Digestive Diseases and Sciences, Vol. 34, No. 10 (October 1989), pp. 1629-1636 REVIEW ARTICLE Polyamines in Gastrointestinal Cancer RAMI SAYDJARI, COURTNEY M. TOWNSEND, Jr., SAM C. BARRANCO, and JAMES C. THOMPSON KEY WORDS: polyamines; cancer; gastrointestinal. Polyamines are ubiquitous, low-molecular-weight compounds that play an important role in a variety of fundamental intracellular processes. Several ex- cellent reviews of polyamine function and biochem- istry are available (1-5). 1 The great potential value of understanding polyamines and, thereby, of ap- plying polyamine antimetabolites in the fight against cancer has long been recognized (6-11). In this review, we will attempt to summarize current knowledge of the role of polyamines in the growth of gastrointestinal cancers. The biosynthesis of polyamines in mammalian systems begins with the decarboxylation of orni- thine to form the diamine putrescine (Figure 1). This is the first and probably rate-limiting step in the polyamine biosynthetic pathway; the step is gov- erned by the enzyme ornithine decarboxylase (ODC) (EC 4.1.1.17). Generally ODC is present in small quantities in the resting cell. ODC has the shortest half-life (10-45 min) of any known mam- malian enzyme, and it is subject to complex regu- latory mechanisms (12-14). Aminopropyltrans- ferases utilize decarboxylated S-adenosylme- thionine as an aminopropyl group donor to form the triamine, spermidine, and the tetramine, spermine. Spermidine synthase and spermine synthase are the enzymes responsible for these steps in the pathway. Decarboxylated S-adenosylmethionine is formed by the action of S-adenosylmethionine decarboxylase (SAMDC), which also has a short half-life (60 min). SAMDC is another key regulatory enzyme in the Manuscript received July 9, 1988; revised manuscript received December 12, 1988; accepted March 16, 1989. From the Department of Surgery, The University of Texas Medical Branch, Galveston, TX 77550; and Eastern Virginia Medical School, Department of Radiation and Oncology, Nor- folk, Virginia. Supported by grants from the National Institutes of Health (537 DK 15241-17, PO1 DK 35608, and RCDA CA 00854), and a grant from the American Cancer Society (PDT-220). Address for reprint requests: Dr. Courtney M. Townsend, Jr., Department of Surgery, The University of Texas, Medical Branch, Galveston, Texas 77550. biosynthesis of polyamines (15). Although the steps described are nearly irreversible, some interconver- sion of polyamines is accomplished by spermidine/ spermine Nl-acetyltransferase and polyamine oxi- dase. Mammalian cells require polyamines for growth and differentiation (4). Polyamines have been linked to the regulation of DNA, RNA, and to synthesis of protein (1). Membrane stability and cyclic AMP- independent protein kinases are apparently also influenced by polyamines (1). The mechanisms by which polyamines exert these effects are not well understood. Comparatively high levels of polyamines are found in rapidly proliferating cells (10). Similarly, nondividing cells that are actively synthesizing pro- tein (eg, pancreatic islet cells and prostate cells) also have high concentrations of polyamine (3). A depletion of intracellular polyamines causes a slow- ing and eventual cessation of cell growth and divi- sion (10). These observations have raised great interest in the development of polyamine antime- tabolites as tools for improving the understanding of polyamine biochemistry and as potential antitumor agents. Several pharmacological inhibitors of polyamine biosynthesis have been developed (1). ODC and SAMDC have been the primary focus of these efforts because of the key regulatory role they play in the production of polyamines (7). Important among the inhibitors of these enzymes are a- difluoromethylornithine (DFMO), 1,3-diaminopro- pane (DAP), and methylglyoxyl-bis(guanyl-hydra- zone) (MGBG). DFMO and DAP are both inhibitors of ODC. DFMO has been tried extensively in various tumor models as well as in human cancer patients (16-20). MGBG is a potent competitive inhibitor of SAMDC and has also been studied for its potential antitumor activity (1, 21). Digestive Diseases and Sciences, Vol. 34, No. 10 (October 1989) 0163-2116/89/1000-162956.00/0 9 1989 Plenum PublishingCorporation 1629