Document 3QxDN9jbq2ReokxygyLEvyoDJ

Am J Clin Oncol (CCT) 26(4 Suppl 2): S48S57, 2003. 2003 Lippincott Williams & Wilkins, Inc., Philadelphia Development of COX Inhibitors in Cancer Prevention and Therapy Asad Umar, Ph.D., D.V.M., Jaye L. Viner, M.D., M.A., William F. Anderson, M.D., M.P.H., and Ernest T. Hawk, M.D., M.P.H. On the strength of in vitro, in vivo, observational, and clinical data, nonsteroidal antiinflammatory drugs (NSAIDs)--also referred to as COX inhibitors-- have emerged as lead compounds for cancer prevention, and possible adjuncts to cancer therapy. Thus far, the routine use of NSAIDs for these indications is limited, largely owing to toxicity concerns, the paucity of efficacy data for any specific target organ, and uncertainties with regard to the most appropriate regimen (i.e., the best agent, formulation, dose, route of administration, and duration). Strategies to address these concerns primarily aim to improve the therapeutic index (i.e., benefit:risk ratio) of COX inhibitors by 1) minimizing systemic exposures whenever feasible, 2) achieving greater mechanistic specificity, 3) coadministering agents that provide prophylaxis against common toxicities, and 4) coadministering other effective anticancer agents. Clinical trials testing most of these strategies have been completed or are under way. The National Cancer Institute has a substantial research portfolio dedicated to the identification, testing, and development of NSAIDs as preventive and therapeutic anticancer agents. Discovering how to apply NSAIDs in persons with-- or at risk for-- cancer, although challenging, has the potential for considerable clinical and public health benefits. Key Words: Cyclooxygenases--COX-1--COX-2--Cancer prevention--Cancer therapy--Molecular target--Clinical trials--Nonsteroidal antiinflammatory drugs (NSAIDs), celecoxib--Sulindac--Aspirin. Over the last 30 years, we have come to understand that carcinogenesis advances through cumulative structural and functional genomic aberrations that are sequentially expressed within each, and ultimately across all, higher levels of biologic organization (e.g., organelles, cells, tissues, organ).1 Crucial aberrations may result in a pathologic imbalance between cellular proliferation and apoptosis, thereby fostering a progressively deviant cell population. Fortunately, organisms are endowed with multiple mechanisms--repair, replacement/recruitment, From the Gastrointestinal & Other Cancers Research Group, National Cancer Institute, Division of Cancer Prevention, Bethesda, Maryland, U.S.A. This work was prepared in our capacity as employees of the U.S. federal government. Address correspondence and reprint requests to Dr. Ernest T. Hawk, National Cancer Institute, Division of Cancer Prevention, EPN, Suite 2141, 6130 Executive Boulevard, Bethesda, MD 20892-7317, U.S.A.; eh51p@nih.gov replication, and redundancy--that can preserve structural and functional integrity. Nevertheless, in some instances these mechanisms are overwhelmed and unrepaired damage goes unchecked, potentially leading to the development of cancer.2 Understanding the molecular genesis of cancer is integral to advances in cancer prevention and therapy.3 Technologic innovations in endoscopic and noninvasive imaging, mutation analysis, gene expression, and protein analysis are enhancing our abilities to characterize the cellular and molecular genesis of neoplasia. Data arising from these inquiries are being iteratively transformed into information that can improve cancer risk assessments (i.e., molecular risk profiling), bolster the accuracy and reliability of outcome determinations (i.e., molecular monitoring), and improve anticancer agent identification and development (i.e., molecular targeting). CYCLOOXYGENASE (COX) AS A MOLECULAR TARGET FOR CANCER PREVENTION AND THERAPY Ideal molecular targets for anticancer agents are 1) uniquely expressed in neoplasia relative to normal tissues in terms of structure, amount, location, timing, and/or activity; 2) functionally active in initiating or promoting cancer development and progression; 3) accessible to applied interventions; 4) amenable to modulation; and 5) when modulated, result in measurable and reliable clinical benefits (e.g., analgesia; reduced rates of lesion incidence, recurrence, grade; improved quality of life; etc.). Based on these criteria, COX, or perhaps just the COX-2 isoform, is a promising target for both cancer prevention and therapy. COX activity, which derives from COX-1 and COX-2 isozymes, converts arachidonic acid to PGG2, and then to PGH2, which is ultimately metabolized by tissue-specific enzymes in a variety of bioactive prostaglandins (PGs) and thromboxanes. These downstream prostanoids act as auto- or paracrine stimulants, influencing a broad array of physiologic functions. For example, COX-1 produces constitutive prostanoids necessary for normal tissue functions, whereas COX-2 expression is ordinarily low S48 DEVELOPMENT OF NSAIDs FOR PREVENTION AND THERAPY S49 at baseline, but surges in the context of inflammation or neoplasia.4 Indeed, human neoplasias of most organs-- bladder,58 breast,9,10 uterine cervix,11,12 central nervous system (CNS),1316 colorectum,10,1737 esophagus,38 43 head and neck,44,45 liver,46 50 lung,5155 pancreas,56 60 prostate,61 64 skin,65 67 and stomach68 77-- overexpress COX-2 and produce more prostanoids (particularly PGE2) than healthy tissues from which they are derived. In 1996, Oshima et al.78 proved the principle that COX-2 was functionally important in carcinogenesis, by demonstrating that knocking out the COX-2 gene in a rodent model of intestinal carcinogenesis resulted in substantial tumor reductions. More recently, investigators have reported the transforming capacity of COX-2 gene transfection in a rodent mammary cancer model.79 These data confirm the relevance of COX-2 to neoplasia, and the potential importance of COX-2 as a target for cancer prevention and therapy. NSAIDs as Anticancer Agents Four complementary lines of evidence establish NSAIDs as important agents for cancer prevention and as possible adjuncts to treatment: 1) COX inhibitors stimulate anticancer effects in in vitro systems; 2) COX inhibitors--and COX-2 gene deletions--inhibit carcinogenesis in carcinogen-induced and genetically driven rodent models (as documented in more than 100 peerreviewed scientific publications); 3) COX inhibitors reduce the incidence of colorectal precancerous lesions (e.g., adenomas), cancer incidence, and cancer mortality (in more than 25 observational studies); and 4) COX inhibitors regress precancerous lesions (i.e., colorectal aberrant crypt foci and adenomas, and actinic keratoses of the skin) in genetic and sporadic cancer risk cohorts (as reported in more than 17 uncontrolled and controlled clinical trials). The data are most compelling for colorectal neoplasia; however, emerging animal, epidemiologic, or clinical trial data suggest protective and therapeutic effects of NSAIDs in a broad range of extracolonic tissues (e.g., skin, oral mucosa, esophagus, lung, bladder, myeloma, acute myelogenous and chronic lymphocytic leukemias) as well. In Vitro Data NSAIDs appear to induce a number of anticancer effects. First, they may serve as competitive inhibitors of COX-related carcinogen activation, thereby rendering threatening exposures less toxic. This mechanism is particularly relevant to the aerodigestive organs (i.e., lung and colon), which are commonly exposed to a broad range of exogenous chemicals (i.e., xenobiotics).80,81 Cancerous overexpression of COX-2 has also been shown to increase the production of angiogenic growth factors [e.g., vascular endothelial growth factor (VGEF), basic fibroblast growth factor (bFGF), and transforming growth factor-beta (TGF-)]; and stimulate endothelial cell migration with the formation capillary-like net- works.82 These effects can be blocked by selective COX2,82,83 as well as some nonselective COX,84 inhibitors. COX-2 overexpression has been clearly associated with suppressed apoptosis. While many molecular pathways regulate apoptosis, BCL-2 family of proteins--and more specifically, the BAX to BCL-2 ratio--is a key determinant of apoptosis. For example, rat intestinal epithelial cells engineered to overexpress COX-2 have decreased amounts of the BAX protein, increased amounts of the BCL-2 protein, and are resistant to apoptosis.79,85 NSAID inhibition of BCL-2 expression increases the BAX to BCL-2 ratio, thereby restoring apoptosis; human colorectal cancer cells that lack BAX genes have a reduced apoptotic response to NSAIDs.86 Apoptotic pathways controlled by the Rel/NF-B family of transcription factors may also be regulated by NSAIDs. Although the exact antiapoptotic mechanisms remain unclear, numerous studies confirm the importance of COX-mediated apoptosis in cancers of the esophagus,87,88 gallbladder,89 CNS,90 head and neck,91 hematopoietic system,92 lung,93 pancreas,60 and prostate.94 In total, COX inhibitors appear to reset the balance between cell proliferation and apoptotic cell death, thus prompting tumor stabilization or regression.95,96 Chronic inflammation and immune suppression are acknowledged risk factors for epithelial carcinogenesis.97,98 Inflammation results in the generation of reactive oxygen species and increased prostaglandin E2 (PGE2) synthesis, which is in itself immunosuppressive.99 In contrast, inhibitors of prostaglandin synthesis block immunosuppression and retard tumorigenesis.100 Tumor progression is associated with tumor enlargement, lymph node and/or systemic metastases, tumor invasion, and increased cancer-specific mortality. In cancer cell lines, stable overexpression of COX-2 has been associated both with increased production of prostaglandins and increased cellular invasiveness.101 Consistent with these in vitro findings, selective COX-2 inhibitors have been observed to inhibit metastasis in animals.102,103 Matrix metalloproteinases (MMPs) and cell adhesion molecules play important roles in tumor invasion, and recent evidence suggests that NSAIDs may modulate both MMPs and cell cell adhesion.104 Animal Data Twenty-five years of preclinical studies show that inhibition or elimination of COX activity by pharmacologic or genetic manipulations yields fewer animals with tumors, fewer tumors per animal, and smaller tumors.105 In fact, gene knockout mice carrying a mutant APC gene have been used to investigate molecular mechanisms of colorectal polyp formation. When APC heterozygotes, the only viable strain of this mutant, were crossed with COX-2 knockout mice, COX-2 / mice developed 68% fewer adenomas and COX-2 / mice developed 86% fewer adenomas than wild-type COX / mice.78 Use of pharmacologic COX-2 inhibitors, such as celecoxib or rofecoxib, have also demonstrated profound preventive effects against intestinal carcinogenesis.106108 Be- Am J Clin Oncol (CCT), Vol. 26, No. 4 Suppl 2, 2003 S50 A. UMAR ET AL. yond their effects against intestinal cancer, NSAIDs inhibit the development of cancer in a wide variety of organs including the skin,109 esophagus,110 lung,111 breast,112 prostate,113 bladder,114 and hematolymphoid organs.115,116 NSAIDs also inhibit the growth of a variety of tumor xenografts, suggesting their potential efficacy in therapeutic applications as well.117 Human Observational Studies More than 25 retrospective and prospective epidemi- ologic studies report that regular aspirin or NSAID use reduces the risk of colorectal adenoma, carcinoma, and/or carcinoma-related mortality by approximately 40% to 50%.118 These studies show remarkably consistent reductions across the spectrum of colorectal neoplasia regardless of gender, age, tumor location, and familial predisposition. Only two studies have shown no risk reduction for colorectal cancer in persons using aspirin.119,120 Although data are less consistent and compelling for extracolonic organs, in aggregate, studies show strong associations between NSAID use and reductions in sitespecific cancer risks in the bladder,121 breast,122127 esophagus,128131 stomach,128,132 colorectum (as summarized by Giovannucci),118 and lung.126 Indeed, upper GI malignancies in particular seem to be strongly prevented by aspirin and/or NSAID use.128133 Clinical Trials: Nonrandomized and Randomized In the genetic syndrome of familial adenomatous poly- posis (FAP), more than 15 case series or reports describe the chemopreventive effects of sulindac or other NSAIDs against prevalent adenomas.134 The first report described almost complete regression of colorectal adenomas in four patients given sulindac for 4 to 12 months.135 Subsequent studies--nonrandomized and randomized, placebo-controlled-- have confirmed significant reductions in colorectal adenoma size and number in patients treated with sulindac. Responses to NSAIDs generally occur within a few months, but complete regression is rare and the ramifications of long-term NSAID administration in this cohort have yet to be established.134 Indeed, four cases of colorectal cancer have been reported in FAP patients while they were taking sulindac, although the implications of these data are difficult to interpret outside the context of larger sulindac-treated cohorts. With regard to sporadic colorectal neoplasia, the chemopreventive efficacy of NSAIDs has been reported experimentally in three small studies measuring polyp regression, with mixed results.136138 The Physicians' Health Study is the only large, placebo-controlled trial of aspirin (325 mg every other day over 5 years) that has been completed to date.139 At the trial's end, no significant difference was seen in the self-reported frequency of new colorectal malignancies (RR 1.15; 95% CI 0.80 1.65). COX INHIBITORS AND CANCER: THE DHHS RESEARCH PORTFOLIO The Department of Health and Human Services (DHHS) has a substantial research portfolio dedicated to the identification, testing, and development of NSAIDs and NSAID-derivatives for cancer prevention. The portfolio is detailed in the CRISP (Computer Retrieval of Information on Scientific Projects) Database, a publicly accessible database of biomedical research supported by DHHS, which is updated weekly by the Office of Extramural Research, NIH. A search of this database using keyword combinations of "cyclooxygenase," "nonsteroidal antiinflammatory," "neoplasia," or "cancer" revealed 107 unique projects with 181 associated scientific codes (each project was assigned up to two codes to describe its scientific goals) that were subsequently categorized by primary scientific objective and target organ (depicted in Fig. 1). The portfolio spans a broad range of scientific inquiries, with almost equal representation from the basic and clinical sciences. Included in the portfolio are basic research in key mechanism(s) associated with NSAID efficacy, in vivo NSAID efficacy studies in preinvasive and invasive neoplasia models, and clinical trials testing NSAIDs, NSAID derivatives, selective COX-2 inhibitors, or corticosteroids (which also inhibit COX expression) in different cohorts at risk for cancer of the colorectum, duodenum, esophagus, oral mucosa, lung, skin, or prostate. IMPROVING THE THERAPEUTIC INDEX OF COX INHIBITORS Despite persuasive data on the efficacy of NSAIDs against neoplasia/cancer, the development of NSAIDs for preventive and therapeutic anticancer applications has been hampered by concerns relating to potential toxicities, such as gastric ulceration, renal or hepatic dysfunction, and antiplatelet effects. These toxicities are often attributed to COX-1 inhibition, particularly in the context of long-term drug exposure. At least four strategies may improve the therapeutic index of NSAIDs applied with chemopreventive or therapeutic intent. Reducing Systemic Exposures to NSAIDs NSAID-induced toxicities are dependent on several factors, including the dose and duration of exposure to the agent, as well as patient age and comorbidities.140 The therapeutic index of NSAIDs may be improved by topical applications that concentrate NSAID effects on the therapeutic target while minimizing systemic side effects. For example, Wattenberg recently demonstrated the improved efficacy and reduced toxicity of inhalational, as opposed to oral, corticosteroids (e.g., dexamethasone, budesonide) in a carcinogen-induced model of lung neoplasia.141143 Based on these findings, topical COX inhibitors are being tested as antineoplastic agents in several NCI-sponsored clinical trials, such as the Phase IIb chemoprevention trial of an aerosolized corti- Am J Clin Oncol (CCT), Vol. 26, No. 4 Suppl 2, 2003 DEVELOPMENT OF NSAIDs FOR PREVENTION AND THERAPY S51 FIG. 1. DHHS Research Portfolio Related to NSAIDs and Cancer of Various Organs, as of 2001. Derived from the CRISP (Computer Retrieval of Information on Scientific Projects), a publicly accessible database of biomedical research supported by the U.S. Department of Health and Human Services. Each contract or grant was assigned up to two codes to reflect the major areas of scientific investigation, as determined by a review of project titles and abstracts. costeroid in persons with bronchial dysplasia. (S. Lam, personal communication). In addition, the application of topical NSAIDs in cancer prevention was recently given credence by Food and Drug Administration (FDA) ap- proval of topical diclofenac (Solaraze; SkyePharma, Inc.)144 for the regression of actinic keratoses (http:// www.fda.gov/cder/approval/index.htm), which are puta- tive precursors of squamous cell skin cancer. Dose reduction is another strategy for improving the therapeutic index, and this strategy has been tested in several chemoprevention studies with mixed success. Ruffin et al.145 conducted a trial of aspirin at doses from 40.5 to 648 mg/d to identify the lowest dose that reliably suppressed PGE2 concentrations in colorectal mucosa with a minimum of systemic toxicity, and noted that aspirin doses of 81 to 160 mg/d were well tolerated and achieved this goal. These data are tempered by null results from the Physician Health Study, in which aspirin administered at 325 mg every other day over 5 years had no appreciable effect on colorectal neoplasia.120 Calaluce et al.146 conducted a Phase IIb trial of piroxicam at 7.5 mg/d over 24 months and noted that although mean PGE2 concentrations in rectal mucosa were reliably reduced, the incidence of significant GI toxicity was com- parable to that seen at higher dose levels; thus the potential for long-term improvement in the therapeutic index with this approach was negligible. Target Specific Anticancer Activities of NSAIDs The most striking anticancer properties of NSAIDs (as outlined earlier) include the following: 1) reduction in arachidonic acid products, (2) prevention of free radical induced genetic damage, 3) interference with the metabolic activation of carcinogens, 4) reduction of proliferation, 5) induction of apoptosis (i.e., restoration of growth regulation in transformed malignant cells), 6) immune stimulation, and 7) antiangiogenic effects.147 Further inquiry in the specific molecular mechanisms that account for the profound anticancer effects of NSAIDs may facilitate the identification of agents with the most favorable therapeutic indices from among this class of compounds. Although challenging, opportunities to identify new agents with greater mechanistic specificity abound. NSAID Derivatives The side effects of traditional NSAIDs, coupled with reported toxicities in approximately 3% of chronic users, motivated the development of derivatives with an improved safety profile that retain the anticancer efficacy of the parent compound. Sulindac sulfone reportedly has negligible COX inhibition and antiinflammatory activity in rodent models, but profoundly reduces tumor incidence, multiplicity, and burden when administered shortly after the induction of carcinogenesis.148,149 Pub- Am J Clin Oncol (CCT), Vol. 26, No. 4 Suppl 2, 2003 S52 A. UMAR ET AL. TABLE 1. NCI-sponsored clinical chemoprevention and chemotherapeutic trials with COX inhibitors or NSAID derivatives alone and in combination with other agents* Intervention Cohort Primary Goal Phase Prevention trials Aspirin Celecoxib Celecoxib Celecoxib Celecoxib Celecoxib Celecoxib Celecoxib Celecoxib Celecoxib Sulindac sulfone Aspirin folate Celecoxib DFMO Celecoxib selenium Celecoxib selenium Piroxicam calcium Sulindac DFMO Therapy Trials Celecoxib Celecoxib/5-FU/cisplatin/XRT/brachytherapy Celecoxib/trastuzumab Indomethacin/5-FU/phenylbutyrate Colorectum--sporadic Colorectum--FAP Colorectum--HNPCC Colorectum--sporadic Colorectum--sporadic Esophagus--Barrett's Prostate Bladder Skin--sporadic Skin--genetic Duodenum--FAP Colorectum--sporadic Colorectum--FAP Colorectum--sporadic Esophagus--squamous Colorectum--sporadic Colorectum--sporadic Prostate Cervical Breast--metastatic CRC--metastatic Adenoma prevention Adenoma suppression Biomarker modulation Adenoma prevention ACF regression Dysplasia regression/prevention PIN reduction Cancer prevention AK regression/prevention Cancer suppression/prevention Adenoma regression Adenoma prevention Adenoma regression Adenoma prevention Dysplasia regression/prevention Adenoma prevention Adenoma prevention Efficacy study Efficacy study Efficacy study in HER2/neu breast cancer Dose escalation study of 5-FU III II/III II II II II II II/III II/III II II III III III II III II/III I I/II II I/II Source, NCI's cancer database PDQ (physician's data query). * As of 2001. DFMO, -difluoromethylornithine; FAP, familial adenomatous polyposis; HNPCC, hereditary nonpolyposis colorectal carcinoma; ACF, aberrant crypt foci; PIN, prostatic intraepithelial neoplasia; AK, actinic keratosis; 5-FU, 5-fluorouracil; XRT, external beam radiotherapy. lished efficacy data from chemoprevention studies of Min mice are less impressive.150,151 Van Stolk recently conducted a phase I/II trial of sulindac sulfone given over 6 months in patients with FAP in which adenoma number and size were stabilized.152 Data from other clinical trials in cancer prevention and therapy have yet to be published. R-flurbiprofen, a noncyclooxygenase-inhibiting enantiomer of flurbiprofen, has little of the ulcerogenic tendency of the parent compound, flurbiprofen.153 Nevertheless, preclinical studies of R-flurbiprofen have shown substantial reductions in tumor multiplicity and prolonged survival,113,151,154 although these results have yet to be extended to human chemoprevention trials. Selective COX-2 Inhibitors The therapeutic index of NSAIDs improved with the discovery of COX-2 selective inhibitors [e.g., celecoxib (Celebrex, Pharmacia, Inc.) and rofecoxib (Vioxx, Merck and Co.], which recently received FDA approval as antiinflammatory agents, and have subsequently become lead compounds for cancer prevention and therapy. In a recent trial involving more than 8,000 patients with arthritis, celecoxib was associated with 40% to 50% fewer symptomatic ulcers compared to other nonselective COX inhibitors.155 Thus, COX-2 selective inhibitors have partially fulfilled the search for a "safer" aspirin.156 Nine in vivo studies--two involving NS-398, one with MF tricyclic, two with nimesulide, one with rofecoxib, and three with celecoxib-- have proven the efficacy of COX-2 selective inhibitors in reducing aberrant crypt foci and colorectal tumors in carcinogen-induced and genetically-induced rodent models.78,107,108,157162 In addition, profound preventive effects have been reported with COX-2 selective inhibitors in animal models of breast,163165 skin,166,167 bladder,168,169 lung,170 and prostate94 cancer. Based on these impressive preclinical efficacy data, COX-2 selective inhibitors advanced in clinical cancer prevention and therapy trials. Although one small case series of nimesulide administered over 10 weeks showed no reduction in rectal adenoma burden in seven persons with FAP,171 a more definitive randomized, placebo-controlled trial of celecoxib administered over 6 months to 83 FAP subjects showed significant regression and reductions in colorectal adenoma number and size, with a frequency and side effect profile comparable to placebo.172 In the latter study, celecoxib improved the endoscopic appearance of both the colorectum and the duodenum, suggesting that it may reduce FAP-related neoplastic risk in both organs. On the strength of these data, the FDA approved celecoxib as an adjunct to standard surveillance and prophylactic surgery for patients with FAP (http://www.fda.gov/cder/approval/index.htm). On the strength of preclinical and clinical efficacy data with celecoxib and rofecoxib, and the ubiquitous overexpression of COX-2 in human neoplasia, the NCI is Am J Clin Oncol (CCT), Vol. 26, No. 4 Suppl 2, 2003 DEVELOPMENT OF NSAIDs FOR PREVENTION AND THERAPY S53 collaborating with academic and pharmaceutical collaborators on a broad range of Phase II/III cancer prevention and treatment trials with COX inhibitors (Table 1). Provide Prophylaxis Against Gastrointestinal Toxicities of NSAIDs A recent Cochrane Review of randomized, controlled clinical trials of agents that provide prophylaxis against NSAID-induced gastropathy suggests that misoprostol, proton pump inhibitors, and double-dose H2-receptor antagonists protect against chronic NSAID-related upper GI endoscopic damage.173 Coadministration of any of these agents with NSAIDs for cancer prevention has yet to be fully explored, both in animals and humans, to determine whether prophylaxes such as these impair the anticancer efficacy, or the incidence of NSAID-related side effects in persons with, or at risk for, cancer. Coadminister With Other Anticancer Interventions Finally, the therapeutic index of NSAIDs may be enhanced through combinations with other effective dietary manipulations, chemopreventives, or chemotherapeutics.174,175 In carcinogen-induced and genetically driven rodent models of colorectal cancer, for example, the synergistic efficacy of NSAIDs in combination with difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, has been reliably and reproducibly demonstrated.176180 In addition, several studies show that the same degree of inhibition is sustained even with 30% to 50% reductions of the NSAID, DFMO, or both. NSAIDs have been shown to boost the preclinical efficacy of other classes of agents as well, including statins and EGFR inhibitors such as EKB-569 (Wyeth-Ayerst).181,182 This strategy holds tremendous promise for cancer prevention and treatment,183 and is being actively investigated in NCI-sponsored clinical trials (Table 1). COX INHIBITORS IN CANCER THERAPY COX inhibitors are showing promise as adjuncts to cancer treatment. Preclinical studies dating back 15 years demonstrate the efficacy of NSAIDs, and more recently NSAID derivatives and COX-2 inhibitors, in reducing the growth of tumor xenografts including melanoma184 and cancers of the stomach,185 colorectum,186188 and prostate.189 Despite these promising findings, the only published clinical efficacy data come from one randomized, placebo-controlled trial of indomethacin or prednisolone in 135 patients with malnutrition and various advanced malignancies.190 At the conclusion of the trial, Lundholm and colleagues reported that compared to the placebo group, patients taking indomethacin had significantly less pain and somewhat surprisingly, an improved mean survival (510 vs. 250 days) as well. This finding needs independent corroboration before it can be considered definitive, but it provides a compelling impetus for additional work to fully explore the potential of NSAIDs in cancer therapy. LOOKING TO THE FUTURE: NSAIDs IN CANCER PREVENTION AND THERAPY The long-term risks and benefits of a preventive or therapeutic agent depend on several factors, including the agent's mechanism(s) of action; pharmacokinetic properties (absorption, distribution, metabolism, and excretion); intended route, frequency, and duration of use; and the clinical risks and options of the intended cohort(s). In aggregate, these complex factors drive the development of promising agents, the utility of which can only be established through rigorous clinical trials that carefully pair agents with appropriate cohorts based on known mechanisms of risk and activity. NSAIDs and COX-2 selective inhibitors--particularly when combined with other anticancer agents-- have enormous appeal because they are relatively safe and could offer efficacy against a broad range of common chronic diseases such as cancer, arthritis, cognitive degeneration, and cataracts.191193 As a result, the federal government, industry, and academia are devoting substantial resources to test antiinflammatory drugs for the management of these conditions. If NSAIDs are shown to reduce the incidence of cancer at one or multiple sites, their potential utility is staggering. Indeed, discovering how to apply NSAIDs, COX-2 selective inhibitors, or both in persons at risk for these common diseases of aging has the potential for significant clinical and public health rewards. REFERENCES 1. Hawk E, Viner JL, Lawrence JA. Biomarkers as surrogates for cancer development. Curr Oncol Reports 2000;2:24250. 2. Umar A, Kunkel TA. 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