Researchers in the Division of Cancer Prevention, Department of Medicine, at Stony Brook University have discovered that a novel derivative of sulindac, a non-steroidal anti-inflammatory drug (NSAID) known to prevent colon cancer, is more effective and safer than sulindac in preventing colon cancer in animals. The study results are reported in the October issue of the journal Gastroenterology, and online at http://www.gastrojournal.org.
Colon cancer is one of the most common forms of cancer worldwide. The National Cancer Institute estimates that there about 150,000 new colorectal cancer cases each year in the United States, with 50,000 dying from the disease annually. Research and clinical trials have shown that some colon cancers can be prevented, and the push to find a safe and effective way to prevent the disease has been the focus of colorectal cancer researchers for years.
"We are very pleased with the results, which set the stage for the further evaluation of this novel compound," says Bail Rigas, M.D., Professor of Medicine and of Pharmacology, and Chief of the Divisions of Cancer Prevention and Gastroenterology at Stony Brook University Medical Center. "Our laboratory study of the compound demonstrated the right attributes for its intended use: high efficacy and the promise of superb safety."
Dr. Rigas and colleagues found that in an animal model of colon cancer, use of the compound prevented 90 percent of intestinal tumors and no detectable toxicity was detected. The compound, which may potentially lead to the development of a new NSAID for humans, is called phospho-sulindac. The research team used phospho-sulindac in combination with difluoromethylornithine (DFMO) to prevent colon cancer in tumor animal models.
Within the past decade, the use of NSAIDs has been shown in human trials to be effective in preventing colorectal tumors. One NSAID, sulindac, in combination with DFMO, had been shown in some studies to reduce the recurrence of colon adenomas by as much as nearly 70 percent. However, the safety profile of NSAIDs in preventing colon cancer has been problematic.
"Agent safety is extremely important for cancer prevention, or chemoprevention," says Dr. Rigas. "For chemoprevention, a compound is given long-term to a patient who is at risk for developing a certain form of cancer or having a cancer recur after being treated. Thus safety is critical."
Dr. Rigas explained that chronic administration of NSAIDs, including sulindac, has been consistently associated with side effects, mainly gastrointestinal and renal in nature, which can affect up to 20 percent of patients taking NSAIDs and even carry the risk of death if serious.
The Stony Brook-led team of researchers considered testing this derivative of sulindac because from previous research they expected the toxicity profile to be improved over sulindac, and because of its enhanced properties in tumor prevention. They continue to test the compound with various laboratory models.
"We are working diligently on the elucidation of the mechanism of action of this compound on the best formulation of phospho-sulindac that will further enhance its impressive performance as a chemoprevention agent," says Gerardo Mackenzie, Ph.D, Research Scientist, Division of Cancer Prevention, and lead author of the study.
"This compound we developed represents a potentially significant development in pharmacology, as it is one of a class of new compounds that may greatly improve the efficacy and safety of conventional NSAIDs," adds Francis Johnson, Ph.D., Professor of Chemistry at Stony Brook University and co-author of the Gastroenterology paper.
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