Piroxicam is a nonsteroidal anti-inflammatory drug (NSAID) widely used for treatment of inflammatory arthritis. Recent experimental and clinical studies suggest that piroxicam, as well as other NSAIDs, may be useful for chemoprevention of colon cancer. While there is less information regarding NSAlDs for chemoprevention of urinary bladder malignancy, there are compelling data which suggest that this should be evaluated.
A major effect of NSAlDs is inhibition of cyclooxygenase, 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 E2 (PGEz), are biological modifiers which can significantly affect cell proliferation and tumor growth. High levels of PGE2 stimulate growth of certain tumor cell lines while inhibition of prostaglandin synthesis with indomethacin or piroxicam can cause suppression. The mechanisms for this effect are unclear. Studies in cultured cells exposed to indomethacin show inhibition of GI-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 indirectly from modulation of important control signals, such as calcium flux. In addition to cyclooxygenase, NSAlDs can inhibit activity of other enzymes, including phosphodiesterases and cyclic GMP-AMP protein kinases, which may be central to cancer initiation and promotion. NSAlDs can also interfere with transmernbrane 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 PGE2 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. PGE2 can act as a feedback inhibitor for cellular immune processes, such as T-cell proliferation, lymphokine production, and cytotoxicity. This effect is also seen for rnacrophage activity and natural killer cell toxicity. In general, either increased production of PGE2 or increased sensitivity to normal amounts of PGE2 results in depressed cellular immunity. Cyclooxygenase inhibitors (NSAIDs) such as piroxicam which decrease PGE2 production can stimulate cellular immune function both in vifro and in viva.
A variety of tumor cell lines and human malignancies produce large quantities of prostaglandins. O f interest, the concentration of PGE2 is increased in certain prernalignant lesions, such as benign adenomatous colon polyps, and further increased incancerouscolontissue. Thisobservation, taken incontextwith the effectsof prostaglandinson tumorcellgrowth and immune surveillance, provides strong rationale for study of NSAfDs as potential agents for colon and bladder cancer chemoprevention.
During the last decade, more than a dozen animal studies have shown significant protection against development of colon cancer by treatment with NSAlDs piroxicam, indomethacin, and sulindac. Other studies have shown that aspirin protects rats given known 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 adenornas 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 rationale for use of piroxicam and other inhibitors of cyclooxygenase as cancer