Nucleic Acids Research Advance Access originally published online on May 5, 2007
Nucleic Acids Research 2007 35(11):3581-3589; doi:10.1093/nar/gkm285
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Nucleic Acids Research, 2007, Vol. 35, No. 11 3581-3589
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Chemistry |
Pixantrone can be activated by formaldehyde to generate a potent DNA adduct forming agent
1Department of Biochemistry, La Trobe University, Bundoora, VIC 3086, Australia and 2Cell Therapeutics Europe, I-20091 Bresso, Italy
*To whom correspondence should be addressed. Tel: +61 03 9479 1517; Fax: +61 03 9479 2467; Email: s.cutts{at}latrobe.edu.au
Received December 28, 2006. Revised March 23, 2007. Accepted April 11, 2007.
Mitoxantrone is an anti-cancer agent used in the treatment of breast and prostate cancers. It is classified as a topoisomerase II poison, however can also be activated by formaldehyde to generate drug–DNA adducts. Despite identification of this novel form of mitoxantrone–DNA interaction, excessively high, biologically irrelevant drug concentrations are necessary to generate adducts. A search for mitoxantrone analogues that could potentially undergo this reaction with DNA more efficiently identified Pixantrone as an ideal candidate. An in vitro crosslinking assay demonstrated that Pixantrone is efficiently activated by formaldehyde to generate covalent drug–DNA adducts capable of stabilizing double-stranded DNA in denaturing conditions. Pixantrone–DNA adduct formation is both concentration and time dependent and the reaction exhibits an absolute requirement for formaldehyde. In a direct comparison with mitoxantrone–DNA adduct formation, Pixantrone exhibited a 10- to 100-fold greater propensity to generate adducts at equimolar formaldehyde and drug concentrations. Pixantrone–DNA adducts are thermally and temporally labile, yet they exhibit a greater thermal midpoint temperature and an extended half-life at 37°C when compared to mitoxantrone–DNA adducts. Unlike mitoxantrone, this enhanced stability, coupled with a greater propensity to form covalent drug–DNA adducts, may endow formaldehyde-activated Pixantrone with the attributes required for Pixantrone–DNA adducts to be biologically active.
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