Abstract |
Treatment of EMT6 mouse mammary tumor cells with mitomycin C (MC) results in the formation of six major MC-DNA adducts. We identified the last unknown of these ("adduct X") as a guanine N(2) adduct of 2, 7-diaminomitosene (2,7-DAM), in which the mitosene is linked at its C-10 position to guanine N(2). The assigned structure is based on UV and mass spectra of adduct X isolated directly from the cells, as well as on its difference UV, second-derivative UV, and circular dichroism spectra, synthesis from [8-(3)H] deoxyguanosine, and observation of its heat stability. These tests were carried out using 17 microg of synthetic material altogether. The mechanism of formation of adduct X involves reductive metabolism of MC to 2,7-DAM, which undergoes a second round of reductive activation to alkylate DNA, yielding adduct X and another 2,7-DAM-guanine adduct (adduct Y), which is linked at guanine N7 to the mitosene. Adduct Y has been described previously. Adduct X is formed preferentially at GpC, while adduct Y favors the GpG sequence. In contrast to MC-DNA adducts, the 2,7-DAM-DNA adducts are not cytotoxic.
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Authors | Y Palom, M F Belcourt, S M Musser, A C Sartorelli, S Rockwell, M Tomasz |
Journal | Chemical research in toxicology
(Chem Res Toxicol)
Vol. 13
Issue 6
Pg. 479-88
(Jun 2000)
ISSN: 0893-228X [Print] United States |
PMID | 10858321
(Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Antibiotics, Antineoplastic
- Cross-Linking Reagents
- DNA Adducts
- DNA, Neoplasm
- Mitomycin
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Topics |
- Animals
- Antibiotics, Antineoplastic
(metabolism, pharmacology)
- Chromatography, High Pressure Liquid
- Cross-Linking Reagents
(metabolism, pharmacology)
- DNA Adducts
(biosynthesis, chemistry)
- DNA Damage
(drug effects)
- DNA, Neoplasm
(chemistry, drug effects)
- Female
- Mammary Neoplasms, Animal
- Mass Spectrometry
- Mice
- Mitomycin
(metabolism, pharmacology)
- Molecular Structure
- Tumor Cells, Cultured
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