Colorectal cancer is one of a number of cancers that may be amenable to prevention. The NSAIDs (non-steroidal anti-inflammatory drugs) have been shown to be effective chemopreventative agents in humans, but their mechanism of action is not clear. The polyamines are cellular polycations that are essential for cell growth and are overproduced in cancer cells. It is our hypothesis that inhibition of polyamine metabolism is an integral part of the mechanism of cancer prevention mediated by NSAIDs.
The human diet contains significant amounts of amines and amine-related compounds that are present either naturally or as a result of food processing or storage. Some of these compounds are beneficial to health, while others are known to be hazardous or the dangers associated with them are poorly understood. Thus there is a need to bring together information from diverse scientific areas in order to evaluate the potential risks or benefits to human health of dietary amines.
Just over 30 years ago, the late Diane Russell published the first in a series of papers linking polyamines and cancer. These early studies led to a flurry of research activity in the polyamine field that continues to this day attempting to identify a role for the polyamines in cancer development, treatment and/or prevention. The recognition that polyamines are critical for the growth of cancer cells, and consequently the identification of their metabolic pathways as a target for therapeutic intervention, led to the development of a number of useful inhibitors of polyamine biosynthesis. Arguably the most significant addition to the polyamine field in the last 30 years was the synthesis of α-difluoromethylornithine (DFMO), which is being tested currently as a cancer chemopreventative agent in man and is used also as a highly effective trypanocidal agent. Although an extremely useful tool experimentally, DFMO has been disappointing in clinical trials with little therapeutic efficacy. Despite this setback, the polyamine pathway is still considered a viable target for chemotherapeutic intervention. This has led to the development of the polyamine analogues as multifunctional inhibitors that will produce inhibition of tumour cell growth, polyamine depletion and optimum therapeutic efficacy.
The naturally occurring polyamines are found in all living cells, where they fulfil a number of critical functions in relation to cell growth. The quest to identify these functions has been the subject of five independent colloquia hosted by the Biochemical Society and today still occupies several hundred scientists across Europe, the U.S.A. and Japan.