Implications for Tumor Control During Protection of Normal Tissues With Antioxidants
Authors: Kevin Camphausen, Deborah Citrin, Murali C. Krishna, James B. Mitchell
Journal: Journal of Clinical Oncology (2005)

The use of antioxidants during antineoplastic radiation therapy has long been a controversial topic. Antioxidants are known for their ability to scavenge free radicals, potentially reducing the damage caused by ionizing radiation to treated tissues. Reduction of normal tissue injury from radiotherapy with antioxidant supplementation is intriguing; however, it raises significant concerns about the possible inadvertent simultaneous protection of tumor tissues. This issue is not limited to the clinical trial setting, given that increasing numbers of the American public take vitamin supplements and naturopathic remedies during therapy. DNA damage is the most lethal form of cellular damage caused by ionizing radiation. With the types of ionizing radiation used in clinical practice today, approximately two thirds of DNA damage is caused by short-lived (nanoseconds to microseconds) high-energy primary and secondary free radicals. To act as a radioprotector by scavenging these free radicals, an antioxidant needs to be present in sufficient concentrations and have efficient radical scavenging capabilities in proximity to the target (DNA) during the radiation exposure. -tocopherol and -carotene would not be expected to provide significant protection against radiationinduced primary and secondary reactive species compared with conventional radioprotectors. However, free-radical generation in tissues may continue after the radiation exposure as a consequence of an inflammatory response, with the generation of cytokines and sustained production of longer lived free radicals. In this setting, particularly in normal tissues, -tocopherol and -carotene may in fact be quite effective toward protecting against sustained freeradical damage. Interestingly, it is now becoming clear that free radicals can also serve as initiators (triggers) for complex signal transduction and gene expression pathways governing proand antisurvival responses. For example, -tocopherol can modulate transcriptional and posttranscriptional regulation of protein kinase C, cyclooxigenase, and lipoxygenase. Whether radiation induces a similar inflammatory response in tumors is less clear, given their markedly different redox status. To further complicate the issue of supplementation, the concentration of the agent or the surrounding environment can alter the antioxidant effects of many molecules. As for the microenvironment, -carotene is an antioxidant at low oxygen concentrations; however, it acts as a pro-oxidant at high oxygen concentrations. To illustrate this complex relationship of dose, agent, and microenvironment, consider the following two large randomized studies that have assessed the efficacy of -carotene as a preventative agent in patients at high risk of malignancy. The Alpha-Tocopherol, Beta-Carotene cancer prevention trial randomly assigned 29,133 male smokers to supplementation with -tocopherol, -carotene, both, or placebo, and unexpectedly found an increased risk of lung cancer in participants who received -carotene supplementation. Supplementation with -tocopherol alone in this study appeared to have no adverse effect on lung cancer incidence. In addition, the -Carotene and Retinol Efficacy trial randomly assigned 18,314 men and women at high risk of developing lung cancer to the combination of daily -carotene and retinyl palmitate (vitamin A) or placebo. This large study was stopped early because of evidence of a significant increase in the risk of lung cancer and lung cancer mortality in the treatment group compared with the placebo group. It is hypothesized that the increased incidence of lung cancers seen in both of these large, randomized studies is at least partially due to the pro-oxidant nature of -carotene when used at high doses or in oxygen-rich environments, such as the lung. How do the preclinical findings that antioxidants improve the efficacy of radiotherapy translate into clinical outcomes? Numerous clinical studies investigating the effects of antioxidants in combination with radiotherapy or JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 24 AUGUST 2