New paradigms for cancer prevention
Raymond N. DuBois
Departments of Medicine and Cell Biology, Vanderbilt University Medical Center, The Vanderbilt-Ingram Cancer Center, Nashville, TN 37232-2279, USA
Abbreviations: COX-2, cyclooxygenase-2; EGFR, epidermal growth factor receptor; NSAIDS, non-steroidal anti-inflammatory drugs.
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Introduction
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Non-steroidal anti-inflammatory drugs (NSAIDs) have been studied extensively for their ability to delay or inhibit the development of malignant and pre-malignant lesions (1). There has been a considerable amount of attention focused on this class of drugs because of previous clinical and epidemiologic studies indicating that they possess anti-neoplastic activity. Clinical observations by Waddell and Loughry first indicated that use of these agents led to regression of adenomas in patients with Familial Adenomatous Polyposis (FAP) (2). Ten years later, clinical trials confirmed a significant reduction in the size and number of adenomas in FAP patients treated with sulindac (3). Since Waddell's first clinical observation, a number of studies have been completed in a variety of animal and laboratory models confirming an anti-neoplastic effect of NSAIDs (4). However, it is clear from all of the studies published to date that use of NSAIDs alone does not eradicate all tumors. NSAIDs are known to inhibit the activity of cyclooxygenase enzymes (5) and other pathways (6,7) that are known to promote neoplastic transformation of cells.
For effective prevention of colorectal cancer, complete elimination of all adenomas is the desirable outcome. Since the use of one agent alone does not completely eliminate premalignant disease, combinations of different agents for cancer prevention may be more effective. Several reports have been published demonstrating that the combination of an NSAID plus difluoromethylornithine is much more effective than using either single agent alone (810). Importantly, there appears to be less toxicity associated with this combination of agents because lower dosages of each agent can be given to obtain the same or better effect. Based on these findings, one would predict that the use of combinations of chemopreventive agents would be more effective.
A recent report by Torrance et al. (11) indicates that treatment with an NSAID plus an epidermal growth factor receptor (EGFR)-kinase inhibitor leads to a significant reduction in polyp number in the Min mouse model. The results are dramatic, with polyp incidence in Min mice being reduced by >95% using the co-administration of sulindac and EKB-569. Surprisingly, nearly half of the animals in the treated group did not develop any discernible polyps over the duration of the study. Since Stanley Cohen's initial discovery of the EGF 40 years ago (12), it was predicted that a therapeutic target for cancer would emerge from a better understanding of this signaling pathway (13). The first drug approved for cancer therapy from this general signaling pathway was an antibody targeted for the Her-2/neu receptor. However, a role for EGFR-kinase inhibitors in cancer prevention was previously noted because the EGFR signaling pathway was known to be dysregulated in many different types of cancer, including carcinomas of the colon, breast and lung (14). The precise role of the EGFR in neoplastic transformation continues to be an area of intense investigation. Obviously, activation of the EGFR-associated tyrosine kinase activity stimulates multiple signaling pathways, which culminates in increased cell division, altered cell motility and a number of other biologic responses. EGFR activation also leads to increased expression of the cyclooxygenase-2 (COX-2) gene (15). Several groups have shown a role for COX-2 in carcinogenesis (1621). The cyclooxygenase pathway may have particular significance because the activity of this enzyme is inhibited by NSAIDs. Therefore, inhibition of EGFR-associated tyrosine kinase activity affects a number of signaling pathways, including the induction of cyclooxygenase expression. Addition of an NSAID inhibits the remaining cyclooxygenase activity in addition to its effect on apoptosis and PPAR
(22). It will be important to determine the cancer preventive effect of a combination of COX-2 selective inhibitors plus EGFR-kinase inhibitors. Since COX-2 selective NSAIDs have an improved gastrointestinal safety profile (23,24) these drugs may be better tolerated in humans. Therefore, the effectiveness of targeting multiple signaling pathways in a systematic way is required to determine the most effective combination of agents for cancer prevention.
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Notes
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To whom correspondence should be addressedEmail: raymond.dubois{at}mcmail.vanderbilt.edu
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References
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Received September 22, 2000;
accepted November 20, 2000.