Bleomycin scission

Cooperative work with Prof. Nobuo Tanaka (Professor Emeritus of the University of Tokyo) in 1969 showed the mechanism of action of bleomycin to involve DNA strand-scission. The difficult total synthesis of bleomycin was accomplished (1981) in cooperation with Takita and others, including Hamao s son, Yoji Umezawa. H. Umezawa was very satisfied with the success of this total synthesis, and his sustained enthusiasm for improved bleomycins led to peplomycin (1978 used clinically since 1981) and libro-mycin(1985). 

GUoni, L., Takeshita, M., Johnson, F., Iden, C., and Grollman, A. P., 1981, Bleomycin-induced strand-scission ofDNA. Mechanism of deoxyiibose cleavage,/. Biol. Chem. 256 8608-8615. 

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(16) 8608-8615 Gniazdowski M, Czyz M (1999) Transcription factors as targets of anticancer drugs. Acta Biochim Pol 46(2) 255-262... 

The bleomycins (50) are hardly simple amines, but they do have two NH2 groups and a CONH2 group at the N-terminal domain, as well as potential donor nitrogens in pyrimidine and imidazole, which can complex metal ions." " The complexing of iron to bleomycin" " " has a significant effect on bleomycin-DNA interactions—metal complexes can mediate strand scission—and on alkene oxidation. Both may involve hydroperoxide intermediates." " " " ... 

In the presence of ferrous ions and oxygen, copper-free bleomycin causes a double-stremd scission of The bleomycin-Cu ... 

Bleomycin intercalates between bases (f d ouble-stranded DNS(34). In this connection, it is interesting that phleomycin which has the dihydrobithiazole moiety, does not intercalate with DNA (33). It causes more single-strand scission than double-strand scission (30). 

Screening of microbial products has led to the discovery of a number of growth-inhibiting compounds that have proved to be clinically useful in cancer chemotherapy. Many of these antibiotics bind to DNA through intercalation between specific bases and block the synthesis of RNA, DNA, or both cause DNA strand scission and interfere with cell replication. All of the anticancer antibiotics now being used in clinical practice are products of various strains of the soil microbe Streptomyces. These include the anthracyclines, bleomycin, and mitomycin. 

Burger RM, Peisach J, Horwitz SB (1982a) Stoichiometry of DNA strand scission and aldehyde formation by bleomycin. J Biol Chem 257 8612-8614... 

Hecht SM, Long EC, van Atta RB, De Vroom E, Carter BJ (1990) On the mechanism of bleomycin activation and polynucleotide strand scission. In Bleasdale C, Golding BT (eds) Mol. Mech. Bioorg. Processes, Conference Proceedings. Royal. Soc. Chem., London, pp 100-114 Held AM, Halko DJ, Hurst JK (1978) Mechanisms of chlorine oxidation of hydrogen peroxide. J Am Chem Soc 100 5732-5740... 

Bleomycin (Blenoxane) causes chain scission and fragmentation of DNA. With the exception of the skin and lungs, most tissues can enzymatically inactivate bleomycin. Bleomycin is used in the management of squamous cell carcinoma of the head, neck, and esophagus in combination with other drugs in patients with testicular carcinoma, and in the treatment of Hodgkin s disease and other lymphomas. Bleomycin causes stomatitis, ulceration, hyperpigmentation, erythema, and pulmonary fibrosis. 

Bleomycins are thought to react with DNA and cause strand scission they have also been shown to have a type of oxygen transferase activity.1... 

Bleomycin [blee oh MYE sin] is a mixture of different copper chelating glycopeptides that, like the anthracycline antibiotics, cause scission of DNA by an oxidative process. 

In isolated rat nuclei, SOD inhibits bleomycin-induced membrane peroxidation, but has no effect on bleomycin-catalysed DNA scission [57]. Thus, it may be possible to use iron chelators to reduce the toxic extracellular side effects of these drugs, whilst leaving the intracellular therapeutic mode of action unaltered. In fact, it has been demonstrated that the cardiotoxicity of adriamycin can be inhibited by the chelating agent ICRF-187 [60],... 

The natural product bleomycin mediates strand scission in the presence of iron and oxygen by a related mechanism (6, 12, 14) however, no diffusible intermediate is generated. Electrochemical and related studies showed that the mechanism of iron bleomycin (Fe-BLM) involves first reduction of Fe(III)-BLM, reaction of Fe(II)-BLM with 02, and reduction of the Fe(II)-BLM-02 adduct to activated Fe-BLM (15). 

Bleomycin (CCS) Complexes with Fe and 02 —> DNA strand scission (G2 phase) Hodgkin s, testicular, head, neck, skin CA Pneumonitis, pulmonary fibrosis, mucocutaneous reactions (blisters), alopecia, hypersensitivity... 

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