Taxanes and COX-2 inhibitors: from molecular pathways to clinical practice

The taxanes paclitaxel and docetaxel are widely used antineoplastic agents that have demonstrated significant clinical activity against a number of human tumor types. Taxanes promote microtubule polymerization and stabilization which inhibits mitosis and leads to apoptosis. Taxanes induce a number of other molecular pathways. One such example is their ability to promote transcription of the cyclo-oxygenase (COX)-2 gene and to stabilize the COX-2 messenger RNA transcript. This leads to increased production of prostaglandins, which have been implicated in tumorigenesis. Increased COX-2 activity has been associated with tumor growth, poor prognostic characteristics, and unfavorable clinical outcome; therefore, up-regulation of COX-2 might attenuate the anti-tumor effect of the taxanes. This provides the rationale for the use of COX-2 inhibitors in combination with taxanes, as this could theoretically improve the clinical efficacy of paclitaxel and docetaxel. Results from preclinical studies have generally shown enhanced anticancer activity from the addition of COX-2 inhibitors to taxane treatment. Data from Phase II clinical studies in patients with non-small cell lung cancer (NSCLC) have suggested a marginal improvement in response rate when celecoxib is added to taxane therapy when compared with historical trials in similar patient groups receiving taxane therapy. There may also be a role for COX-2 inhibitors in ameliorating some of the side effects of taxane treatment, such as fatigue, myalgia, and arthralgia. Randomized clinical trials would be needed to establish whether COX-2 inhibitors improve the therapeutic profile of docetaxel or paclitaxel in patients with solid tumors.