Key Points
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Non-steroidal anti-inflammatory drugs (NSAIDs) are effective chemopreventive agents against colorectal neoplasia.
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NSAID use is associated with a reduced risk of several other types of malignancies, but randomized controlled trials for primary or secondary prevention are still needed.
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A key mechanism for NSAID efficacy is cyclooxygenase (COX) inhibition and reduced production of prostaglandins.
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COX2-specific inhibitors (COXibs) might be less toxic to the gastrointestinal tract than NSAIDs that target both COX1 and COX2. However, cardiovascular toxicity associated with COXibs raises concerns.
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Inherited genetic factors can explain some inter-individual differences in NSAID metabolism and prostaglandin synthesis.
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Initial epidemiological studies indicate that only in a genetically defined subset of the population will NSAIDs prevent colorectal neoplasia, which suggests pharmacogenetic effects.
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Pharmacogenetic investigations are expected to help establish the individual risk–benefit ratio for NSAID use and therefore allow tailoring of chemoprevention.
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In general, a multi-agent, multi-targeted approach to chemoprevention is to be recommended. However, NSAIDs are effective as single agents because they work early in carcinogenesis across multiple pathways.
Abstract
Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) show indisputable promise as chemopreventive agents. Possible targets include cancers of the colon, stomach, breast and lung. However, recent studies raise concern about potential cardiovascular toxicity associated with the use of NSAIDs that specifically target the enzyme cyclooxygenase 2. These findings, and others that show that inherited genetic characteristics might determine preventive success, argue for new strategies that are tailored to individual medical history and genetic make-up.
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We would like to thank Richard Kulmacz for comments on the review and Elizabeth Poole and Linda Massey for assistance with the manuscript.
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Glossary
- Antipyretics
-
Antipyretics are drugs that prevent or reduce fever by lowering the body temperature from a raised state.
- Analgesics
-
Any member of the diverse group of drugs that are used to relieve pain. Analgesics include NSAIDs, narcotic drugs such as morphine, and synthetic drugs with narcotic properties.
- Free radicals
-
Free radicals are atoms with an unpaired electron. Many are highly reactive and can easily damage biological molecules.
- Eicosanoids
-
Multipotent signalling molecules that function in both an autocrine and paracrine fashion. They include the leukotrienes and prostaglandins.
- Odds ratio and relative risk
-
The odds ratio in case–control studies is an approximation of the relative risk, which defines the risk of disease of a group of individuals who are exposed to a certain factor (for example, NSAIDs) relative to those who are not exposed.
- Metachronous
-
Occurring at another time. When an individual develops a second polyp, this is not recurrent in the way that we describe the re-emergence of a primary cancer because the second polyp is almost always a separate pathological event, separated in space (location in the colon) and time from the first.
- Polymorphism
-
A location in the human genome where at least two sequence variants exist in the human population with appreciable frequency (>1%). Polymorphisms can include single-nucleotide polymorphisms, deletions and insertions, or a variable number of a specific repeated sequence.
- dbSNP rs20417
-
This nomenclature denotes the registered number of a polymorphism in the dbSNP database.
- C-reactive protein
-
An acute-phase protein and non-specific marker of inflammation that is secreted by the liver in response to pro-inflammatory cytokines, such as interleukin 6. Interleukin 6 synthesis can be regulated by cyclooxygenase 2 through the production of prostaglandin E2.
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Ulrich, C., Bigler, J. & Potter, J. Non-steroidal anti-inflammatory drugs for cancer prevention: promise, perils and pharmacogenetics. Nat Rev Cancer 6, 130–140 (2006). https://doi.org/10.1038/nrc1801
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DOI: https://doi.org/10.1038/nrc1801