Enzyme inhibitor
This set of glycopeptide antibiotics and anticancer agents (Bleomycin A1:
FW = 1415.55 g/mol; CAS 11056-06-7; R = –NH (CH2) 3-SOCH3);
Bleomycin A2, R = –NH (CH2) 3-S+CH3); Bleomycin B1, R = –NH (CH2) 4-
NCH (=NH) NH2); Bleomycin A5, R = –NH (CH2) 3–NH (CH2) 4–NH2); and
Bleomycin A6, R = –NH (CH2) 3–NH (CH2) 4–NH (CH2) 3–NH2), often
abbreviated BLM and produced by Streptomyces verticillus, are DNA
strand-breaking agents that exploit their interaction with Fe (II) ion. More
than two-hundred bleomycins have been isolated from different strains of
Streptomyces, with molecular weights ranging from 1000 to 10,000.
Bleomycin’s activity is associated with single-strand DNA cleavage through
the generation of hydroxyl free radicals. Although the exact in vivo
mechanism of bleomycin’s action as an antineoplastic agent is unknown,
available evidence indicates that the main mode of action is the inhibition of
DNA synthesis with lesser effects arising from effects on RNA and protein
synthesis. Bleomycin can stop the cell cycle at G2 and is often used to
induce synchrony in cell cultures. Primary Mode of Action: Bleomycin forms
chelation complexes with Fe2+, Co2+, Cu2+, Ni2+, and Zn2+. Upon binding of a
bleomycin-Fe2+-O2 complex to DNA, the coplanar bithiazole moiety
intercalates in the minor groove of DNA, whereupon the iron is oxidized to
Fe3+, and the resulting complex of bleomycin acts on deoxyribose.
Bleomycin interacts with either Fe (II) and O2 or Fe (III) and H2O2 to form an
activated complex that attacks DNA. Under aerobic conditions, both
reactions yield similar quantities of free bases as well as products consisting
of the base plus deoxyribose carbon-atoms 1 to 3. Under anaerobic
conditions, activated bleomycin releases only free base. The yield of free
base is the same under aerobic or anaerobic conditions, when DNA is in
excess. When DNA concentration is limiting, more base is released under
anaerobic than under aerobic conditions. Drug self-destruction proceeds as
quickly and completely in the presence or absence of O2.
Pharmacokinetics: Bleomycin is rapidly absorbed following intramuscular
(IM) or subcutaneous (SC), administration reaching peak plasma
concentrations in 30 to 60 minutes and exhibiting a systemic bioavailability
of 100% (IM) and 70% (SC). Upon IV bolus administration, bleomycin is
widely distributed, with a mean volume of distribution of 17.5 L/m2. Protein
binding has not been studied. Bleomycin is inactivated by a cytosolic
cysteine proteinase enzyme, bleomycin hydrolase, which is widely
distributed in normal tissues (exception: skin and lungs, where toxicity is
highest. Target (s) : DNA polymerase; protein-glutamine g-
glutamyltransferase (transglutaminase), by bleomycin alone or copper-
bleomycin; RNA polymerase; DNA ligase; dopamine b-
monooxygenase; tyrosine monooxygenase.
