Coxibs: pharmacology, toxicity and efficacy in cancer clinical trials.

This chapter briefly summarizes the current knowledge about the role of nonsteroidal anti-inflammatory drugs (NSAIDs), specially focusing on those selective for cyclooxygenase (COX)-2 (coxibs), on colorectal cancer (CRC) onset, and progression. Both epidemiological and experimental studies have reported that these drugs reduce the risk of developing colonic tumors. However, the promising use of coxibs in chemoprevention was halted abruptly due to the detection on enhanced cardiovascular (CV) risks. Thus, we discuss the clinical data and plausible mechanisms of CV hazards associated with traditional NSAIDs and coxibs. The extent of inhibition of COX-2-dependent prostacyclin, an important vasoprotective and anti-thrombotic pathway, in the absence of a complete suppression of COX-1-dependent platelet function, at common doses of NSAIDs, might play a role in CV toxicity. Coxibs might still be reserved for younger patients with familial adenomatous polyposis (FAP). However, it should be taken into consideration that recent findings of enhanced thromboxane (TX)A(2) biosynthesis in colon tumorigenesis, detected in humans. In this context, the use of low-dose aspirin (which mainly acts by inhibiting platelet COX-1-dependent TXA(2)) may have a place for chemoprevention of CRCs (see also Chap. 3 ). The possible use of coxibs to prevent CRC will depend mainly on research progresses in biomarkers able to identify the patients uniquely susceptible to developing thrombotic events by inhibition of COX-2.