Potential Lung Disease Biomarkers Yield Clues to COX-2 Inhibitor Side Effects

In searching for a simple way to identify individuals with smoking-related lung injury, scientists at Weill Cornell Medical College have stumbled upon a potential explanation for why the class of pain-relievers known as COX-2 inhibitors increases the risk of heart problems among users.

The findings are notable in two ways, explains Dr. Andrew J. Dannenberg, director of the Weill Cornell Cancer Center and the Henry R. Erle, M.D.–Roberts Family Professor of Medicine at Weill Cornell Medical College and a leading gastroenterologist at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. “Not only could they lead to the development of a simple urine test to determine which smokers are at increased risk of developing chronic obstructive pulmonary disease or emphysema, but they might also pave the way for new drugs or combinations of drugs that harness the benefit of COX-2 inhibitors, including cancer-fighting properties, with reduced cardiovascular toxicity.”

Dr. Dannenberg is senior author of a new study detailing the findings which appears in the April issue of Cancer Prevention Research. A collaboration led by Weill Cornell Medical College and Memorial Sloan-Kettering Cancer Center, the research study was funded by Weill Cornell’s Clinical and Translational Science Center (CTSC), an NIH-funded consortium for biomedical collaboration on New York’s Upper East Side, as well as by the Flight Attendant Medical Research Institute (FAMRI), Pfizer Inc., and a Memorial Sloan-Kettering Cancer Center Prevention Control and Population Research Program Pilot Project Award.

COX-2 inhibitors were developed to selectively target the cyclooxygenase-2 (COX-2) enzyme, which plays an important role in inflammation. The idea was to treat pain and arthritis without the potentially dangerous gastrointestinal side effects of other non-steroidal anti-inflammatory drugs (NSAIDs). This class of drugs has also been shown to reduce colorectal polyps, a precursor to colorectal cancer. But two blockbuster COX-2 inhibitors, Vioxx (rofecoxib) and Bextra (valdecoxib), were pulled off the market after reports that they elevated the risk of heart attack, stroke and death in users. Celebrex (celecoxib) is the only COX-2 inhibitor still available.

The current trial was originally designed to identify biomarkers in urine which could indicate the presence of incipient, smoking-related lung disease. The researchers had hypothesized that early-stage lung injury could “turn on” the COX-2 gene, increasing levels of the major prostaglandin metabolite PGE-M in the urine.

In addition to determining PGE-M levels, the investigators also looked at levels of the biomarker leukotriene E4 (LTE4), formed by the 5-lipoxygenase (5-LO) pathway. Both biomarkers, representing these two different pathways, are synthesized from arachidonic acid. The 5-LO pathway has also been implicated in inflammation, cancer and cardiovascular problems.

For this study, 28 never-smokers, 26 former smokers and 28 current smokers took 200 milligrams of Celebrex twice a day for about a week. At the beginning of the study, current smokers had higher levels of both PGE-M and LTE4 than never-smokers. High PGE-M levels suggest higher levels of COX-2 activity. Twice-daily doses of Celebrex resulted in reduced PGE-M levels in all three groups, with the largest drop seen among those who had high starting levels of PGE-M.

“But we also found that Celebrex treatment led to increases in urinary LTE4 levels, primarily among individuals who had started out with high PGE-M levels,” says first author Dr. Anna J. Duffield-Lillico, a consultant with the Department of Epidemiology and Biostatistics and the Department of and Surgery at Memorial Sloan-Kettering Cancer Center. “This indicated that Celebrex ‘shunted’ or redirected arachidonic acid into the 5-LO pathway from the COX pathway. When one went down, the other went up.” This is important because other studies have suggested an important role for the 5-LO pathway in Atherosclerosis, heart attacks and stroke.

And it is this increased shunting of arachidonic acid into the 5-LO pathway that may help explain why COX-2 inhibitors contribute to cardiovascular problems, the researchers say.

“More studies are needed to see if these two biomarkers are reliable indicators of the presence of low-level lung inflammation,” notes Dr. Dannenberg.

And more research is necessary to understand the role of COX-2 inhibitors in the heart, especially to see if their anti-cancer effects can be attained without the counterbalancing negative effects.

Study co-authors include Drs. Xi Kathy Zhou, Kotha Subbaramaiah and Aradhana Ghosh of Weill Cornell Medical College; Dr. Jay O. Boyle and Ms. Geera S. Butala of Memorial Sloan-Kettering Cancer Center; Dr. Robert A. Newman of the University of Texas M.D. Anderson Cancer Center; and Drs. Jason D. Morrow and Ginger L. Milne of Vanderbilt University School of Medicine.

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Weill Cornell Medical College’s Clinical and Translational Science Center
Weill Cornell Medical College is one of 39 medical research institutions working together as a national consortium to improve the way biomedical research is conducted across the country. The Clinical and Translational Science Center (CTSC) is funded through a $49 million Clinical and Translational Science Award (CTSA) from the National Center for Research Resources at the National Institutes of Health (NIH), which oversees the program. The CTSA consortium shares a common vision to reduce the time it takes for laboratory discoveries to become treatments for patients, and to engage communities in clinical research efforts. The program also addresses the critical need to train the next generation of clinical researchers. Weill Cornell’s CTSC integrates existing inter-institutional resources among Upper East Side partner institutions, and the resulting New York City consortium forms a unique and cohesive biomedical complex. By breaking down institutional silos and barriers that separate scientific disciplines, the CTSC endeavors to accelerate the clinical application of basic science discoveries.

NewYork-Presbyterian Hospital/Weill Cornell Medical Center
NewYork-Presbyterian Hospital/Weill Cornell Medical Center, located in New York City, is one of the leading academic medical centers in the world, comprising the teaching hospital NewYork-Presbyterian and Weill Cornell Medical College, the medical school of Cornell University. NewYork-Presbyterian/Weill Cornell provides state-of-the-art inpatient, ambulatory and preventive care in all areas of medicine, and is committed to excellence in patient care, education, research and community service. Weill Cornell physician-scientists have been responsible for many medical advances—including the development of the Pap test for cervical cancer; the synthesis of penicillin; the first successful embryo-biopsy pregnancy and birth in the U.S.; the first clinical trial for gene therapy for Parkinson’s disease; the first indication of bone marrow’s critical role in tumor growth; and, most recently, the world’s first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. NewYork-Presbyterian Hospital also comprises NewYork-Presbyterian Hospital/Columbia University Medical Center, NewYork-Presbyterian Morgan Stanley Children’s Hospital, NewYork-Presbyterian Hospital/Westchester Division and NewYork-Presbyterian Hospital/The Allen Pavilion. NewYork-Presbyterian is the #1 hospital in the New York metropolitan area and is consistently ranked among the best academic medical institutions in the nation, according to U.S.News & World Report. Weill Cornell Medical College is the first U.S. medical college to offer a medical degree overseas and maintains a strong global presence in Austria, Brazil, Haiti, Tanzania, Turkey and Qatar.