COMPARISON OF OXYGEN RADICAL GENERATION FROM THE REDUCTIVE ACTIVATIONOF DOXORUBICIN, STREPTONIGRIN, AND MENADIONE BY XANTHINE-OXIDASE AND XANTHINE DEHYDROGENASE

Investigations into the enzymes responsible for the reductive activati on of antineoplastic agents are of particular interest with regard to the use of these agents in the treatment of solid tumors, Xanthine oxi dase (EC 1.1.3.22; XO) and xanthine dehydrogenase (EC 1.1.1.204; XDH) are two enzymes capable of the reductive activation of antineoplastic agents. Previously, XDH, the enzymatic precursor of XO, was not extens ively studied because of difficulties in its isolation. Research in th e reductive activation of antineoplastic agents by XDH has increased w ith the discovery of a rapid and high-yield purification procedure for XDH, In the present investigation, the potential for drug activation of doxorubicin (DOX), streptonigrin (STN), and menadione (MD) by XO an d XDH was assessed through oxygen consumption studies. These studies w ere conducted at pH 7.4 and pH 6.0 to reflect physiological and the ac idic pH of solid tumors, respectively. Apparent kinetic constants were determined for DOX, STN, and RID activation by XO and XDH at both pH levels. Higher oxygen consumption was observed for XDH drug activation in comparison to XO drug activation at equivalent enzyme activity for both pH levels. Drug-induced oxygen consumption was affected by pH, H ence, drug activation for DOX, STN, and RID was dependent upon the for m of the xanthine-converting enzyme and the pH. (C) 1997 Academic Pres s.