title: Correlation of in Situ Oxazolidine Formation with Highly Synergistic Cytotoxicity and DNA Cross-Linking in Cancer Cells from Combinations of Doxorubicin and Formaldehyde.
abstract: 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 anthracycline prodrug design and development.
authors.affiliation: Department of Chemistry and Biochemistry, University of Colorado Boulder , Boulder, Colorado 80309, United States.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Barthel
authors.affiliation: Department of Chemistry and Biochemistry, University of Colorado Boulder , Boulder, Colorado 80309, United States.
authors.forename: Erin L
authors.initials: EL
authors.lastname: Mooz
authors.affiliation: Department of Biostatistics, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
authors.forename: Laura Elizabeth
authors.initials: LE
authors.lastname: Wiener
authors.affiliation: Department of Biostatistics, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
authors.forename: Gary G
authors.initials: GG
authors.lastname: Koch
authors.affiliation: Department of Chemistry and Biochemistry, University of Colorado Boulder , Boulder, Colorado 80309, United States.
authors.forename: Tad H
authors.initials: TH
authors.lastname: Koch
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D003432:Cross-Linking Reagents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000737:chemistry* / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000096:biosynthesis / Q000737:chemistry / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D004950:Esterases / Q000378:metabolism; D005557:Formaldehyde / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008099:Liver / Q000201:enzymology; D015394:Molecular Structure; D010080:Oxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013552:Swine; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D004273:DNA, Neoplasm; D010080:Oxazoles; D011355:Prodrugs; C545998:doxazolidine; C064210:oxazolidine; D005557:Formaldehyde; D004317:Doxorubicin; D004950:Esterases