Revival of 2-(difluoromethyl)ornithine (DFMO), an inhibitor of polyamine biosynthesis, as a cancer chemopreventive agent

Abstract

ODC (ornithine decarboxylase), a key enzyme of polyamine biosynthesis, is an inducible enzyme exhibiting high activity in tumour cells, suggesting ODC as a target for antineoplastic therapy. Among the inhibitors of polyamine-related enzymes, the ODC inactivator DFMO [2-(difluoromethyl)ornithine] became the most well-known. The drug is usually cytostatic and its effects on growth are reversed by micromolar concentrations of polyamines in the cellular environment. ODC inactivation is associated with decreased transcription of the growth-related c-myc and c-fos genes. DFMO used as a single drug has only minor effects on tumour growth. The low efficacy of the drug is due to the use of exogenous (gastrointestinal) polyamines by the mammalian organism. Although it was disappointing in most therapeutic attempts, DFMO showed potential in cancer chemoprevention based on its ability to lower polyamine levels in colorectal mucosa at low dosages with no demonstrable toxicity over long periods of use. DFMO in combination with other drugs prevents and inhibits the development of a variety of chemically induced cancers in animals with doses far lower than those administered for therapy. Low doses of several NSAIDs (non-steroidal anti-inflammatory drugs) and DFMO administered in combination have been shown to be more effective in inhibiting chemically induced colon tumours in rats than are high doses of these agents given individually. This combination has gained further interest after findings suggesting that ODC polymorphism is a genetic marker for colon cancer risk and supporting the use of DFMO and aspirin or other NSAIDs in combination as a strategy for colon cancer prevention.