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Phleomycin

  • Ch. F. EarhartJr.
Chapter
Part of the Antibiotics book series (ANTIBIOTICS, volume 5 / 2)

Abstract

Maeda et al. reported the isolation of phleomycin in 1956. It is a broad spectrum antibiotic with unusually high specific activity against Mycobacteriumphlei and its name is derived from this latter property (Maeda, 1965). Phleomycin is isolated from the water-soluble, basic fraction of the culture fluid of Streptomyces verticillus. As initially isolated, phleomycin is a copper-containing blue powder (Takita, 1959); treatment with hydroxyquinoline removes the copper, leaving a white powder which, except for a slight reduction in activity against mycobacteria, has undiminished antibacterial properties. In 1964 Ikekawa et al. demonstrated that copper-containing phleomycin is a mixture of approximately 12 related components. These compounds, A, B, C, D1 D2, E, F, G, H, I, J, and K, were resolved by Sephadex column chromatography. Unless otherwise indicated, “phleomycin” will continue to refer to this complex of antibiotics for the remainder of this review.

Keywords

Sulfhydryl Compound Ehrlich Carcinoma Apurinic Site Minimal Growth Inhibitory Concentration Thymidine Triphosphate 
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.

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References

  1. Angyal, A.M., Grigg, G.W., Badger, R.J., Brown, D.J., Lister, J.H.: Purines as amplifiers of the antibiotic activity of phleomycin against Escherichia coli B. J. Gen. Microbiol. 85, 163–168 (1974)PubMedGoogle Scholar
  2. Argoudelis, A.D., Bergey, M.E., Pyke, T.R.: Zorbamycin and related antibiotics. I. Production, isolation, and characterization. J. Antibiot. 24, 543–557 (1971)PubMedCrossRefGoogle Scholar
  3. Bhushan, K., Brown, D.J., Lister, J.H., Stephanson, L.G., Yoneda, F.: Purine studies. XVII. The synthesis of 2-substituted 6,9-di-and 6, 8, 9-tri-methylpurines as amplifiers of phleomycin. Aust. J. Chem. 28, 2553–2559 (1975)CrossRefGoogle Scholar
  4. Bradner, W.T., Pindell, H.M.: Antitumour properties of phleomycin. Nature (London) 196, 682–683 (1962)CrossRefGoogle Scholar
  5. Brown, D.J., Stephanson, L.G.: Purine studies. XIII. The metabolism of 2,9-dimethyl-8-methylthiopurine and 2-carbamoylmethylthio-6,9-dimethylpurine in mice. Aust. J. Chem. 27, 1371–1375 (1974)CrossRefGoogle Scholar
  6. Brown, D.J., Stephanson, L.G.: Purine studies. XIX.Rodential metabolism of 2-(6′,8′,9′-trimethylpurin-2′-ylthio) propionamide and related purines. Aust. J. Chem. 29, 1031–1037 (1976)CrossRefGoogle Scholar
  7. Brown, D.J., Dunlap, W.C., Grigg, G.W., Kelly, J.: Thiazolo[5,4-d] pyrimidine derivatives as amplifiers of phleomycin against E. coli. Aust. J. Chem. 30, 1775–1783 (1977)CrossRefGoogle Scholar
  8. Decad, G.M., Nikaido, H.: Outer membrane of gram-negative bacteria. XII. Molecular sieving function of cell wall. J. Bacteriol. 128, 325–336 (1976)PubMedGoogle Scholar
  9. Djordjevic, B., Kim, J.: Lethal effects of phleomycin in different stages of the division cycle of HeLa cells. Cancer Res. 27, 2255–2260 (1967)PubMedGoogle Scholar
  10. Falaschi, A., Kornberg, A.: Phleomycin, an inhibitor of DNA polymerase. Fed. Proc. 23, 940–945 (1964)PubMedGoogle Scholar
  11. Farrell, L.D., Reiter, H.: Phleomycin-stimulated degradation of deoxyribonucleic acid in Escherichia coli. Antimicrob. Agents Chemother. 4, 320–326 (1973)PubMedCrossRefGoogle Scholar
  12. Farrell, L.D., Reiter, H.: Phleomycin-stimulated solubilization of deoxyribonucleic acid in Escherichia coli. II. Inhibition of solubilization by bacteriophage T4. Can J. Microbiol. 22, 645–653 (1976)PubMedCrossRefGoogle Scholar
  13. Friedman, R.M., Stern, R., Rose, J.A.: Phleomycin stimulation of thymidine triphosphate incorporation by animal cell nuclei. J. Natl. Cancer Inst. 52, 693–697 (1974)PubMedGoogle Scholar
  14. Grigg, G.W.: Induction of DNA breakdown and death in Escherichia coli by phleomycin. Its association with dark repair processes. Mol. Gen. Genet. 104, 1–11 (1969)PubMedGoogle Scholar
  15. Grigg, G.W.: Amplification of phleomycin induced death and DNA breakdown by caffeine in Escherichia coli. Mol. Gen. Genet. 107, 162–172 (1970)PubMedCrossRefGoogle Scholar
  16. Grigg, G.W., Edwards, M.J., Brown, D.J.: Effects of coumarin, thiopurines, and pyronin Y on amplification of phleomycin-induced death and deoxyribonucleic acid breakdown in Escherichia coli. J. Bacteriol. 107, 599–609 (1971)PubMedGoogle Scholar
  17. Grigg, G.W., Gero, A.M., Hughes, J.M., Sasse, W.H.F., Bliese, M., Hart, N.K., Johansen, O., Kissane, P.: Amplifications of phleomycin and bleomycin-induced antibiotic activity in Escherichia coli by aromatic cationic compounds. J. Antibiot. 30, 870–878 (1977)PubMedCrossRefGoogle Scholar
  18. Harrison, D.G.: CXXXIV. The catalytic action of traces of iron on the oxidation of cysteine and glutathione. Biochem. J. 18, 1009–1022 (1924)PubMedGoogle Scholar
  19. Hecht, T.T., Summers, D.F.: The effect of phleomycin on poliovirus RNA replication. Virology 40, 441–447 (1970)PubMedCrossRefGoogle Scholar
  20. Hotta, Y., Stern, H.: The action of phleomycin on meiotic cells. Cancer Res. 29, 1699–1703 (1969)PubMedGoogle Scholar
  21. Ikekawa, T., Iwami, F., Hiranka, H., Umezawa, H.: Separation of phleomycin components and their properties. J. Antibiot. 17A, 194–199 (1964)Google Scholar
  22. Ishizuka, M., Takayama, H., Takeuchi, T., Umezawa, H.: Studies on antitumor activity, antimicrobial activity and toxicity of phleomycin. J. Antibiot. 19A, 260–271 (1966)Google Scholar
  23. Ishizuka, M., Takayama, H., Takeuchi, T., Umezawa, H.: Activity and toxicity of bleomycin. J. Antibiot. 20A, 15–24(1967)Google Scholar
  24. Ito, Y., Ohashi, Y., Egawa, Y., Yamaguchi, T., Furumai, T., Enomoto, K., Okuda, T.: Antibiotic YA 56, a new family of phleomycin-bleomycin group antibiotics. J. Antibiot. 24, 727–731 (1971)PubMedCrossRefGoogle Scholar
  25. Iwata, A., Consigli, R.A.: Effect of phleomycin on polyoma virus synthesis in mouse embryo cells. J. Virol. 7, 29–40 (1971)PubMedGoogle Scholar
  26. Jacobs, N.F., Neu, R.L., Gardner, L.I.: Phleomycin-induced mitotic inhibition and chromosomal abnormalities in cultured human leucocytes. Mutat. Res. 7, 251–253 (1969)PubMedCrossRefGoogle Scholar
  27. Jocelyn, P.C.: Biochemistry of the SH group. London: Academic Press Inc. 1972Google Scholar
  28. Kajiwara, K., Kim, U., Mueller, G.: Phleomycin, an inhibitor of replication of HeLa cells. Cancer Res. 26, 233–236 (1966)PubMedGoogle Scholar
  29. Kersten, H., Kersten, W.: Inhibitors of nucleic acid synthesis. Berlin, Heidelberg, New York: Springer 1974CrossRefGoogle Scholar
  30. Kihlman, B.A., Odmark, G., Hartley, B.: Studies on the effects of phleomycin on chromosome structure and nucleic acid synthesis in Vicia faba. Mutat. Res. 4, 783–790 (1967)PubMedCrossRefGoogle Scholar
  31. Kleijer, W.J., Hoeksema, J.I., Sluyter, M.L., Bootsma, D.: Effects of inhibitors on repair of DNA in normal human and xeroderma pigmentosum cells after exposure to X-rays and ultraviolet irradiation. Mutat. Res. 17, 385–394 (1973)PubMedCrossRefGoogle Scholar
  32. Koch, G.: Differential effect of phleomycin on the infectivity of poliovirus and poliovirus-induced ribonucleic acids. J. Virol. 8, 20–34 (1971)Google Scholar
  33. Krueger, W.C., Pschigoda, L.M., Reusser, F.: Interactions of DNA with zorbamycin, phleomycin, and bleomycin; ultraviolet absorption and circular dichroism measurements. J. Antibiot. 26, 424–428 (1973)PubMedCrossRefGoogle Scholar
  34. Lindahl, T., Ljungquist, S.: Apurinic and apyrimidinic sites in DNA. In: Molecular mechanisms for repair of DNA, Part A. Hanawalt, P.C., Setlow, R.B., (eds.), pp. 31–38. New York: Plenum Press 1975CrossRefGoogle Scholar
  35. Ljungquist, S.: A new endonuclease from Escherichia coli acting at apurinic sites in DNA. J. Biol. Chem. 252, 2808–2814 (1977)PubMedGoogle Scholar
  36. Lown, J.W., Sim, S-K.: The mechanism of the bleomycin-induced cleavage of DNA. Biochem. Biophys. Res. Commun. 77, 1150–1157 (1977)PubMedCrossRefGoogle Scholar
  37. Maeda, K.: Streptomyces products inhibiting mycobacteria. New York: John Wiley and Sons Inc. 1965Google Scholar
  38. Maeda, K., Kosaka, H., Yagishita, K., Umezawa, H.: A new antibiotic, phleomycin. J. Antibiot. 9 A, 82–85 (1956)Google Scholar
  39. Mandel, M., Marmur, J.: Use of ultraviolet temperature profile for determining the guanine plus cytosine content of DNA. In: Methods in enzymology. Grossman, L.D., Moldave, K., (eds.), Vol. 12b, pp. 195–206. New York: Academic Press Inc. 1968Google Scholar
  40. Mathews, C.K.: Bacteriophage biochemistry. New York: Van Nostrand Reinhold Co. 1971Google Scholar
  41. Mattingly, E.: Induction of chromosome and chromatid-type aberrations by phleomycin. Mutat. Res. 4, 51–57 (1967)PubMedCrossRefGoogle Scholar
  42. McIntosh, M.A., Earhart, C.F.: Effect of ribonuclease on the association of deoxyribonucleic acid with the membrane in Escherichia coli. J. Bacteriol. 122, 592–598 (1975)PubMedGoogle Scholar
  43. Nagai, K., Yamaki, H., Suzuki, H., Tanaka, N., Umezawa, H.: The combined effects of bleomycin and sulfhydryl compounds on the thermal denaturation of DNA. Biochem. Biophys. Acta 179, 165–171 (1969)PubMedGoogle Scholar
  44. Nakayama, H.: Phleomycin-induced lethality and DNA degradation in Escherichia coli K12. Mutat. Res. 29, 21–33 (1975)PubMedCrossRefGoogle Scholar
  45. Ohashi, Y., Abe, H., Kawabe, J., Ito, Y.: The constitutional amine of antibiotic YA-56. Agric. Biol. Chem. 37, 2387–2391 (1973)CrossRefGoogle Scholar
  46. Pietsch, P.: Phleomycin: biological and chemical variations in different batches. Microbios 1, 387–392 (1969 a)Google Scholar
  47. Pietsch, P.: Structural events in DNA in transcription and replication: the influence of histones on in vitro reactions of actinomycin-D and phleomycin-909. Cytobios 4, 375–391 (1969 b)Google Scholar
  48. Pietsch, P.: Biopolymers in drug technology: the use of DNA in purifying phleomycin. Biotechnol. Bioeng. 15, 1039–1044 (1973)PubMedCrossRefGoogle Scholar
  49. Pietsch, P.: Phleomycin and bleomycin. In: Handbook of experimental pharmacology, Part 2. Sartorelli, A.C., Johns, D.G., (eds.),Vol. 38, pp. 850–876. Berlin, Heidelberg, New York: Springer 1975Google Scholar
  50. Pietsch, P., Clapper, G.: Receptivity of DNA to phleomycin. Cytobios 1, 145–152 (1969)Google Scholar
  51. Pietsch, P., Corbett, C.: Competitive effects of phleomycin and mercuric chloride in vivo. Nature (London) 219, 933–934 (1968)CrossRefGoogle Scholar
  52. Pietsch, P., Eng, R.: Phleomycin: enhancement of properties by treatment with acid. Microbios 1, 213–223 (1969)Google Scholar
  53. Pietsch, P., Garrett, H.: Primary site of reaction in the in vitro complex of phleomycin in DNA. Nature (London) 219, 488–489 (1968)CrossRefGoogle Scholar
  54. Pietsch, P., Garrett, H.: Phleomycin: evidence of in vivo binding to DNA. Cytobios 1A, 7–15 (1969 a)Google Scholar
  55. Pietsch, P., Garrett, H.: Phleomycin-induced changes in the ultrastructure of DNA. Biophys. J. 9A, 126 (1969b)Google Scholar
  56. Pietsch, P., Corbett, C., Briden, D.W., Jewett, G.: Diffusability of phleomycin studied by means of neutron activation analysis. Physiol. Chem. Phys. 1, 232–236 (1969)Google Scholar
  57. Pitts, J.D., Sinsheimer, R.L.: Effects of phleomycin upon replication of bacteriophage øX174. J. Mol. Biol. 15, 676–680 (1965)CrossRefGoogle Scholar
  58. Post, L., Price, A.R.: Inhibition of bacteriophage PBS2 replication in Bacillus subtilis by phleomycin. J. Virol. 15, 363–371 (1975)PubMedGoogle Scholar
  59. Reiter, H., Milewskiy, M., Kelley, P.: Mode of action of phleomycin on B. subtilis. J. Bacteriol. 111, 586–592 (1972)PubMedGoogle Scholar
  60. Ryder, O.A., Smith, D.W.: Isolation of membrane-associated folded chromosomes from Escherichia coli: effect of protein synthesis inhibition. J. Bacteriol. 120, 1356–1363 (1971)Google Scholar
  61. Shive, K., Earhart, C.: Phleomycin-induced solubilization of deoxyribonucleic acid in uninfected and T bacteriophage-infected Escherichia coli B. Antimicrob. Agents Chemother. 10, 150–156 (1976)PubMedCrossRefGoogle Scholar
  62. Sleigh, M.J.: The mechanism of DNA breakage by phleomycin in vitro. Nucl. Acids Res. 3, 891–901 (1976)PubMedGoogle Scholar
  63. Sleigh, M.J., Grigg, G.W.: Induction of local denaturation in DNA in vitro by phleomycin and caffeine. FEBS Lett. 39, 35–38 (1974)PubMedCrossRefGoogle Scholar
  64. Sleigh, M.J., Grigg, G.W.: The mechanism of sensitivity to phleomycin in growing Escherichia coli cells. Biochem. J. 155, 87–99 (1976)PubMedGoogle Scholar
  65. Sleigh, M.J., Grigg, G.W.: Sulphydryl-mediated DNA breakage by phleomycin in Escherichia coli. Mutat. Res. 42, 181–189 (1977)PubMedCrossRefGoogle Scholar
  66. Stern, R., Rose, J.A., Friedman, R.M.: Phleomycin-induced cleavage of deoxyribonucleic acid. Biochemistry 13, 307–312 (1974)PubMedCrossRefGoogle Scholar
  67. Takasawa, S., Kawamoto, I., Okachi, R., Kohakura, M., Yahashi, R., Nara, T.: A new antibiotic victomycin (XK 49-1-B-2). II. Isolation, purification and physiochemical and biological properties. J. Antibiot. 28A, 366–371 (1975 a)CrossRefGoogle Scholar
  68. Takasawa, S., Kawamoto, I., Sato, S., Yahashi, R., Okachi, R., Yamamoto, M., Sato, T., Nara, T.: Platomycins A and B. II. Physiochemical properties. J. Antibiot. 28A, 662–667 (1975b)CrossRefGoogle Scholar
  69. Takita, T.: Studies on purification and properties of phleomycin. J. Antibiot. 12A, 285–289 (1959)Google Scholar
  70. Tanaka, N., Yamaguchi, H., Umezawa, H.: Mechanism of action of phleomycin, a tumour-inhibitory antibiotic. Biochem. Biophys. Res. Commun. 10, 171–174 (1963)PubMedCrossRefGoogle Scholar
  71. Tevethia, S.S., Rapp, F.: The effect of phleomycin on the replication of papovavirus SV40 and other DNA viruses in simian cells. Cancer Res. 29, 912–917 (1969)PubMedGoogle Scholar
  72. Umezawa, H.: Bleomycin. In: Antibiotics. Corcoran, J., Hahn, F., (eds.), Vol. III, pp. 21–33. New York: Springer 1975Google Scholar
  73. Umezawa, H., Maeda, K., Takeuchi, T., Okami, Y.: New antibiotics, bleomycin A and B. J. Antibiot. 19A, 200–209 (1966)Google Scholar
  74. Watanabe, M., August, J.T.: Replication of RNA bacteriophage R23. II. Inhibition of phagespecific RNA synthesis by phleomycin. J. Mol. Biol. 33, 21–33 (1968)PubMedCrossRefGoogle Scholar
  75. Worcel, A., Burgi, E.: Properties of a membrane-attached form of the folded chromosome of Escherichia coli. J. Mol. Biol. 82, 91–105 (1974)PubMedCrossRefGoogle Scholar
  76. Yamane, T., Davidson, N.: On the complexing of deoxyribonucleic acid (DNA) by mercuric ion. J. Am. Chem. Soc. 83, 2599–2607 (1960)CrossRefGoogle Scholar

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© Springer-Verlag Berlin · Heidelberg 1979

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  • Ch. F. EarhartJr.

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