Piroxicam and other cyclooxygenase inhibitors: Potential for cancer chemoprevention

Piroxicam is a nonsteroidal anti‐inflammatory drug (NSAID) widely used for treatment of inflammatory arthritis. Recent experimental and clinical studies suggest tha piroxicam, as well as other NSAIDs, may be useful for chemoprevention of colon cancer. While there is less information regarding NSAIDs for chemoprevention of urinary bladder malignancy, there are compleeing data which suggest that this should be evaluated. A major effect of NSAIDs is inhibition of cyclooxygensase, the rate‐limiting enzyme for conversion of arachidonic acid to important signal molecules, including prostaglandins, which profoundly affect cellular functions in many tissues. The initial enzyme reaction leading to formation of prostaglandin H can be accompanied by cooxidation of xenobiotics resulting in extrahepatic and local tissue production of reactive products which are carcinogenic. The end product prostaglandins, especially prostaglandin E 2 (PGE 2 ), are biological modifiers which can significantly affect cell proliferation and tumor growth. High levels of PGE 2 stimulate growth of certain tumor cell lines while inhibiton of prostaglandin synthesis with indomethacin or piroxicam can cause supperssion. The mechanisms for this effect are unclear. Studies in cultured cells exposed to indomethacin show inhibition of G 1 ‐to‐S phase progression of the cell cycle and a reduction in overall DNA synthesis. It is unclear whether this effect on cell growth results from some direct action of the NSAID or a reduction in prostaglandins or indirecly from modulation of important control signals, such as calcium flux. In addition to cycloxygenase, NSAIDs can inhibit activity of other enzymes, including phosphodiesterases and cyclic GMP‐AMP protein kinases, which may be central to cancer initiation and promoton. NSAIDs can also interfere with transmembrane ion fluxes and with cell‐to‐cell binding. Prostaglandins can modulate a variety of immunological responses and thereby play an important role in host antitumor immunity. For example, high levels of tissue PGE 2 are frequently associated with suppression of immune surveillance and killing of malignant cells. Conversely, immune responses are generally enhanced by drugs that inhibit prostaglandin synthesis. PGE 2 can act as a feedback inhibitor for cellular imune processes, such as T‐cell proliferation, lymphokine production, and cytotoxcicity. This effect is also seen for macrophage activity and natural killer cell toxicity. In general, either increased production of PGE 2 or increased sensitivity to normal amounts of PGE 2 results in depressed cellular immunity. Cyclooxygenase inhibitor (NSAIDs) such as piroxicam which decrease PGE 2 production can stimulate cellular immune function both in vitro and in vivo . A variety of tumor cell lines and human malignancies produce large quantities of prostaglandis. Of interest, the concentration of PGE 2 is increased in certain premalignant lesions, such as benign adenomatous colon polyps, and further increased in cancerous colon tissue. This observation, taken in context with the effects of prostaglandins on tumor cell growth and immune surveillance, provides strong rationale for study of NSAIDs as potential agents for colon and bladder cancer chemoprevention. During the last, decade, more than a dozen animal studies have shown siginificant protection against developemnt of colon cancer by treatment with NSAIDs piroxicam, indomethacin, and sulindac. Other studies have shown that aspirin protects rats given knwon carcinogens against colon and bladder cancer. Moreover, patients with familial adenomatous polyposis who are at high risk for colon cancer have, in many instances, experienced regression of colon adenomas during treatment with NSAIDs, particularly sulindac. Most recently, two large epidemiological surveys have reported compelling evidence which suggests the NSAID aspirin may have significant protective activity against colon cancer. This presentation will summarize the retionale for use of piroxicam and other inhibitors of cyclooxygenase as cancer chernoprevention agents and will briefly review results of our approach to evaluating piroxicarn as an agent to prevent colon cancer. With this as background, the potential for NSAlDs in chernoprevention against bladder cancer will be explored.