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Nucleic Acids Research, 2000, Vol. 28, No. 4 1019-1025
© 2000 Oxford University Press

Interstrand cross-linking by Adriamycin in nuclear and mitochondrial DNA of MCF-7 cells

Carleen Cullinane, Suzanne M. Cutts, Con Panousis and Don R. Phillips*

Department of Biochemistry, La Trobe University, Bundoora, Victoria 3083, Australia

Activation of Adriamycin by formaldehyde leads to the formation of drug–DNA adducts in vitro and these adducts stabilise the DNA to such a degree that they function as virtual interstrand cross-links. The formation of these virtual interstrand cross-links by Adriamycin was investigated in MCF-7 cells using a gene-specific interstrand cross-linking assay. Cross-linking was measured in both the nuclear-encoded DHFR gene and in mitochondrial DNA (mtDNA). Cross-link formation increased linearly with Adriamycin concentration following a 4 h exposure to the drug. The rate of formation of Adriamycin cross-links in each of the genomes was similar, reaching maximal levels of 0.55 and 0.4 cross-links/10 kb in the DHFR gene and mtDNA respectively, following exposure to 20 µM Adriamycin for 8 h. The interstrand cross-link was short lived in both DNA compartments, with a half-life of 4.5 and 3.3 h in the DHFR gene and mtDNA respectively. The kinetics of total Adriamycin adduct formation, detected using [14C]Adriamycin, was similar to that of cross-link formation. Maximal adduct levels (30 lesions/10 kb) were observed following incubation at 20 µM drug for 8 h. The formation of such high levels of adducts and cross-links could therefore be expected to contribute to the mechanism of action of Adriamycin.

* To whom correspondence should be addressed. Tel: +61 3 9479 2182; Fax: +61 3 9479 2467; Email: d.phillips@latrobe.edu.au The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors


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