Formation of DNA adducts by formaldehyde-activated mitoxantrone.
Recent studies with the anthracycline Adriamycin have demonstrated its activation by formaldehyde and subsequent binding to DNA in vitro. Since formaldehyde levels are known to be higher in cells of myeloid origin and the structurally related drug mitoxantrone is most effective against cancers of myeloid origin, this indicates a possible role of formaldehyde in the activation of mitoxantrone. In vitro studies revealed that the activation of mitoxantrone by formaldehyde leads to the formation of drug-DNA adducts. These adducts stabilised DNA such that they functioned as virtual interstrand crosslinks. The interstrand crosslinks were formed in the presence of mitoxantrone and formaldehyde in a time- and concentration-dependent manner. In the absence of formaldehyde no crosslinks were formed, indicating a key role in drug activation and DNA binding. The adducts (virtual crosslinks) were relatively unstable with 50% crosslinks remaining after 10 min at 60 degrees C in 45% formamide. Like Adriamycin, the mitoxantrone-formaldehyde-DNA crosslinks are heat labile and do not display the stability associated with covalent interstrand crosslinks.
Parker
B S
BS
Department of Biochemistry, La Trobe University, Bundoora, Victoria 3083, Australia.
Cullinane
C
C
Phillips
D R
DR
D003432:Cross-Linking Reagents / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000378:metabolism; D004347:Drug Interactions; D005557:Formaldehyde / Q000378:metabolism*; D006207:Half-Life; D008942:Mitoxantrone / Q000737:chemistry / Q000378:metabolism*; D010957:Plasmids / Q000235:genetics / Q000378:metabolism; D013696:Temperature; D013997:Time Factors
D003432:Cross-Linking Reagents; D018736:DNA Adducts; D005557:Formaldehyde; D004317:Doxorubicin; D004247:DNA; D008942:Mitoxantrone