REDUCTIVE ACTIVATION OF DOXORUBICIN BY XANTHINE DEHYDROGENASE FROM EMT6 MOUSE MAMMARY-CARCINOMA TUMORS

The role of enzymes in the reductive activation of various chemotherap eutic agents is an area of considerable interest in studies to better understand the selective toxicities of these agents. Xanthine dehydrog enase (XDH) is an enzyme capable of reductive activation of chemothera peutic agents. Previously, this enzyme has not been extensively studie d because of difficulties in its isolation. We recently isolated this enzyme from EMT6 mouse mammary carcinoma cells and showed that this en zyme is capable of activating mitomycin C. In this study, we examined whether XDH could activate the clinically important antineoplastic age nt, doxorubicin. Drug activation was determined under aerobic and hypo xic conditions and at various pHs in order to simulate the different e nvironments found in solid tumors. The results of these studies show t hat XDH reacts with doxorubicin via a two-electron reduction. This red uction is different from the modified and more extensively studied for m of the enzyme. xanthine oxidase (XO), which reacts with doxorubicin via a one-electron reduction. Under hypoxic conditions, the formation of large quantities of 7-deoxydoxorubicin aglycone, a deactivation pro duct of doxorubicin metabolism may serve to moderate doxorubicin's ant ineoplastic activity. Under aerobic conditions, however, XDH activatio n led to a greater rate of formation of oxygen radicals than XO thereb y possibly potentiating doxorubicin's cytotoxicity to aerobic tumor ce lls. Kinetic constants were determined for doxorubicin activation by X DH. (C) 1997 Elsevier Science Ireland Ltd.