Colon cancer chemoprevention: clinical development of aspirin as a chemopreventive agent.
We have studied aspirin as a potential chemopreventive for colorectal cancer, completing Phase I studies on aspirin pharmacology and potential biomarker assays (prostaglandins, PGE2 and PGF2 alpha and cyclooxygenase modulation) in normal human subjects. These studies have determined the optimal dose of aspirin for future Phase IIa and IIb chemopreventive trials in high-risk cohorts of patients for colon cancer. Aspirin's effects on rectal prostaglandins are prolonged, detectable even after aspirin and its metabolite are removed from the plasma. Aspirin-mediated inhibition of prostaglandin production in the human rectal epithelium may be related to direct suppression of cyclooxygenase transcription and not to enzyme inactivation by acetylation. A systematic method to monitor adherence (self-report, telephone contact, pill count, and microelectronic monitoring) has been established for future trials. Strategies to improve recruitment of high-risk cohorts have been developed. Phase IIa non-randomized studies with aspirin at 81 mg in high-risk cohorts (resected Duke's A colon cancer, Duke's C colon cancer treated with adjuvant therapy and disease-free at 5 years, history of colon adenomas > 1 cm, two or more first-degree relatives with colon cancer, and familial adenomatous polyposis and hereditary non-polyposis colorectal cancer syndromes) are currently being conducted for surrogate end-point biomarker (prostaglandins, cyclooxygenase, cellular mucins, and proliferation) modulation.
Krishnan
K
K
Department of Internal Medicine, James H. Quillen College of Medicine, Johnson City, Tennessee, USA.
Ruffin
M T
MT
Brenner
D E
DE
D000818:Animals; D001241:Aspirin / Q000627:therapeutic use*; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D003110:Colonic Neoplasms / Q000517:prevention & control*; D006801:Humans
D001241:Aspirin