Abstract
Combination chemoprevention for cancer was proposed a quarter of a century ago, but has not been implemented in standard medical practice owing to limited efficacy and toxicity. Recent trials have targeted inflammation and polyamine biosynthesis, both of which are increased in carcinogenesis. Preclinical studies have demonstrated that DFMO (difluoromethylornithine), an irreversible inhibitor of ODC (ornithine decarboxylase) which is the first enzyme in polyamine biosynthesis, combined with NSAIDs (non-steroidal anti-inflammatory drugs) suppresses colorectal carcinogenesis in murine models. The preclinical rationale for combination chemoprevention with DFMO and the NSAID sulindac, was strengthened by the observation that a SNP (single nucleotide polymorphism) in the ODC promoter was prognostic for adenoma recurrence in patients with prior sporadic colon polyps and predicted reduced risk of adenoma in those patients taking aspirin. Recent results from a phase III clinical trial showed a dramatic reduction in metachronous adenoma number, size and grade. Combination chemoprevention with DFMO and sulindac was not associated with any serious toxicity. A non-significant trend in subclinical ototoxicity was detected by quantitative audiology in a subset of patients identified by a genetic marker. These preclinical, translational and clinical data provide compelling evidence for the efficacy of combination chemoprevention. DFMO and sulindac is a rational strategy for the prevention of metachronous adenomas, especially in patients with significant risk for colorectal cancer. Toxicities from this combination may be limited to subsets of patients identified by either past medical history or clinical tests.
Highlights
Increased concentrations of polyamines are found in cancerous tissue [1]
The APC tumour suppressor gene is a component of the WNT cascade and has been identified as the germ-line mutation in FAP [5]
Combination DFMO and sulindac was effective in reducing tumour number by more than 80% when compared with the untreated controls in the ApcMin/+ mouse model (P < 0.0001) [29]
Summary
Increased concentrations of polyamines are found in cancerous tissue [1]. Polyamines are influenced by factors such as import, export, biosynthesis and catabolism. Excluding the high-risk CV patients, the numbers of CV events were similar between treatment and placebo arms [28] These clinical results from a phase III trial proved to be consistent with preclinical studies in mouse models. The clinical implications are twofold: (i) first DFMO is effective in the reduction of adenomatous polyps and (ii) secondly, the combination of DFMO and sulindac can further reduce the risk of CRC through the reduction in the number of high-grade intestinal adenomas These highgrade adenomas are those lesions most likely to progress to colon cancer. The phase III trial with DFMO and sulindac provided strong evidence for preventing disease recurrence in patients with prior adenomas, the chemoprevention has not been evaluated in higher risk populations. The intention for the database is to quantify dietary polyamines and qualify them as a risk factor for carcinogenesis
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