Comparison of oxygen radical generation from the reductive activation of doxorubicin, streptonigrin, and menadione by xanthine oxidase and xanthine dehydrogenase.
Investigations into the enzymes responsible for the reductive activation of antineoplastic agents are of particular interest with regard to the use of these agents in the treatment of solid tumors. Xanthine oxidase (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 extensively studied because of difficulties in its isolation. Research in the reductive activation of antineoplastic agents by XDH has increased with 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 and XDH was assessed through oxygen consumption studies. These studies were conducted at pH 7.4 and pH 6.0 to reflect physiological and the acidic pH of solid tumors, respectively. Apparent kinetic constants were determined for DOX, STN, and MD 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. Hence, drug activation for DOX, STN, and MD was dependent upon the form of the xanthine-converting enzyme and the pH.
Yee
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SB
Department of Nutrition and Biochemistry Graduate Program, University of Nevada, Reno, Nevada 89557-0132, USA.
Pritsos
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CA
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism; D004317:Doxorubicin / Q000378:metabolism*; D005260:Female; D006863:Hydrogen-Ion Concentration; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010084:Oxidation-Reduction; D010101:Oxygen Consumption; D011355:Prodrugs / Q000378:metabolism; D017382:Reactive Oxygen Species; D013308:Streptonigrin / Q000378:metabolism*; D014812:Vitamin K / Q000378:metabolism*; D014968:Xanthine Dehydrogenase / Q000378:metabolism*; D014969:Xanthine Oxidase / Q000378:metabolism*
D000970:Antineoplastic Agents; D011355:Prodrugs; D017382:Reactive Oxygen Species; D014812:Vitamin K; D013308:Streptonigrin; D004317:Doxorubicin; D014968:Xanthine Dehydrogenase; D014969:Xanthine Oxidase