INTRODUCTION Cancer is one of the leading causes of death in countries throughout the world. In the United States, approxi- mately 500 000 people die annually of cancer (1). Appropriate prevention plus effective therapy is the foun- dation of our fight against cancer. However, some aspects of our thinking concerning prevention and treatment are not only inconsistent, but are often even contradictory. This review, using oxidation-reduction metabolism as an example, sheds light on the often paradoxical observa- tions seen in cancer prevention and treatment, and explains the origin of these paradoxical findings in terms of a new threshold theory. Reactive oxygen species (ROS), the oxidative products of biological compounds, are ubiquitous in nature and in man are produced mainly by incomplete reduction of oxygen during respiration, by exposure to radiation, by oxidative chemicals, or by release from phagocytic cells in response to bacterial invasion or tumor. These mole- cules are mainly represented by a family of oxygen-cen- tered derivatives, including superoxide radicals (O 2 ·– ), hydrogen peroxides (H 2 O 2 ), hydroxyl radicals (OH·), hypochlorous acid (HOCl), and sometimes singlet oxygen ( 1 O 2 ) (2,3). Since free radicals are molecules that contain one or more unpaired electrons with anti-parallel spins in their outer orbit, they react easily with biologic struc- tures, particularly polyunsaturated membrane lipids, DNA, and amino acids. The resultant disintegration of bio-membranes, DNA damage, and enzyme deactivation are severe events in cell biochemistry and frequently lead to cell dysfunction, transformation, or death (2,4). There are, however, many molecules present that pro- tect tissues from the damaging effects of ROS, including cellular enzymes (e.g. superoxide dismutase (SOD), cata- lase, and glutathione synthase) and metal ion chelators. A threshold concept for cancer therapy Q. Kong, J. A. Beel, K. O. Lillehei Department of Neurosurgery, University of Colorado Health Sciences Center, Denver, USA Summary Oxygen free radicals have been implicated in many disease processes, including aging and carcinogenesis, and have been associated with a variety of complications resulting from the treatment of cancer. As a result, the treatment of free radical-induced disease with antioxidants or free radical scavengers has become an important therapeutic modality. Ironically, these same oxygen free radicals also play a critical role in anti-cancer therapies. The use of antioxidants such as superoxide dismutase (SOD), in this setting, has been found to decrease the efficacy of anti-tumor therapies, which depend on free radical generation for their action. In addition, increased antioxidant activity can often be utilized by the tumor cell to favor increased growth. Therefore, the appropriate application of oxygen free radicals and antioxidants seems to be critically important in designing proper strategies for both prevention and treatment of malignant disorders. This review will summarize free radical and antioxidant regimens that have been employed to date, examine some of the problems associated with these regimens, introduce the ‘threshold concept’ explaining the dual effects of oxygen free radicals and antioxidants, and discuss a novel hypothesis regarding therapy that could potentially improve outcome in cancer patients. © 2000 Harcourt Publishers Ltd Received 22 October 1998 Accepted 25 August 1999 Correspondence to: Qingzhong Kong, MD, PhD, Department of Neurosurgery, C-307, University of Colorado Health Sciences Center, 4200 East 9th Ave., Denver, CO 80262, USA. Phone: +1 303 315 0073; Fax: +1 303 315 6197; E-mail: qing.kong@uchsc.edu 29 Medical Hypotheses (2000) 55(1), 29–35 © 2000 Harcourt Publishers Ltd doi: 10.1054/mehy.1999.0982, available online at http://www.idealibrary.com on