Human mesothelioma samples overexpress both cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (NOS2): In vitro antiproliferative effects of a COX-2 inhibitor

Accumulating data demonstrate overexpression of both inducible NO synthase (NOS2) and cyclooxygenase-2 (COX2) in many epithelial neoplasias, In additi on, cyclooxygenase inhibitors have been shown to have antineoplastic and pr ophylactic efficacy against human colon cancer and in mouse models of this disease. Mesothelioma arises in a context of asbestos exposure and chronic inflammation, which would be expected to enhance the expression of these in ducible enzymes. This study demonstrates that both inducible enzymes were e xpressed in 30 human mesothelioma tissues but were not detectable in nonrea ctive mesothelial tissues from the same individuals. In contrast, areas of reactive mesothelial cells stained positively for these enzymes. In vitro e xposure of human mesothelioma cell lines to the COX2 inhibitor, NS398, reve aled dose- and time-dependent antiproliferative activity, whereas the NOS2 inhibitor, 1400W, had no detectable inhibitory effect, Surprisingly, nonmal ignant human mesothelial isolates expressed both NOS2 and COX2 in vitro at the same level as mesothelioma cell lines but were less sensitive to NS398 inhibition. This finding indicates that these nonmalignant isolates may ret ain properties of reactive mesothelial cells and suggests that targets in a ddition to COX2 mag be involved in the antiproliferative response of mesoth elioma cell lines. These results have clinical significance because of the selective activity of the drug coupled with the therapeutic resistance and poor prognosis of mesothelioma, The findings presented here suggest that fu rther preclinical studies of these inhibitors in animal models of mesotheli oma would be of great interest.