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.
Abbreviations used: DFMO, α-difluoromethylornithine; ODC, ornithine decarboxylase; ADOMETDC, S-adenosylmethionine decarboxylase; SSAT, spermidine/spermine N1-acetyltransferase; BENSpm, bis(ethyl)norspermine; BESpm, bis(ethyl)spermine; BEHSpm, bis(ethyl)homospermine; PENSpm, N1-propargyl-N11-ethylnorspermine; CPENSpm, N1-cyclopropyl-methyl-N11-ethylnorspermine; CHENSpm, N1-cycloheptylmethyl-N11-ethylnorspermine; IPENSpm, (S)-N1-(2-methyl-1-butyl)-N11-ethyl-4,8-diazaundecane.
678th Meeting of the Biochemical Society, held at Imperial College, London, 16–18 December 2002