Intestinal tumor and agmatine (decarboxylated arginine): low content in colon carcinoma tissue specimens and inhibitory effect on tumor cell proliferation in vitro.

BACKGROUND: The polyamine system is a promising target for anticancer therapy. Ideally, an antineoplastic compound affecting this system should inhibit both ornithine decarboxylase and the polyamine transporter, and toxicity should be mild. Agmatine, decarboxylated L-arginine, appears to be such a compound. METHODS: Adenosine triphosphate levels and the protein content of cell populations in culture were identified as surrogate markers for cell count. Agmatine content in cells and tissue specimens was measured by high-performance liquid chromatography. Antizyme levels were estimated by Western blotting. RESULTS: Agmatine inhibited the proliferation of six human intestinal tumor cell lines in a concentration-dependent manner; this inhibition probably was attributable to an interaction between agmatine and the intracellular polyamine system. Consistent with the inverse relation between cell proliferation and agmatine concentration was the finding that agmatine content in human colon carcinoma tissue was approximately one-half as great as it was in adjacent macroscopically normal tissue. CONCLUSIONS: The results of the current study were compatible with the hypothesis that agmatine possesses antineoplastic action against intestinal tumor cells. It is likely that this activity is attributable to agmatine's regulatory role in polyamine homeostasis.

Gastrointestinal uptake of agmatine: distribution in tissues and organs and pathophysiologic relevance.

The authors report on (1) the absorption of agmatine from the gastrointestinal tract as an important source of this polycation in the organism, (2) its organ distribution, and (3) its putative role in liver regeneration. When rats received 0.5 microCi [(14)C]agmatine contained in 5 grams of standard rat chow after a fasting period of 24 hours, radioactivity was recovered in all organs investigated, in blood, and in urine. In the liver 67% +/- 7% of administered radioactivity was found. After partial (two-thirds) hepatectomy, administration of 250 mg and 500 mg agmatine by gavage for 6 days reduced liver regeneration at day 7 by 20% and 22%, respectively, compared with animals that received no agmatine. Agmatine is absorbed from the gastrointestinal tract, probably by means of a specific transporter. It is likely that agmatine in the chyme of the gut represents an essential source of agmatine in the tissues of the organism. An increase in the availability of gastrointestinal agmatine for absorption impairs liver regeneration and may contribute to the development of liver diseases.

Exposure of rat isolated stomach and rats in vivo to [(14)C]agmatine: accumulation in the stomach wall and distribution in various tissues.

The aims of the present study were: (i) to investigate the accumulation of radioactivity in the stomach wall after luminal exposure of the rat isolated stomach to[(14)C]agmatine and (ii) to determine the distribution of radioactivity in various tissues after oral administration of this radiolabelled polyamine to rats in vivo. In isolated rat stomach, [(14)C]agmatine was accumulated in part by an energy-dependent uptake process that could be inhibited by phentolamine. These findings correspond to properties of the recently identified specific agmatine transporter in human glioma cells, suggesting that in rat stomach [(14)C]agmatine is taken up by such a carrier. In in vivo experiments, rats received 0.5 microCi [(14)C]agmatine adsorbed to 5 g rat standard chow after a fasting period of 24 h. After oral ingestion of [(14)C]agmatine, radioactivity was recovered in all organs investigated as well as in blood and urine. Radioactivity also seemed to be secreted into the pancreaticobiliary fluid, as it was recovered in the luminal content of distal ileum and sigmoid colon. Accumulation of radioactivity in organs and distal gut luminal content was dose-dependently decreased by simultaneous administration of putrescine. In conclusion, the present data are compatible with the view that agmatine can be absorbed in rat at least from the stomach and probably also from the gut by means of an energy-dependent agmatine transport mechanism. Agmatine itself and/or its degradation products, which also have the potential to be pharmacologically active, are unevenly distributed between the organs. Putative secretion of radioactivity into the pancreaticobiliary fluid suggests the potential for an enterohepatic circulation of agmatine. In view of the high intraluminal concentration of agmatine in the stomach and distal gut and the operation of an agmatine transporter, it is rather likely that agmatine in the chyme of the gut represents an important source for agmatine detected in the tissues of the organism.