NicOx's NO-ASA, NCX 4040, reduces the developement of intestinal tumors

Cancers of the colon and rectum remain responsible for 56,000 deaths every year in the US, second only to lung cancer. Surgery remains the main form of treatment and is often the only treatment used in early-stage disease. Current surgical practices can however cure only 40%-50% of early-stage cases thereby driving the development of pharmaceutical approaches to colorectal cancer.

The global colorectal cancer market was estimated to be worth approximately US$1 billion in 2001, of which 60% of the revenues were derived from the US. The market has been predicted to rise further to US$2.5-3 billion within a five-year period. Camptosar currently dominates the US colorectal cancer market, but severe diarrhea as a side effect is a clear drawback for this drug (for a full analysis of therapeutic and market opportunities for colon cancer click here).

Early detection or prevention of the colorectal cancer is particularly important and the observation that non-steroidal anti-inflammatory drugs (NSAIDs) prevent the development of colon and other cancers in humans has revolutionized the approach to colon cancer prevention. Aspirin (ASA) has emerged as the prototypical chemoprevention agent against colon cancer. Current efforts are now being directed towards improving efficacy and reducing side effects. Of note, the NSAID class produces gastro-intestinal side effects precluding their use in at risk individuals.

Nitric oxide (NO) facilitates the repair of injury to the gastrointestinal tract by stimulating mucus secretion and by regulating the blood flow in the capillaries of the gastrointestinal tract and the mucus membrane. The multiple indications of NO therapeutics including gastroprotective activity has led to a surge in pharmaceutical activity.

Grafting NO to NSAIDS combines the chemopreventive properties of traditional NSAIDs against cancer with enhanced safety. Furthermore, the chemopreventative activity of NSAIDs appears to be increased by the presence of the NO. NO-ASA is particularly potent as a chemopreventive agent and the gastrointestinal toxicity of NO-ASA is minimal in humans.

The French company NicOx is one of the leaders in developing NO derivatives. One of their candidates, NCX 4040 is currently in preclinical development for the prevention of colon cancer. In their recent BBRC paper, Dr Basil Rigas' group from the American Health Foundation Cancer Center in collaboration with Dr Khosrow Kashfi at City University of New York Medical School and others report on the ability of this novel nitric oxide-donating derivative of aspirin to inhibit the development of gastrointestinal tumors in the Min mouse. These mice spontaneously develop small intestinal tumors and are commonly used in studies designed to assess molecules designed to prevent colon carcinogenesis. Consistent with human toxicity data, at the doses of NCX 4040 employed, Williams et al failed to observe evidence of GI toxicity however the number of tumors identified was reduced by 59%. These results demonstrate the tumor inhibitory properties of NCX 4040.

NCX 4016, another nitric oxide-donating derivative of ASA in development by NicOx, has completed Phase IIa evaluation in patients with symptomatic peripheral arterial obstructive disease (PAOD). In a phase I study NCX 4016 displayed an optimal gastric safety profile compared with aspirin and according to the NicOx website a US $3.3 million grant has been awarded by the National Cancer Institute of the NIH to the University of Michigan to conduct a clinical trial of nitric oxide-donating aspirin as a chemopreventive agent. The results of this trial along with further data on NCX 4040 are eagerly awaited.

Entry date Friday, April 16, 2004

Adapted from Williams et al, Biochem Biophys Res Commun. 2004 Jan 16;313(3):784-8.