Abstract
The effect of difluoromethylornithine (DFMO), a specific inhibitor of ornithine decarboxylase activity, was evaluatedin vivo andin vitro on the growth of a gastrin-sensitive human colon carcinoma (WiDr).In vivo, mice bearing the tumor treated with pentagastrin had larger tumors with higher ornithine decarboxylase activity and polyamine content (P<0.05) than mice not treated with pentagastrin. Difluoromethylornithine treatment significantly decreased ornithine decarboxylase in both the pentagastrin-treated and the untreated animals; however, DFMO had no effect on tumor volume, weight, protein, or DNA content. In cell culture, gastrin treatment increased WiDr cell number and [3H]thymidine incorporation in the presence or absence of serum. In serum-free conditions, however, gastrin stimulated cell growth without concomitantly increasing ODC activity. DFMO, on the other hand, decreased both ODC activity and growth. These studies suggest that the trophic effect of gastrin on WiDr human colon cancer is independent of ODC activity. Since gastrin treatment increased ODC activityin vivo, gastrin may interactin vitro with other factors present in serum that can alter ODC activity.
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Dembinski AB, Johnson LR: Growth of pancreas and gastrointestinal mucosa in antrectomized and gastrin-treated rats. Endocrinology 105:769–773, 1979
Johnson LR: Regulation of gastrointestinal growth.In Physiology of the Gastrointestinal Tract. LR Johnson (ed). New York, Raven Press, 1987, pp 301–333
Sirinek KR, Levine BA, Moyer MP: Pentagastrin stimulates growth of normal and malignant human colon epithelial cells. Am J Surg 149:35–38, 1985
Smith JP, Solomon TE: Effects of gastrin, proglumide and somatostatin on growth of human colon cancer. Gastroenterology 95:1541–1548, 1988
McGregor DB, Morriss LL, Manalo PB, Bomberger RA, Pardini RS: Pentagastrin stimulation of human colon carcinoma. Arch Surg 124:470–472, 1989
Smith JP, Wood JG, Solomon TE: Elevated gastrin levels in patients with colon cancer or adenomatous polyps. Dig Dis Sci 34:171–174, 1989
Seitz J-F, Giovannini M, Gouvernet J, Gauthier AP: Elevated serum gastrin levels in patients with colorectal neoplasia. J Clin Gastroenterol 13:541–545, 1991
Scemama JL, DeVries L, Pradayrol L, Seva C, Tronchere H, Vaysse N: Cholecystokinin and gastrin peptides stimulated ODC activity in a rat pancreatic cell line. Am J Physiol 256:G846-G850, 1989
Rosewicz S, Lewis LD, Liddle RA, Logsdon CD: Effects of cholecystokinin on pancreatic ornithine decarboxylase gene expression. Am J Physiol 255:G818-G821, 1988
Seidel ER: Hormonal regulation of the postprandial induction of gastrointestinal ornithine decarboxylase activity. Am J Physiol 251:G460-G466, 1986
Pegg AE, McCann PP: Polyamine metabolism and function. Am J Physiol 243:C212-C221, 1982
McCormack SA, Johnson LR: Role of polyamines in gastrointestinal mucosal growth. Am J Physiol 260:G795-G806, 1991
Narisawa T, Takahashi M, Niwa M, Koyama H, Kotanagi H, Kusaka N, Yamazaki Y, Nagasawa O, Koyama K, Wakizaka A, Fukawa Y: Increased mucosal ornithine decarboxylase activity in large bowel with multiple tumors, adenocarcinoma, and adenoma. Cancer 63:1572–1576, 1989
Luk GD, Baylin SB: Ornithine decarboxylase as a biological marker in familial colonic polyposis. N Engl J Med 311:80–83, 1984
McGarrity TJ, Peiffer LP, Bartholomew MJ, Pegg AE: Colonic polyamine content and ornithine decarboxylase activity as markers for adenomas. Cancer 66:1539–1543, 1990
Tempero MA, Nishioka K, Knoh K, Zetterman RK: Chemoprevention of mouse colon tumors with difluoromethylornithine during and after carcinogen treatment, Cancer Res 49:5793–5797, 1989
Tutton PJM, Barkla DH: Comparison of the effects of an ornithine decarboxylase inhibitor on intestinal epithelium and on intestinal tumors. Cancer Res 46:6091–6094, 1986
Seidel ER, Snyder RG: Pentagastrin induction of spermine/spermidineN 1-acetyltransferase and mucosal polyamines. Am J Physiol 256:G16-G21, 1989
Solomon TE, Morrisset J, Wood JG, Bussjaeger LJ: Additive interaction of pentagastrin and secretin on pancreatic growth in rats. Gastroenterology 92:429–435, 1987
Osieka R, Houchens DP, Goldin A, Johnson RJ: Chemotherapy of human colon cancer xenografts in athymic nude mice. Cancer 40:2640–2650, 1977
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ: Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275, 1951
Burton K: A study of the condition and mechanisms of the diphenylamine reaction for the colorimetric estimation of deoxyribonucleic acid. Biochem J 62:315–323, 1956
Pegg AE, Seely JC: Ornithine decarboxylase (mouse kidney).In Methods Enzymol 94:158–166, 1983
Seiler N, Knodgen B: High performance liquid chromatographic procedure for the simultaneous determination of the natural polyamines and their monoacetyl derivatives. J Chroma 221:227–235, 1980
McCormack SA, Johnson LR: Putrescine uptake and release by colon cancer cells. Am J Physiol 256(Gastrointest Liver Physiol 19):G868-G877, 1989
Pegg AE, Erwin BG: Induction of spermidine/spermineN 1-acetyltransferase in rat tissues by polyamines. Biochem J 231:285–289, 1985
Danzin D, Bolkenius FN, Claverie N, Wagner J, Grove J: Secretin-induced accumulation ofN 1-acetyl-spermidine and putrescine in rat pancreas. Biochem Biophys Res Commun 109:1234–1236, 1982
Seidel ER, Tabata K, Dembinski AB, Johnson LR: Attenuation of trophic response to gastrin after inhibition of ornithine decarboxylase. Am J Physiol 249:G16-G20, 1985
Hosomi M, Lirussi F, Stace NH, Vaja S, Murphy GM, Dowling RH: Mucosal polyamine profile in normal and adapting (hypo- and hyperplastic) intestine: Effects of DFMO treatment. Gut 28:103–107, 1987
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Supported by NIH First CA50303 and American College of Physicians Research and Teaching Award to Dr. Smith.
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Smith, J.P., Kramer, S.T. & Demers, L.M. Effects of gastrin and difluoromethylornithine on growth of human colon cancer. Digest Dis Sci 38, 520–528 (1993). https://doi.org/10.1007/BF01316509
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DOI: https://doi.org/10.1007/BF01316509