Cancer Redox Biology Faculty Calls a Workshop
everal oxidation-reduction mechanisms are important in cancer etiology and treatment. There is so much to learn about nitric oxide (NO) and its oxidation-reduction reaction, called redox, that David Wink, PhD, of the NCI CCR Radiation Biology Branch, formed the Cancer Redox Biology (CRB) Faculty to do just that. The Faculty has successfully enhanced communication and promoted collaboration among biochemists, chemists, clinical oncologists, epidemiologists, and others interested in the molecular mechanisms by which redox stress alters cancer development and tumor spread.
The CRB Faculty recently assessed the state of the science in a workshop on “Redox-Based Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) in Cancer Treatment, Prevention and Angiogenesis: A Novel Solution to an Old Problem.” It was, in part, a response to an extensive hearing by the U.S. Food and Drug Administration (FDA) in 2005 that suggested the entire class of NSAIDs might have problematic side effects.
Dr. David Wink of CCR’s Radiation Biology Branch (right) presents Nobel Laureate Dr. Louis Ignarro (UCLA) with a lifetime achievement award at the Grand Rounds Lecture at the workshop.
A few years before, researchers had claimed that NSAIDs such as aspirin could inhibit cyclooxygenase (COX) enzymes and help prevent colorectal cancer. The oncology community soon discovered that aspirin causes side effects such as stomach ulcers. Renewed optimism followed with the discovery of selective COX-2 inhibitors, such as celecoxib or rofecoxib, which targeted COX-2 exclusively, reducing prostaglandin (PG) E2 levels in cells without causing stomach toxicity. However, these new agents also brought new side effects.
The workshop assessed NSAIDs from a CRB perspective. The day opened with Dr. Louis Ignarro, Nobel Laureate in Medicine from the David Geffen School of Medicine at the University of California, Los Angeles, delivering the Grand Rounds Lecture. He presented his exceptional discoveries that clarified the role of NO as a unique signaling molecule beneficial for patients who have heart disease.
The CRB Faculty and invited speakers then shared some of the translational research aimed at the COX-2 target. NO-aspirin, a potential new drug to inhibit COX-2 enzymes with NO covalently attached, drew much attention from the scientists. Data presented by Basil Rigas, MD, DSc, of the Cancer Prevention Division of the State University of New York at Stony Brook showed that NO-aspirin was over 1,000-fold more potent than aspirin at inhibiting colon cancer cellular proliferation. And in animal models of colon and pancreatic cancer, it reduced tumor proliferation with little toxicity. Novel NSAIDs such as this may eventually provide more treatment options to patients with adenocarcinomas in breast and lung tissues.
Other researchers showed that the selective COX-2 inhibitor celecoxib is proving effective in lung cancer treatment. In a phase II clinical trial, celecoxib increased the survival of lung cancer patients compared with those who received chemotherapy alone. In a phase I study, again treating lung cancer, this agent used in combination with radiotherapy increased patient response more than radiation alone.
Sulfur (S)-NSAIDs were evaluated as well. Piero del Soldato, PhD, of CTG Pharma in Milan, Italy, reported that the S-NSAIDs showed little gastrointestinal toxicity. Grace Yeh, PhD, and David Roberts, PhD, described their important properties with respect to cancer prevention and treatment. Larry Keefer, PhD, presented chemical delivery systems that can target NO to specific sites within the body.
The CRB Faculty is an excellent example of successful multidisciplinary teaming within the CCR that leverages existing resources to support translational research. The success of this Faculty stems from a well-defined mission, strong leadership, and excellent communication among the members. Much preclinical work on NO remains to be done, but based on the pace of the CRB Faculty to date, this work will be accomplished soon and used to guide researchers in their selection of lead compounds to take forward to clinical trials.