Abstract
Recently evidence has accumulated to indicate that a number of anticancer agents of both natural and synthetic origin function, in part, by enzymatic reductive activation and site specific binding to cellular duplex DNA followed by oxygen dependent scission of the DNA strands involving single and/or double strand breaks. These agents include the heterocyclic bis-quinonoid antibiotics saframycins A, S and R (Arai et al., 1977; Lown et al, 1982; Lown et al., 1983) and the glycopeptide antibiotics bleomycin A2 and B2 (Sausville et al., 1978; Lown & Sim, 1977), tallysomycin (Lown & Joshua, 1980) and neo-carzinostatin (Kappen & Goldberg, 1978). By employing ethidium binding assays in conjunction with certain cellular protective and repair enzymes, as well as other techniques including e.p.r., several of the reactive species involved in the critical macromolecular lesions have been identified. The results have permitted the tentative formulation of a mechanism involving paramagnetic intermediates for those cytotoxic events (Sausville et al., 1978; Lown, 1983).
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References
ADLER, A.D., LONGO, F.R., KAMPAS, F. & KIM, J. (1970). On the preparation of metalloporphyrin. J. Inorg. Nucl. Chem., 32, 2443–2445.
ARAI, T., TAKAHASHI, K. & KUBO, A. (1977). New antibiotics, saframycins A, B, C, D andE. J. Antibiotics (Tokyo), 30, 1015–1018.
BURGER, R.M., HORWITZ, S.B., PEISACH, J. & WITTENBERG, J.R. (1979). Oxygenated iron bleomycin. A short-lived intermediate in the reaction of ferrous bleomycin with 02. J. biol. Chem., 254, 12299–12302.
BURGER, M., PEISACH, J. & HORWITZ, S.B. (1980). Activated bleomycin: a transient complex of drug, iron, and oxygen that degrades DNA. J. biol. Chem. , 256, 116–76.
CAUGHEY, W.S., ALBEN, J.A., FUJIMOTO, W.Y. & YORK, J.L. (1966). Substituted deuteroporphyrins 1. Reactions at the periphery of the porphyrin ring. J. org. Chem., 31, 2631–2640.
DERVAN, P.B. & BECKER, M.M. (1978). Molecular recognition of DNA by small molecules. Synthesis of bis(methidium)-spermine, a DNA polyintercalating molecule. J. Am. Chem. Soc, 100, 1968–1970.
GERAN, R.I., GREENBURG, N.H., MACDONALD, M.M., SCHUMACHER, A.M. & ABBOTT, B.J. (1972). Protocols for screening chemical agents and natural products against animal tumors and other biological systems. Cancer Chemother. Rep., 3, No. 2: 1–103.
HASHIMOTO, Y., LEE, CS., SHUDO, K. & OKAMOTO, T. (1983). Synthesis of porphyrin (Fe)-intercalators which cause DNA scission. Tet. Lett., 24, 1523–1526.
HECHT, S.M. (ed.) (1979). Bleomycin: Chemical, Biochemical and Biological Aspects. Heidelberg and New York: Springer-Verlag.
HERTZBERG, R.P. & DERVAN, P.B. (1982). Cleavage of double helical DNA by (methidiumpropyl-EDTA) iron(II). J. Am. Chem. Soc, 104, 313–315.
KAPPEN, L.S. & GOLDBERG, I.H. (1978). Gaps in DNA induced by neocarzinostatin bear 3’ and 5’-phosphoryl termini. Biochemistry, 17, 729–734.
LI, L.H., KUENTZEL, S.L., MURCH, L.L., PSCHIGODA, L.M. & KRUEGER, W.C. (1979). Comparative biological and biochemical effects of nogalamycin and its analogs on L1210 leukaemia. Cancer Res., 39, 4816–4822.
LOWN, J.W. (1982). Newer Approaches to the Study of the Mechanisms of Action of Antitumor Antibiotics. Ace. Chem. Res., 15, 381–387.
LOWN, J.W., HANSTOCK, C.C., JOSHUA, A.V., ARAI, T. & TAKAHASHI, K. (1983). Structure and conformation of saframycin R determined by high field 1H and 13C-NMR and its interactions with DNA in solution. J. Antibiotics (Tokyo), 36, 1184–1194.
LOWN, J.W. & JOSHUA, A.V. (1980). Interactions of the glycopeptide antitumor antibiotics bleomycin and tallysomycin with DNA in vitro. Biochem. Pharmac, 29, 521–532.
LOWN, J.W. & JOSHUA, A.V. (1982). Bleomycin models. Haemin-acridines which bind to DNA and cause oxygen-dependent scission. J. Chem. Soc. Chem. Commun., 1298–1300.
LOWN, J.W., JOSHUA, A.V. & LEE, J.S. (1982). Molecular mechanisms of binding and single-strand scission of DNA by the antitumor antibiotics saframycins A and C. Biochemistry, 3, 419–428.
LOWN, J.W. & SIM, S.K. (1977). The mechanism of the bleomycin-induced cleavage of DNA. Biochem. Biophys. Res. Commun., 11, 1150–1157.
MORGAN, A.R., LEE, J.S., PULLEYBLANK, D.E., MURRAY, N.L. & EVANS, D.H. (1979). Ethidium fluorescence assays. Part 1. physicochemical studies. Part II, enzymatic studies and DNA protein interactions. Nucleic Acids Res., 7, 547–594.
MORGAN, A.R. & PULLEYBLANK, D.E. (1974). Native and denatured DNA, cross-linked and palindromic DNA and circular covalently-closed DNA analyzed by a sensitive fluorometric procedure. Biochem. Biophys. Res. Commun., 61, 396–403.
SAUSVILLE, E.A., PEISACH, J. & HORWITZ, S.B. (1978). Effect of chelating agents and metal ions on the degradation of DNA by bleomycin. Biochemistry, 17, 2740–2746.
STAAB, H.A., LUKING, M. & DURR, F.H. (1962). Darstellung von imidazoliden. Synthese von amiden, hydraziden und hydroxamsauren nach der imidazolid methode. Chem. Ber., 95, 1275–1283.
WALSH, C. (1979). Enzymatic Reaction Mechanisms, pp. 464–500 San Francisco: Freeman.
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© 1984 Macmillan Publishers Limited
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Lown, J.W., Plenkiewicz, J., Ong, C.W., Joshua, A.V., McGovren, J.P., Hanka, L.J. (1984). Models for bleomycin antitumour antibiotics: haeminacridines which bind to DNA, cause oxygen-dependent strand scission, and exhibit anticancer properties. In: Paton, W., Mitchell, J., Turner, P. (eds) IUPHAR 9th International Congress of Pharmacology. Palgrave, London. https://doi.org/10.1007/978-1-349-86029-6_37
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DOI: https://doi.org/10.1007/978-1-349-86029-6_37
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