139th National Cancer Advisory Board
damage cells. Oxidative stress plays a role in almost every single disease or degenerative processes such as aging, heart disease, and a variety of acute and chronic neuronal diseases. On the other side, however, oxygen can produce other molecules, such as nitric oxide, which is associated with air pollution, cigarette smoke, and all the deleterious effects witnessed in brown smog over cities. Around 1980, nitric oxide, which is an active ingredient in nitroglycerin, was discovered to regulate blood pressure. This changed the perception about toxic intermediates; hydrogen peroxide and NO may be important in regulating a number of physiological processes. Other molecules also have been discovered to influence body regulations. Carbon monoxide, for example, recently has been found to serve as a key regulatory molecule of inflammation. Hydrogen sulfide, the compound that makes eggs stink, is found in µM levels in the human brain.
The goal of the faculty is to bring together researchers within CCR/NIH and the extramural community to provide a vehicle to discuss and facilitate collaboration in redox biology. The Steering Committee agreed on three objectives to foster cooperation: (1) establish a course in “Redox Biology in Cancer,” with complementary seminars; (2) hold workshops to expand on promising areas identified by the Steering Committee (two workshops have been held on the topics of imaging and biomarkers for oxidative stress, and redox-based non steroidal anti-inflammatory drugs (NSAIDs); and (3) focus collaborative research on identified areas of need. Measurement remains the most controversial issue in redox biology. Dr. Wink shared the lecture topics and speakers for the redox biology course that has been taught for the past 3 years. He noted that, even with a relatively young faculty, a number of different collaborative papers have been published during the past 2 years.
The current Redox Faculty is focusing on redox-based NSAIDs, which alleviate the gut toxicity of conventional NSAIDs. Another advantage of these novel compounds is that some moieties offer anti- thrombotic properties; this is important because chronic use of NSAIDs can lead to drug toxicity, and NSAIDs have thrombotic properties that can lead to stroke and heart attack. Dr. Wink mentioned that common NSAIDs include aspirin, indomethicin, sulindac, and diclofenac. Redox-active moieties include nitrogen oxide, thiol-based NSAIDs (e.g., ADT and oltipraz), and superoxide (SOD) mimetics (e.g., nitroxides). Collaborators working with these compounds include Drs. Piero Del Soldato (CTG), Bruce King (Wake Forest University), Larry Keefer (LCC/CCR/NCI), and the Division of Cancer Prevention.
The redox-based NSAIDs have been examined for potential use in chemoprevention, treatment, and imaging. Dr. Wink described chemoprevention properties of redox-based NSAIDs, as studied by Dr. Grace Yeh, LM/CCR. Dr. Yeh has been interested in polyaromatic hydrocarbons and how they can be used to block the activation of the polyaromatic hydrocarbons. She studied Phase I enzymes extensively, in which, when a polyaromatic hydrocarbon is present, the xenobiotic responsive element is activated, which in turn activates the p450. The p450s oxidize the polyaromatic hydrocarbons to form the carcinogen, which ultimately labels the DNA. She has screened a number of compounds and natural products and has demonstrated that some compounds can block this pathway. There also is another strategy that can be employed to block the carcinogens, which is a focus on Phase II enzymes. Phase II enzymes upregulate other enzymes that scavenge the carcinogen and detoxify it. The redox faculty is aiming to discover agents that help to block Phase I and increase Phase II. Dr. Yeh’s group surveyed a variety of NSAIDs and found that some worked whereas others did not. The thiol-based NSAIDs, as well as the nitro-aspirin, for instance, would knock down Phase I, and both of these sets of compounds increased Phase II. Tumor biology studies will be examining mammary and lung tumors in animals. Further work also is planned to use compounds provided by the Division of Cancer Prevention to synthesize a better molecule.
Regarding the use of redox-based NSAIDs in cancer treatment, the goal was to identify agents that can help increase efficacy of conventional therapies, particularly radiation and chemotherapy. The