Numerous experimental, epidemiologic, and clinical studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs), particularly the highly selective cyclooxygenase (COX)-2 inhibitors, have promise as anticancer agents. NSAIDs restore normal apoptosis in human adenomatous colorectal polyps and in various cancer cell lines that have lost adenomatous polyposis coli gene function. NSAIDs also inhibit angiogenesis in cell culture and rodent models of angiogenesis. Many epidemiologic studies have found that long-term use of NSAIDs is associated with a lower risk of colorectal cancer, adenomatous polyps, and, to some extent, other cancers. Two NSAIDs, sulindac and celecoxib, have been found to inhibit the growth of adenomatous polyps and cause regression of existing polyps in randomized trials of patients with familial adenomatous polyposis (FAP). However, unresolved questions about the safety, efficacy, optimal treatment regimen, and mechanism of action of NSAIDs currently limit their clinical application to the prevention of polyposis in FAP patients. Moreover, the development of safe and effective drugs for chemoprevention is complicated by the potential of even rare, serious toxicity to offset the benefit of treatment, particularly when the drug is administered to healthy people who have low annual risk of developing the disease for which treatment is intended. This review considers generic approaches to improve the balance between benefits and risks associated with the use of NSAIDs in chemoprevention. We critically examine the published experimental, clinical, and epidemiologic literature on NSAIDs and cancer, especially that regarding colorectal cancer, and identify strategies to overcome the various logistic and scientific barriers that impede clinical trials of NSAIDs for cancer prevention. Finally, we suggest research opportunities that may help to accelerate the future clinical application of NSAIDs for cancer prevention or treatment.

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Nonsteroidal Anti-inflammatory Drugs as Anticancer Agents: Mechanistic, Pharmacologic, and Clinical Issues

Background Experimental studies in animals and observational studies in humans suggest that regular aspirin use may decrease the risk of colorectal adenomas, the precursors to most colorectal cancers. Methods We conducted a randomized, double-blind trial to determine the effect of aspirin on the incidence of colorectal adenomas. We randomly assigned 635 patients with previous colorectal cancer to receive either 325 mg of aspirin per day or placebo. We determined the proportion of patients with adenomas, the number of recurrent adenomas, and the time to the development of adenoma between randomization and subsequent colonoscopic examinations. Relative risks were adjusted for age, sex, cancer stage, the number of colonoscopic examinations, and the time to a first colonoscopy. The study was terminated early by an independent data and safety monitoring board when statistically significant results were reported during a planned interim analysis. Results A total of 517 randomized patients had at least one colon...

A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer.

ROS signalling in the biology of cancer.

Population-based studies have established that long-term intake of non-steroidal anti-inflammatory drugs (NSAIDs), compounds that inhibit the enzymatic activity of cyclooxygenase (COX), reduces the relative risk for developing colorectal cancer. These studies led to the identification of a molecular target, COX-2, that is involved in tumour promotion during colorectal cancer progression. Recent studies in humans indicate that therapy with specific COX-2 inhibitors might be an effective approach to colorectal cancer prevention and treatment.

Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2

In the past 25 years, a majority of cancer studies have focused on examining functional consequences of activating and/or inactivating mutations in critical genes implicated in cell cycle control. These studies have taught us a great deal about the functions of oncogenes and tumor suppressor genes and the signaling pathways regulating cell proliferation and/or cell death. However, such studies have largely ignored the fact that cancers are heterogeneous cellular entities whose growth is dependent upon reciprocal interactions between genetically altered “initiated” cells and the dynamic microenvironment in which they live. This review highlights the aspects of cancer development that, like organogenesis during embryonic development and tissue repair in adult mammals, are regulated by interactions between epithelial cells, activated stromal cells, and soluble and insoluble components of the extracellular matrix.

Tumor stroma and regulation of cancer development.

We carried out a nested case–control study to measure the rate ratio (RR) for invasive female breast cancer in relation to non-steroidal anti-inflammatory drug (NSAID) use. The source population consisted of the female beneficiaries of the Saskatchewan Prescription Drug Plan from 1981 to 1995 with no history of cancer since 1970. Four controls/case, matched on age and sampling time, were randomly selected. Dispensing rates during successive time periods characterized NSAID exposure. RRs associated with exposure during each period were adjusted for exposure during the others. Confounding by other determinants was studied in analyses adjusted with data obtained by interviewing samples of subjects accrued from mid-1991 to mid-1995. We accrued 5882 cases and 23 517 controls. Increasing NSAID exposure 2–5 years preceding diagnosis was associated with a trend towards a decreasing RR (P -trend = 0.003); for the highest exposure level RR = 0.76, 95% confidence interval 0.63–0.92. This protective effect could not be attributed to confounding by other determinants. In analyses involving only the cases, NSAID exposure 2–5 and 6–10 years preceding diagnosis was associated with significantly reduced risks of presenting with a large tumour (> 5 cm diameter) or distant metastasis, but not regional lymph node metastasis. The use of NSAIDs may retard the growth of breast cancers and prevent distant metastasis. © 2000 Cancer Research Campaign

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Nested case-control study of the effects of non-steroidal anti-inflammatory drugs on breast cancer risk and stage.

Epidemiological studies show that non-steroidal anti-inflammatory drugs (NSAIDs) reduce colorectal cancer incidence. We measured the rate ratio for colorectal adenocarcinoma according to dosage and the timing of exposure by means of a case-control study, nested in a non-concurrent cohort linkage study, using the population of beneficiaries of the Saskatchewan Prescription Drug Plan from 1981 to 1995 with no history of cancer since 1970 as the source population. Four controls per case, matched on age and gender and alive when the case was diagnosed, were randomly selected. Dispensing rates, calculated over successive time periods, characterized NSAID exposure. We accrued 3844 cases of colon cancer and 1971 cases of rectal cancer. For colon cancer a significant trend towards a decreasing rate ratio was associated with increasing exposure during the 6 months preceding diagnosis (P-trend = 0.002). For both cancers, significant trends were associated with exposure 11-15 years before diagnosis (colon: P-trend = 0.01; rectum: P-trend = 0.0001). At the highest exposure levels the rate ratio for colon cancer was 0.57 (95% confidence interval (CI) 0.36-0.89); for rectal cancer it was 0.26 (95% CI 0.11-0.61). No protection was associated with exposure during other periods. The timing of NSAID use must be considered in planning intervention trials to prevent colorectal cancer. There may be a 10-year delay before any preventive effect will appear.

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Colorectal cancer prevention by non-steroidal anti-inflammatory drugs: effects of dosage and timing.

To test the hypothesis that tricyclic antidepressant use increases invasive female breast cancer incidence, we carried out a case-control study within the population of female beneficiaries of the Saskatchewan Prescription Drug Plan aged 35 years from 1981-995 with no history of cancer since 1970. This agency has provided full or partial coverage for outpatient prescriptions to Saskatchewan residents since 1975. We accrued 5882 histologically proven cases and 23,517 controls, randomly selected from the source population and individually matched on age and sampling time. Heavy exposure to any tricyclic antidepressants was associated with an elevated rate ratio for breast cancer 11-15 years later (2.02, 95% confidence interval: 1.34-3.04). Post hoc analyses based on the results of genotoxicity studies carried out using Drosophila melanogaster suggested that the increased risk could be attributed to the use of the six genotoxic tricyclic antidepressants, and not to the use of the four nongenotoxic tricyclic antidepressants. However, our results may have been confounded by the effects of other determinants of breast cancer associated with tricyclic antidepressant use.

Belzile E

Papers

Nested case-control study of the effects of non-steroidal anti-inflammatory drugs on breast cancer risk and stage.

Colorectal cancer prevention by non-steroidal anti-inflammatory drugs: effects of dosage and timing.

The effects of tricyclic antidepressants on breast cancer risk