Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 59, Issue 5, Pages 2205-2221Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.5b01956
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Funding
- NIH [R21CA141101, R21CA143549]
- University of Colorado Technology Transfer Office [11BGF-34]
- State of Colorado
- Colorado Center for Drug Discovery
- University of Colorado Cancer Center
- Cancer League of Colorado
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Anthracyclines are a class of antitumor compounds that are successful and widely used but suffer from cardiotoxicity and acquired tumor resistance. Formaldehyde interacts with anthracyclines to enhance antitumor efficacy, bypass resistance mechanisms, improve the therapeutic profile, and change the mechanism of action from a topoisomerase II poison to a DNA cross-linker. Contrary to current dogma, we show that both efficient DNA cross-linking and potent synergy in combination with formaldehyde correlate with the anthracycline's ability to form cyclic formaldehyde conjugates as oxazolidine moieties and that the cyclic conjugates are better cross-linking agents and cytotoxins than acyclic conjugates. We also provide evidence that suggests that the oxazolidine forms in situ, since cotreatment with doxorubicin and formaldehyde is highly cytotoxic to dox-resistant tumor cell lines, and that this benefit is absent in combinations of formaldehyde and, epirubicin, which cannot form stable oxazolidines. These results have potential clinical implications in the active field of anthracydine prodrug design and development.
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