Effect of combination of m-AMSA and doxorubicin on their redox properties and on DNA cleavage.
In vitro studies with the drug combination m-AMSA and doxorubicin were carried out in order to point out whether they can form a redox-system. Indeed, while doxorubicin is known to be bioactivated by NADPH cytochrome P-450 reductase, m-AMSA is readily and reversibly oxidized either chemically or microsomally, to give a quinone diimine with electrophile properties. This redox chemistry has been shown to play a major role in the antineoplastic properties of both drugs. The oxidation of m-AMSA was followed by absorption spectroscopy and the reduction of doxorubicin was observed by circular dichroism. It has been found that both drugs may form a redox-couple and that their association enhances their ability to cut DNA in the absence of cupric ions. Indeed, doxorubicin catalyses the oxidation of m-AMSA in sodium borate buffer (pH 9.25) and conversely the chemical reduction of doxorubicin by m-AMSA induces single and double strand breaks in pBR 322 DNA. This chemical activation may be of importance in vivo, and perhaps the combination of both drugs may lead to a therapeutic advantage.
Bernier
J L
JL
INSERM U 16, Lille, France.
Lohez
M
M
Helbecque
N
N
Hénichart
J P
JP
D000677:Amsacrine / Q000494:pharmacology*; D002942:Circular Dichroism; D003300:Copper / Q000378:metabolism; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D004347:Drug Interactions; D004587:Electrophoresis, Agar Gel; D010084:Oxidation-Reduction; D013053:Spectrophotometry
D000677:Amsacrine; D003300:Copper; D004317:Doxorubicin; D004247:DNA