Malignant mesothelioma (MM) remains the most lethal pleural, peritoneal and pericardial cancer. Here, we characterize the effects of nonsteroidal anti-inflammatory agents (NSAIDs) on in vitro and in vivo experimental MM models. Unlike primary normal mesothelial cells, the selective cyclooxygenase (COX)-2 inhibitor celecoxib reduced the in vitro proliferation of several MM cells derived from previously untreated MM patients. Moreover, celecoxib significantly inhibited MM cell colony formation in soft agarose (63-78% at 5 ؋ 10 ؊5 M; p < 0.05) and it elicited remarkable antitumor activity, leading to long-term survival in >37% of nude mice bearing intraperitoneal MM. Celecoxib was more efficient in inhibiting MM cell growth than acetylsalicylic acid (10
Key words: mesothelioma; NSAIDs; celecoxib; chemopreventionMalignant mesothelioma (MM) is a fatal malignancy most often associated with asbestos exposure with a 3-year survival of Ͻ5%. 1 Its incidence is still increasing with about 3,000 cases per year in the United States and 250,000 deaths expected in Western Europe in the next 30 years. 2 Current approaches, ranging from aggressive surgical treatments to chemotherapy, fail to improve the prognosis of this disease. 3 Most chemotherapeutic agents are not very effective against MM, with typical single-agent response rates of Յ20%. 4 Therefore, multimodality treatments have been developed, and the most favorable outcomes are obtained with a combination of surgery, chemo-and radiation-therapy in highly selected groups of MM patients. 3 However, mortality and morbidity are still high, and this strategy is not curative. 5 Therefore, there is a need for innovative therapies that may offer hope for improved palliation, prolonged survival and even potential cure for MM.Chemopreventive strategies have been investigated in a variety of other solid tumors, such as breast, colon, head and neck and liver cancers, suggesting the potential utility of this approach. 6 Much attention has been given to the use of nonsteroidal antiinflammatory compounds (NSAIDs), such as aspirin and indometacin, as agents able to block the sequence of carcinogenic events leading to an invasive malignancy. 7 It is believed that these antitumor effects involve inhibition of both cyclooxygenase (COX) enzymes, namely COX-1 and -2, and modification of other non-COX targets. 6 Although inhibition of COX-1 activity, which is constitutive in most tissues, can have adverse side effects, that of COX-2, which is inducible and overexpressed in many types of cancer, 7-9 can be used as a new approach to adjuvant therapy in cancer treatment. 7,10 As a result, there was a rationale to develop selective COX-2 inhibitors, such as NS-398 and celecoxib, that block inducible COX-2 activity but that spare COX-1 activity and the normal physiologic functions of this enzyme. 11,12 Recent evidences indicate that COX-2 overexpression is associated with a shortened survival of patients affected by MM 13 and that NS-398 suppresses in vitro MM cell proliferation. 14 Therefore, o...
