Literature DB >> 4201

Studies related to antitumor antibiotics. Part V. Reactions of mitomycin C with DNA examined by ethidium fluorescence assay.

J W Lown, A Begleiter, D Johnson, A R Morgan.   

Abstract

The cytotoxic action of the antitumor antibiotic mitomycin C occurs primarily at the level of DNA. Using highly sensitive fluorescence assays which depend on the enhancement of ethidium fluorescence only when it intercalates duplex regions of DNA, three aspects of mitomycin C action on DNA have been studied: (a) cross-linking events, (b) alkylation without necessarily cross-linking, and (c) strand breakage. Cross-linking of DNA is determined by the return of fluorescence after a heat denaturation step at alkaline pH's. Under these conditions denatured DNA gives no fluorescence. The cross-linking was independently confirmed by S1-endonuclease (EC 3.1.4.-) digestion. At relatively high concentrations of mitomycin the suppression of ethidium fluorescence enhancement was shown not to be due to depurination but rather to alkylation, as a result of losses in potential intercalation sites. A linear relationship exists between binding ratio for mitomycin and loss of fluorescence. The proportional decrease in fluorescence with pH strongly suggests that the alkylation is due to the aziridine moiety of the antibiotic under these conditions. A parallel increase in the rate and overall efficiency of covalent cross-linking of DNA with lower pH suggests that the cross-linking event, to which the primary cytotoxic action has been linked, occurs sequentially with alkylation by aziridine and then by carbamate. Mitomycin C, reduced chemically, was shown to induce single strand cleavage as well as monoaklylation and covalent cross-linking in PM2 covalently closed circular DNA. The inhibition of this cleavage by superoxide dismutase (EC 1.15.1.1) and catalase (EC 1.11.1.6), and by free radical scavengers suggests that the degradation of DNA observed to accompany the cytotoxic action of mitomycin C is largely due to the free radical O2. In contrast to the behavior of the antibiotic streptonigrin, mitomycin C does not inactivate the protective enzymes superoxide dismutase or catalase. Lastly, mitomycin C is able to cross-link DNA in the absence of reduction at pH 4. This is consistent with the postulated cross-linking mechansims.

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Year:  1976        PMID: 4201     DOI: 10.1139/o76-018

Source DB:  PubMed          Journal:  Can J Biochem        ISSN: 0008-4018


  21 in total

1.  Rearrangement of interstrand cross-links into intrastrand cross-links in cis-diamminedichloroplatinum(II)-modified DNA.

Authors:  C Pérez; M Leng; J M Malinge
Journal:  Nucleic Acids Res       Date:  1997-02-15       Impact factor: 16.971

2.  Comparative studies on the action of 7-N-[2-[[2-(gamma-L-glutamylamino)ethyl]dithio]ethyl]mitomycin C and of mitomycin C on cultured HL-60 cells and isolated phage and plasmid DNA.

Authors:  C Ishioka; R Kanamaru; Y Konishi; A Ishikawa; H Shibata; A Wakui
Journal:  Cancer Chemother Pharmacol       Date:  1990       Impact factor: 3.333

Review 3.  The mechanism of action of quinone antibiotics.

Authors:  J W Lown
Journal:  Mol Cell Biochem       Date:  1983       Impact factor: 3.396

4.  Repair synthesis by human cell extracts in DNA damaged by cis- and trans-diamminedichloroplatinum(II).

Authors:  J Hansson; R D Wood
Journal:  Nucleic Acids Res       Date:  1989-10-25       Impact factor: 16.971

5.  Mutagenicity of oxygen free radicals.

Authors:  C S Moody; H M Hassan
Journal:  Proc Natl Acad Sci U S A       Date:  1982-05       Impact factor: 11.205

6.  Thermal stability of DNA adducts induced by cyanomorpholinoadriamycin in vitro.

Authors:  C Cullinane; D R Phillips
Journal:  Nucleic Acids Res       Date:  1993-04-25       Impact factor: 16.971

7.  Lack of Z-DNA conformation in mitomycin-modified polynucleotides having inverted circular dichroism.

Authors:  M Tomasz; J K Barton; C C Magliozzo; D Tucker; E M Lafer; B D Stollar
Journal:  Proc Natl Acad Sci U S A       Date:  1983-05       Impact factor: 11.205

8.  Mitomycin-induced synthesis of a Shiga-like toxin from enteropathogenic Escherichia coli H.I.8.

Authors:  A J Yee; S De Grandis; C L Gyles
Journal:  Infect Immun       Date:  1993-10       Impact factor: 3.441

9.  Bronchial artery infusion of mitomycin C in carcinoma of the lung.

Authors:  S Ekholm; U Albrechtsson; U Tylén
Journal:  Cardiovasc Intervent Radiol       Date:  1983       Impact factor: 2.740

10.  In vitro antineoplastic activity of C7-substituted mitomycin C analogues MC-77 and MC-62 against human breast-cancer cell lines.

Authors:  A Ghiorghis; A Talebian; R Clarke
Journal:  Cancer Chemother Pharmacol       Date:  1992       Impact factor: 3.333

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