Melanoma inhibition by cyclooxygenase inhibitors: role of interleukin-6 suppression, a putative mechanism of action, and clinical implications.

Melanoma progression is often associated with supranormal levels of interleukin-6 (IL-6). Il-6 is an important growth factor for many cases of melanoma. A recent case report by Lejeune et al. [Melanoma Res 2006;16:263-265] of remission of an advanced melanoma during treatment with the cyclooxygenase, (COX) inhibitor rofecoxib can be explained by rofcoxib-mediated lowering of tumor-produced Il-6. Several examples of rofecoxib's ability to lower Il-6 in humans have been published recently in other settings, and many reports indicate that other commonly used COX inhibitors like aspirin, diclofenac, etodolac, indomethacin, naproxen, and many others, also lower Il-6 in humans. These studies are reviewed. The likely mechanism of COX inhibition leading to Il-6 lowering is due to the tendency for Il-6 levels to be controlled by intracellular cyclic adenosine monophosphate (cAMP). Adenylate cyclase is the rate-limiting enzyme in cAMP synthesis. Because adenylate cyclase activity is allosterically enhanced when it binds prostaglandin E, the latter increases Il-6. COX inhibition lowers prostaglandin E levels. This lowers intracellular cAMP levels. Lower cAMP results in lower Il-6 synthesis, lower levels of a required growth factor. Controlled studies are needed to define the role of COX inhibitors in melanoma treatment.