Studies on the chemical reactivity of copper bleomycin
| Autor: | David H. Petering, D. Solaiman, William E. Antholine, Leon A. Saryan |
|---|---|
| Rok vydání: | 1982 |
| Předmět: |
Chemical Phenomena
Stereochemistry chemistry.chemical_element Antineoplastic Agents In Vitro Techniques Ligands Ferroxidase activity Biochemistry Redox Medicinal chemistry Inorganic Chemistry Metal Bleomycin Mice Reaction rate constant Animals Humans Sulfhydryl Compounds Carcinoma Ehrlich Tumor Bond cleavage Ligand DNA Copper Chemistry Kinetics chemistry visual_art visual_art.visual_art_medium Chemical stability Oxidation-Reduction |
| Zdroj: | Journal of Inorganic Biochemistry. 17:75-94 |
| ISSN: | 0162-0134 |
| DOI: | 10.1016/s0162-0134(00)80077-x |
| Popis: | The copper(II) complex of the clinically used antitumor agent bleomycin (Blm) has cytotoxic as well as antitumor properties. To understand the relationship of the bleomycin ligand, copper bleomycin, and other possible metal complexes of this agent, kinetic studies of the formation of Cu(II)Blm, ligand substitution reactions of CuBlm with ethylenediaminetetraaletic acid, and the redox reaction of CuBlm with thiols have been completed and interpreted along with previous studies of the thermodynamic stability of Cu 2+ with bleomycin. Cu(II)Bm is found to be kinetically and thermodynamically stable in ligand substitution processes and is only slowly reduced and dissociated by sulfhydryl reagents. The rate constant of reduction of the complex by 2-mercaptoethanol (2-ME) at pH 7.4 and 25°C is 9.5 × 10 −3 M −1 sec −1 , explaining the inhibition of Fe 2+ -dependent strand scission of DNA by Cu 2+ in the presence of 2-ME. CuBlm forms in preference to Fe(II) Blm and cannot be reduced and dissociated rapidly enough by thiols to liberate Blm and form the reactive iron complex. In agreement with the observed chemical stability of CuBlm, it is also shown that the complex is stable in human plasma and in the presence of Ehrlich cells suspended in ascites fluid. Interestingly, little CuBlm enters these cells to carry out cytotoxic reactions. Finally, it is shown that both Cu 2+ and Zn 2+ , at equivalent concentrations to Fe 2+ , effectively inhibit the strand scission of DNA by Fe(II)Blm plus oxygen. However, at substoichiometric amounts of Cu 2+ , the ferroxidase activity of Blm enables the drug to remain effective in the strand-scission reaction, despite the lowered Cu-free Blm/Fe 2+ ratio. These results are discussed in light of the proposed mechanism of action of bleomycin. |
| Databáze: | OpenAIRE |
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