Abstract
Discovery of molecular pathways critical to carcinogenesis is revolutionizing the treatment and prevention of cancer. Traditional chemotherapeutic approaches usually cause 'global' cytotoxicity to both normal and carcinoma cells. Over the past decade, however, investigators have developed compounds that inhibit tumor formation more selectively by targeting specific signaling pathways, including those involving the epidermal growth factor receptor (EGFR) and cyclooxygenase 2 (COX2). COX2-derived bioactive lipids, including prostaglandin E2, are potent inflammatory mediators that promote tumor growth and metastasis through stimulation of cell proliferation, invasion, and angiogenesis. Recent work has demonstrated significant crosstalk between the COX2 and EGFR pathways, while preclinical data demonstrates a synergistic effect when both pathways are targeted simultaneously. Combination therapy, a common strategy in cancer treatment, is likely to improve outcomes in cancer prevention as well. Ongoing clinical trials designed to assess whether low doses of COX2 and EGFR inhibitors used in combination could prove more effective and result in reduced toxicity than either agent alone may provide new options for cancer prevention and treatment. We discuss advances in cancer prevention by focusing on mechanisms by which bioactive lipids contribute to tumor formation. While cancer chemoprevention is a relatively young field, we argue that this approach to malignant disease bears significant potential.
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Acknowledgements
We acknowledge support from the United States Public Health Services Grants RO-DK-62112 and PO-CA77839. R DuBois is the Hortense B. Ingram Professor of Molecular Oncology and the recipient of an NIH MERIT award (R37-DK47297). We are grateful to the TJ Martell Foundation and the National Colorectal Cancer Research Alliance (NCCRA) for generous support.
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Glossary
- PRIMARY PREVENTION
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Prevention of tumor formation in otherwise healthy patients
- SECONDARY PREVENTION
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Prevention of progression from premalignant lesion to invasive cancer
- TERTIARY PREVENTION
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Prevention of second primary tumor formation in patients cured of their initial tumor
- SECOND PRIMARY TUMORS
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Neoplasia developing from genetically related dysplastic epithelium bordering areas of fully invasive neoplasia. These tumours typically arise following successful removal of the first primary tumor and are associated with high mortality rates
- HISTAMINE 2 RECEPTOR ANTAGONISTS
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Histamine 2 receptor antagonists are used to block the action of histamine on parietal cells in the stomach, decreasing production of gastric acid
- PROTON-PUMP INHIBITORS
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Reduce the production of acid by irreversibly blocking the hydrogen-potassium adenosine triphosphatase enzyme, thereby limiting acid production in the stomach
- THERAPEUTIC RATIO
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This defines the difference between a minimum therapeutically effective dose and a maximum dose capable of inducing intolerable side effects; the difference between the minimum and maximum effective doses. Also known as the therapeutic window
- AZOXYMETHANE
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A potent carcinogen used to induce colon cancer in rats and mice
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Mann, J., Backlund, M. & DuBois, R. Mechanisms of Disease: inflammatory mediators and cancer prevention. Nat Rev Clin Oncol 2, 202–210 (2005). https://doi.org/10.1038/ncponc0140
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DOI: https://doi.org/10.1038/ncponc0140
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