NicOx's nitrosulindac (NCX 1102) emerges as a candidate treatment of bladder cancer
Summary
DailyUpdates 19th April: NSAIDs have shown promising activity in the prevention and possible treatment of cancer. The French pharmaceutical NicOx has successfully improved both the safety and efficacy of NSAIDs by attaching a nitric oxide donor group to various NSAIDs. In a recent study nitrosulindac has been demonstrated to act as an effective and selective cytotoxic and antiproliferative agent against bladder cancer cells. The efficacy of nitrosulindac was considerable better than sulindac.DailyUpdates 19th April: NSAIDs have shown promising activity in the prevention and possible treatment of cancer. The French pharmaceutical NicOx has successfully improved both the safety and efficacy of NSAIDs by attaching a nitric oxide donor group to various NSAIDs. In a recent study nitrosulindac has been demonstrated to act as an effective and selective cytotoxic and antiproliferative agent against bladder cancer cells. The efficacy of nitrosulindac was considerable better than sulindac.
Bladder cancer is one of the most commonly occurring cancers in the world. Over 50,000 new cases of bladder cancer are diagnosed in the United States alone each year and it is estimated that over two million patients worldwide are living with bladder cancer. According to the National Institutes of Health, approximately $1.9 billion is spent in the United States annually on treatment of bladder cancer.If diagnosed in its early stages, the five-year bladder cancer survival rate can reach 90%. However, if the cancer reaches an advanced stage before diagnosis and treatment, the five-year survival rate can be less than 10%. As with many cancers therefore, early detection or prevention of bladder cancer is important and the observation that non-steroidal anti-inflammatory drugs (NSAIDs) prevent the development of a number of cancers in humans has revolutionized the approach to this field. Aspirin (ASA) has emerged as a prototypical chemoprevention agent and current efforts are now being directed towards improving efficacy and reducing side effects of chemopreventive NSAIDs. 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 (click here for an evaluation of NO therapeutics).
Grafting NO to NSAIDS combines the chemopreventive properties of traditional NSAIDs against cancer with enhanced safety. Furthermore, the chemopreventive 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. NCX 4016, one of the company's lead compounds, is a nitric oxide-donating derivative of ASA that 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. Another one of NicOx's molecules, NCX 4040 is currently in preclinical development for the prevention of colon cancer.
More and more however, the NSAIDs are being implicated as candidate therapeutics for patients with diagnosed cancer since this therapeutic class has been shown to reduce the proliferation of cancer cells and to have various other effects such as the ability to reduce cancer pain and cachexia. In their recent Molecular Cancer Therapeutics paper, Huguenin et al focus on a third molecule in development by NicOx, nitrosulindac (NCX 1102) and in particular investigate the ability of this molecule to block the proliferation of bladder cancer cells.
Merck & Co's sulindac (Clinoril) is an NSAID indicated for various musculoskeletal disorders. As with other NSAIDs, sulindac is associated with GI toxicity which can be life-threatening. In their recent study the INSERM group investigate the effect of NCX 1102, which was designed as a safer derivative of sulindac, on three human urothelial epithelial carcinoma cell lines (T24, 647V, and 1207) and primary cultures of normal urothelial cells. Cytotoxicity, antiproliferative effect, cell cycle alterations, morphological changes, and apoptosis were investigated after treatment with NCX 1102 in comparison with the native molecule. NCX 1102 demonstrated cytotoxic and antiproliferative effects on all three cell lines. This contrasted dramatically with sulindac which was without effect at the concentrations used in all cases. No effect was detected for either compounds on normal urothelial cells. This study suggests that NCX 1102 may act as a cell cycle inhibitor and/or inducer of apoptosis with selective action against cancer cells.
As with ASA, attaching an NO group to sulindac greatly increases its anti-cancer activity and on the basis of this new data NCX 1102 represents a promising candidate treatment of bladder cancer.
Source DailyUpdates 19th April; for a full abstract of the original papers see Mol Cancer Ther. 2004 Mar;3(3):291-8.
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