Thalidomide, cyclooxygenase-2, and angiogenesis: potential for therapy.

Very few drugs in modern history have had a history similar to that of thalidomide. First introduced in the late 1950s in Germany (1), thalidomide soon became available in a total of 46 countries, including Canada and the United Kingdom but not the United States. Originally, it was marketed as an over-thecounter sedative-hypnotic and antiemetic drug for use in pregnancy. Thalidomide was withdrawn in the early 1960s after reports of teratogenicity and phocomelia associated with its use (1). In response to this tragedy, the United States Congress enacted legislation in 1962 that required drug manufacturers to provide substantiation to the United States Food and Drug Administration of a drug’s safety and efficacy before marketing (2). In addition, for the first time informed consent was required from patients participating in studies of a new drug (2). Fortunately, research into the effects of thalidomide was not halted. In 1965, Sheskin (3) reported a dramatic therapeutic effect of thalidomide on erythema nodosum leprosum, an inflammatory manifestation of leprosy. This finding prompted evaluation of the drug for use against other diseases. Calabrese and Fleischer (4) reviewed the numerous and diverse inflammatory and autoimmune conditions against which thalidomide has been found to be effective. These include cutaneous lupus erythematosus, conditions associated with HIV infection such as aphthous ulcers, wasting syndrome and diarrhea, and Behçet’s syndrome (4). In 1998, thalidomide was approved by the Food and Drug Administration for the treatment of erythema nodosum leprosum (4), which remains the sole approved indication. Several immunomodulatory and anti-inflammatory properties of thalidomide have been discovered, including inhibition of leukocyte chemotaxis, alternation of tumor necrosis factorinduced adhesion molecule density on leukocytes, reduction of phagocytosis by polymorphonuclear cells, enhancement of interleukin-4 and interleukin-5 production, inhibition of IFNand IFN-12 production, and inhibition of tumor necrosis factorproduction by reducing the half-life of mRNA (4). D’Amato et al. (5) were the first to describe the antiangiogenic effects of thalidomide. In a rabbit model, they demonstrated an inhibitory effect of the drug on basic fibroblast growth factor-induced corneal neovascularization. Recent interest in the antiangiogenic activity of thalidomide has led to studies of the drug in the treatment of numerous hematological and solid malignancies. Singhal et al. (6) reported significant antitumor activity of thalidomide in patients with refractory multiple myeloma. Others demonstrated its activity in Kaposi’s sarcoma (7). Thalidomide is currently being evaluated in the treatment of numerous hematological and solid malignancies. In the United States, more than 20 clinical trials include thalidomide in their regimen, alone or in combination with other antineoplastic drugs. Its use is highly appealing because thalidomide is one of the few putative antiangiogenic agents that is an oral drug, although initial results as a single agent have been somewhat disappointing (8, 9). These studies, however, have looked at patients with end-stage disease making their chance for success less likely. COX, a key enzyme required for prostaglandin synthesis, is transcribed from two distinct genes (10). COX-1 is expressed constitutively in most tissues, whereas COX-2 is induced by a variety of stimuli. COX-2 expression is markedly increased in 85–90% of human colorectal adenocarcinoma, whereas COX-1 levels remain unchanged (10). Epidemiological studies have reported a significant reduction in the risk of developing colon, breast, and lung cancer in persons who were treated with aspirin which inhibits cyclooxygenase (11). Furthermore, Oshima et al. (12) reported that in mice null for COX-2, the number and size of intestinal polyps are dramatically reduced. In addition, treating these mice with a selective COX-2 inhibitor reduced the number of polyps more significantly than did treatment with sulindac, which inhibits both isoenzymes (12). Steinbach et al. (13) treated patients with familial adenomatous polyposis with celecoxib, a selective COX-2 inhibitor, and found a significant reduction in the number of colorectal polyps. Clinical correlates between COX-2 up-regulation and poor prognosis have been reported in several cancers, such as carcinoma of the head and neck (14) and lung cancer (15). Tsujii et al. (16) suggested that COX-2 modulates production of angiogenic factors by colon cancer cells, thus affecting tumorigenicity. Together, these results suggest that COX-2 may contribute to the development of cancer. Its selective blockade may have an important role in cancer prevention and by extrapolation cancer treatment–most likely through an effect on prostaglandins, thereby preventing angiogenesis and stimulating immune surveillance and apoptosis (17, 18). The article in this issue by Fujita et al. (19) raises several Received 7/27/01; accepted 7/30/01. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 To whom requests for reprints should be addressed, at The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 432, Houston, TX 77030-4009. Phone: (713) 792-6363; Fax: (713) 796-8655; E-mail: [email protected]. 2 The abbreviations used are: COX, cyclooxygenase; LPS, lipopolysaccharide. 3311 Vol. 7, 3311–3313, November 2001 Clinical Cancer Research