, Maeda K, Takeuchi T, Okami Y (1966) New antibiotics, bleomycin A and B. Cancer 19: 201–209Google Scholar
  172. Umezawa H, Ishizuka M, Maeda K, Takeuchi T (1967) Studies on bleomycin. Cancer 20: 891–895PubMedGoogle Scholar
  173. Umezawa H, Ishizuka M, Hori S, Chimura H, Takeuchi T, Komai T (1968) The distribution of3H-bleomycin in mouse tissue. J Antibiot 21: 638–649PubMedGoogle Scholar
  174. Umezawa H, Hori S, Sawa T, Yoshioka T, Takauchi T (1974) A bleomycin inactivating enzyme in mouse live. J Antibiot 27: 419–424PubMedGoogle Scholar
  175. Vartio T, Zardi L, Balza E, Towin H, Vaheri A (1982) Monoclonal antibodies in analysis of cathepsin-G digested proteolytic fragments of human plasma fibronectin. J Immunol Methods 55: 309–318CrossRefPubMedGoogle Scholar
  176. Vartio T, Vaheri A, De-Petro G, Barlati S (1983) Fibronectin and its protealytic fragments. Potential as cancer markers. Invasion Metastasis 3[3]: 125–138PubMedGoogle Scholar
  177. Vogelzang NJ, Bosl GJ, Johnson K, Kennedy BJ (1981) Raynauds phenomenon: A common toxicity after combination chemotherapy for testicular cancer. Ann Int Med 95: 288–292PubMedGoogle Scholar
  178. Wangensteen D, Yankovich R, Hoidal J, Neiwoehner D (1983) Bleomycin induced changes in pulmonary microvascular albumin permeability and extravascular albumin space. Am Rev Respir Dis 127: 204–208PubMedGoogle Scholar
  179. Ward HE, Nicholson A, Berend N (1986a) Desferrioxamine infusion does not inhibit bleomycin induced lung damage in the rat. Am Rev Respir Dis 133: 317Google Scholar
  180. Ward HE, Nicholson A, Berend N (1986b) Does systemic N-acetyl cystein (NAC) protect against bleomycin induced lung injury? Am Rev Respir Dis 133: A51Google Scholar
  181. Wasserman SI (1980) The mast cell: its diversity of chemical mediators. Int J Dermathol 19: 7–17Google Scholar
  182. Weatherhall DJ, Montell AE, Anderson WF, Badman DG (eds) (1981) Development of iron chelators for clinical use. Elsevier North Holland, New York, pp 3–12Google Scholar
  183. Weizman SA, Graceffa P (1984) Asbestos catalyzes hydroxyl and superoxide radical generation from hydrogen peroxide. Arch Biochem Biophys 228: 373–376PubMedGoogle Scholar
  184. White DA, Stover DE (1984) Severe bleomycin induced pneumonitis. Clinical features and response to corticosteroids. Chest 86: 723–728PubMedGoogle Scholar
  185. Wilson JHU (1978) Pulmonary toxicity of antineoplastic drugs. Cancer Treat 62: 2008–2013Google Scholar
  186. Woolley DE (1980) Human collagenase: comparative and immunolocalization studies in protein degradation in health and disease. Ciba Foundation Symposium 75: 69–82Google Scholar
  187. Wu JC, Kozarich JW, Stubbe J (1985) Mechanism of bleomycin: evidence for a rate determining 4′-hydrogen abstraction from poly(dA-dU) associated with the formation of both free base and base propenal. Biochemistry 24: 7562–7568CrossRefPubMedGoogle Scholar
  188. Wu JC, Stubbe J, Kozarich JW (1985b) Mechanism of bleomycin: evidence of 4′-ketone formation in poly(dA-dU) associated exclusively with free base release. Biochemistry 24: 7569–7573CrossRefPubMedGoogle Scholar
  189. Yamamoto K, Hutchinson F (1984) The effect of bleomycin on DNA in escherichia coli K12 cells. Chem Biol Interact 51: 233–246CrossRefPubMedGoogle Scholar
  190. Yamauchi K, Basset P, Martinet Y, Crystal R (1987) Normal human alveolar macrophages express the gene coding for TGFβ, a protein with a capacity to express fibroblast growth. Am Rev Respir Dis 135: A66Google Scholar
  191. Yamauchi K, Martinet Y, Basset P, Fells GA, Crystal RG (1988) High levels of transforming growth factor β are present in the epithelial lining of the normal human lower respiratory tract. Am Rev Respir Dis 137: 1360–1363PubMedGoogle Scholar
  192. Yousem SA, Lifson JD, Colby TV (1985) Chemotherapy induced eosinophilic pneumonia. Chest 88: 103–106PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1991

Authors and Affiliations

  • John Hay
    • 1
  • Shahriar Shahzeidi
    • 1
  • Geoffrey Laurent
    • 1
  1. 1.Biochemistry Unit, Department of Thoracic Medicine, National Heart and Lung InstituteUniversity of LondonLondonUK

Personalised recommendations