Cyclooxygenase‐2 in multiple myeloma: prognostic factor or therapeutic target? – Response to Owen et al

Abstract

Baz and Hussein (2006), Owen et al (2007), and I agree that: (i) lower thromboemolic complications and evidence of some inherent anti-myeloma activity warrant the use of low dose aspirin (ASA) in multiple myeloma (MM); and (ii) the prognostic significance of cyclooxygenase (COX) expression and its inhibition with ASA and other COX inhibitors is worthy of further study. Interleukin-6 (IL-6), and tumour necrosis factor-alpha (TNF) both commonly function as growth factors in MM (Kast, 2005, 2006; Kuku et al, 2005). Many other malignancies also use IL-6 as a potent growth factor, for e.g. glioblastomas (Kast & Altschuler, 2006), melanomas, prostate cancer and others. As IL-6 levels tend to bear a positive relation to intracellular cyclic adenosine monophosphate (cAMP) levels, and TNF an inverse relation to cAMP levels, IL-6 and TNF tend to be counter regulated (Kast, 2006). In inflammatory disease and malignancies such as MM, they both can be elevated and attempts to lower one risk raising the other. This is thought to be why COX inhibitors are not disease-modifying anti-rheumatic drugs; they lower IL-6, but increase TNF (Kast, 2006). Although involving few patients, the data of Tsimberidou et al, (reviewed in Kast, 2005), indicate that inadvertent pharmacological elevation of TNF may hasten MM progression. ASA and other COX inhibitors may potentially lower IL-6 but, by the same mechanism, also increase circulating TNF levels (Kast, 2006). That a given medicine has both disease inhibiting and disease enhancing effects is not new or odd. Examples abound. Doxorubicin, often used in MM treatment, both upregulates COX expression and engages nuclear factor κB-mediated anti-apoptosis paths (Minotti et al, 2004). Several currently available drugs have been shown to lower IL-6 in various experimental situations (Kast & Altschuler, 2006) and may do so in MM. Bupropion was recently shown to lower TNF elevations in mice given lipopolysaccharide (Brustolim et al, 2006) and may do so in MM, though with risk of IL-6 elevation. The situation is not simple. Interleukin-6 and TNF are easily measured and correlated to MM disease activity. Efforts to lower both can then begin if lowering is shown to retard MM progression.