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Polyamines and Biosynthetic Enzymes in the Rat Intestinal Mucosa and the Influence of Methylglyoxal-bis(guanylhydrazone)¹

Department of Experimental Therapeutics, Grace Cancer Drug Center, Roswell Park Memorial Institute, New York State Department of Health, Buffalo 14263 [C. W. P., B. G.], and The Division of Gastroenterology and Nutrition, Department of Medicine, State University of New York at Buffalo, Buffalo, New York 14215 [D. D., M. M. W.]

The use of methylglyoxal-bis(guanylhydrazone) (MGBG) in the clinical treatment of myeloid and lymphoid disorders has been limited by severe host toxicity to renewing tissues, particularly the intestinal mucosa. Since the drug is a potent inhibitor of spermidine biosynthesis, the distributions of ornithine and S-adenosylmethionine decarboxylases and polyamine pools have been characterized in the rat intestinal mucosa in an attempt to discern the basis for MGBG toxicity. A method of epithelial cell isolation in which fractions of cells are sequentially collected in a villus tip-to-crypt gradient was used. Ornithine decarboxylase activity was highest in the villus tip region and unexpectedly lowest in the crypts, while S-adenosylmethionine decarboxylase activity showed the opposite pattern. Intracellular polyamine pools were uniform along the gradient corresponding to the villus length and increased appreciably in the crypt region. The relative concentrations of the individual polyamines were highest in the crypts, with spermidine and spermine being nearly equivalent in all regions. Twenty-four hr after a single i.p. injection of MGBG (50 mg/kg), S-adenosylmethionine decarboxylase activity increased markedly, especially in the crypt region (50-fold), while ornithine decarboxylase activity also increased but to a lesser extent. Putrescine pools were most affected by MGBG and were elevated 5- to 6-fold, especially in the crypt region. The results are consistent with an alteration of polyamine biosynthesis by MGBG being involved in the antiproliferative toxicity of the drug.

¹ This investigation was supported in part by Grants CA-22153, CA-13038, and CA-25074 from the National Cancer Institute, Department of Health, Education and Welfare, and Grant PDT-88A from the American Cancer Society, Inc.

² To whom requests for reprints should be addressed.

³ A portion of these findings represent research in partial fulfillment of the requirements for the M.S. degree.

Received 10/17/79. Accepted 3/21/80.

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