A Novel Sulindac Derivative Safely Prevents Colon Cancer in Mouse Model

However, chronic use of this substance was linked to serious liver and gastrointestinal complications that precluded its adoption as an anticancer chemotherapeutic agent.

To avoid the side effect issue investigators at the Stony Brook University School of Medicine (NY, USA) chemically modified sulindac to eliminate its toxic properties while increasing its effectiveness as an anticancer drug. The new compound, phospho-sulindac, was tested in a series of preclinical trials alone and in combination with the drug difluoromethylornithine (DFMO).

Results published in the October 2010 issue of the journal Gastroenterology revealed that compared with sulindac, phospho-sulindac was much more potent in inhibiting the growth of cultured human colon cancer cell lines and more efficacious in preventing the growth of HT-29 xenografts in nude mice. Phospho-sulindac also prevented the growth of intestinal tumors in Apc/Min mice. In combination with DFMO, phospho-sulindac reduced tumor multiplicity in Apc/Min mice by 90%. Phospho-sulindac was much safer than sulindac, as evidenced by positive results obtained by in vitro toxicological evaluation and animal toxicity studies.

At the molecular level, phospho-sulindac increased the intracellular levels of reactive oxygen and nitrogen species, which are key early mediators of its chemopreventive effect.

"We are very pleased with the results, which set the stage for the further evaluation of this novel compound,” said Dr. Basil Rigas, professor of medicine and pharmacology 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.”

"Agent safety is extremely important for cancer prevention, or chemoprevention,” said 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.”

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