The objective of the proposal is to elucidate the interaction and chemical reaction properties of the two anticancer drugs daunomycin (DM) and adriamycin (AM) with nucleic acids containing covalently bound nitroxide radicals as a localized electron source. The electron source serves as an activator of these drugs by first converting them to reduced anthracylines, which then, depending upon the presence or absence of molecular oxygen, are expected to react chemically in different ways with nucleic acid lattices. The proposed system is ideally suited to test the hypothesis that reduced anthracyclines produce O2 and H202 which then will react with proximal DNA to produce strand- scission. In the absence of oxygen it is expected that an intramolecular elimination of the C-7 glycosidic of these drugs will occur with subsequent nucleic acid drug adduct formation. The proposed interaction study will be done by electron spin resonance (ESR) and ultraviolet (UV) spectroscopy. The nucleic acid damage caused by the activated anthracyclines will be monitored by gel electrophoresis to detect strand scission and by high pressure liquid chromatography (HPLC) to isolate nucleic acid drug adducts. The latter will be characterized by high resolution mass spectrometry and nuclear magnetic resonance.
