Abstract
The bleomycins (BLM) are a group of glycopeptide antibiotics which exhibit c linically useful antineoplastic activity and are isolated from Streptomyces verticillus (1,2). They are effective against squamous cell carcinoma, Hodgkin’s disease, and malignant lymphoma and are particularly valuable since they show no immunosuppression(2). The mode of action has attracted a great deal of attention but the molecular mechanism of action is by no means clear. BLM shows interference with nucleic acid metabolism as evidenced by (i) inhibition of DNA synthesis(3), (ii) interference with mitosis(2), and (iii) DNA breakage(4). Recently BLM has been shown to release nucleosomes from chromatin(5). In addition there is interference with enzyme action, e.g., inhibition of ligase action(6), but stimulation of nuclease activity(7). BLM also causes liberation of DNA from DNA-membrane complexesi(8). Thus considerable biochemical evidence suggests that the principal cell target is DNA which is degraded by BLM both in vivo and in vitro (2,4,9-11). DNA cleavage is enhanced in the presence of reducing agents such as 2-mercaptoethanol, dithiothreitol, or ascorbate and by the addition of Fe(II) and requires oxygen(2,1l-13). The DNA cleavage is inhibited by Cu, Zn, Co, Mg, and EDTA(14). These observations led to the suggestion of a direct role of trace metal ions, particularly of Fe, in the mode of action of the antibiotic(12,13) which would be in accord with a general role suggested for Fe in tissue disorders and cancer control(15). Clinical grade BLM was shown to contain 0.02 mole% Fe by atomic absorption(15).
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Lown, J.W. (1979). Contribution of the Superoxide Anion-Hydroxyl Radical Pathway to the Cleavage of DNA by Bleomycin. In: Hect, S.M. (eds) Bleomycin: Chemical, Biochemical, and Biological Aspects. Springer, New York, NY. https://doi.org/10.1007/978-1-4612-6191-9_14
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DOI: https://doi.org/10.1007/978-1-4612-6191-9_14
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