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Differential Effects of Sodium Butyrate and Hexamethylene Bisacetamide on Growth and Secretion of Cultured Human Endocrine Tumor Cells

Differential Effects of Sodium Butyrate and Hexamethylene Bisacetamide on Growth and Secretion of... Abstract • Advanced gastrointestinal endocrine tumors respond poorly to conventional chemotherapy. In this study we examined the effects of two agents that promote cellular differentiation, sodium butyrate and hexamethylene bisacetamide, on the in vitro growth and secretory responses of a human pancreatic carcinoid (BON) and human gastrinoma (PT-2 and PT-SM) cell lines that have been established in our laboratory. We found that both sodium butyrate and hexamethylene bisacetamide strongly inhibited growth of BON, PT-2, and PT-SM cells. With continuous exposure of BON cells to sodium butyrate (2 mmol/L), the doubling time was prolonged, from 60 hours in controls to 156 hours, and saturation density was reduced to 28% that of controls. Hexamethylene bisacetamide (4 mmol/L) reduced saturation density to 37% that of controls in BON cells and prolonged the doubling time, from 60 hours to 103 hours. Antiproliferative effects of similar magnitudes were observed in the gastrinoma cell lines. In contrast, differential effects were produced on amine biosynthesis in BON cells; sodium butyrate stimulated levels of 5-hydroxytryptamine in the cells, whereas hexamethylene bisacetamide caused a profound dose-dependent inhibition of amine biosynthesis. The sigificant antiproliferative activity of sodium butyrate and hexamethylene bisacetamide and the inhibitory effects of hexamethylene bisacetamide on amine biosynthesis warrant evaluation of these agents or analogues for treatment of metastatic carcinoid and gastrinoma. (Arch Surg. 1991;126:467-472) References 1. Akerstrom G. Surgical treatment of carcinoids and endocrine pancreatic tumours . Acta Oncol . 1989;28:409-414.Crossref 2. Kvols LK. Therapeutic considerations for the malignant carcinoid syndrome . Acta Oncol . 1989;28:433-438.Crossref 3. Townsend CM Jr, Thompson JC. Gastrinoma. Semin Surg Oncol. In press. 4. Pierce BG, Speers WC. Tumors as caricatures of the process of tissue renewal: prospects for therapy by directing differentiation . Cancer Res 1988;48:1996-2004. 5. Prasad KN. Butyric acid: a small fatty acid with diverse biological functions . Life Sci . 1980;27:1351-1358.Crossref 6. Schroy PC, Carnright K, Winawer SJ, Friedman EA. Heterogeneous responses of human colon carcinomas to hexamethylene bisacetamide . Cancer Res . 1988;48:5487-5494. 7. Semmel M, Hanania N, Huet S, Pavloff N, Gay F, Biquard JM. Differentiation of Burkitt lymphoma cells by hexamethylenbisacetamide . Mol Biol Rep . 1989;13:151-157.Crossref 8. Young WC, Fanucchi MP, Walsh TD, et al. Phase I trial and clinical pharmacological evaluation of hexamethylene bisacetamide administration by 10-day continuous intravenous infusion at 28-day intervals . Cancer Res . 1988;48:7304-7309. 9. Rephaeli A, Rabizadah E, Nordenberg J, et al. Effect of the cell differentiation inducers butyrate, retinoic acid and low dose cytosine arabinoside on leukemic cells of patients with acute non lymphatic leukemia: comparison of in vitro and in vivo study . Blood . 1986;68:192a. 10. Upp JR Jr, Alexander RW, Poston GJ, et al. Inhibition of a human malignant carcinoid growing in nude mice . Gastroenterology . 1987;92:1676. 11. Upp JR Jr, Trudel JL, Townsend CM Jr, et al. Establishment of a human gastrinoma in nude mice . Surgery . 1988;104:1037-1045. 12. McCaman MW, McCaman RE, Lees GJ. Liquid cation exchange: a basis for sensitive radiometric assays for aromatic amino decarboxylases . Anal Biochem . 1972;45:242-252.Crossref 13. Beauchamp RD, Lyons RM, Coffey RJ, Townsend CM, Moses HL. Carcinoid associated desmoplasia: a role for type beta transforming growth factors . Gastroenterology . 1989;96:A35. 14. Schroy P, Rifkin J, Coffey RJ, Winawer S, Friedman EA. Role of transforming growth factor β1 in induction of colon carcinoma differentiation by hexamethylene bisacetamide . Cancer Res . 1990;50:261-265. 15. Moertel CG, Hanley JA. Combination chemotherapy trials in metastatic carcinoid tumor and the malignant carcinoid syndrome . Cancer Clin Trials . 1979;2:327-334. 16. Bukowski RM, Johnson KG, Peterson RF, et al. A phase II trial of combination chemotherapy in patients with metastatic carcinoid tumors: a Southwest Oncology Group Study . Cancer . 1987;60:2891-2895.Crossref 17. Moertel CG, May GR, Martin JK, Rubin J, Schutt AJ. Sequential hepatic artery occlusion (HAO) and chemotherapy for metastatic carcinoid tumor and islet cell carcinoma (ICC) . Proc Am Soc Clin Oncol . 1985;4:80. 18. Friend C, Zajac-Kaye M, Holland GJ, Pogo BGT. Depletion of sodium butyrate from the culture medium of friend erythroleukemia cells undergoing differentiation . Cancer Res . 1987;47:378-383. 19. Graham KA, Buick RN. Sodium butyrate induces differentiation in breast cancer cell lines expressing the estrogen receptor . J Cell Physiol . 1988;136:63-71.Crossref 20. Muller ED, Laeng H, Schindler R. Butyrate-induced cell differentiation of cell-cycle mutants and 'wild-type' mastocytoma cells: histamine, 5-hydroxytryptamine and metachromatic granules as independently regulated differentiation markers . Differentiation . 1986;32:82-88.Crossref 21. Tanaka M, Levy J, Terada M, Breslow R, Rifkind RA, Marks PA. Induction of erythroid differentiation in murine virus infected erythroleukemia cells by highly polar compounds . Proc Natl Acad Sci USA . 1975;72:1003-1006.Crossref 22. Huet C, Sahuquillo-Merino C, Coudrier E, Louvard D. Absorptive and mucus-secreting subclones isolated from a multipotent intestinal cell line (HT29) provide new models for cell polarity and terminal differentiation . J Cell Biol . 1987;105:345-357.Crossref 23. Gower WR Jr, Ellison EC, Knierim TH, Elkhammas EA, O'Dorisio TM, Fabri PJ. Gastrinoma in vitro: morphological and physiological studies of primary cell cultures . Gastroenterology . 1990;98:936-954.Crossref 24. Elouaer-Blano L, Sobhani I, Ruszniewski P, et al. Gastrin secretion by gastrinoma cells in long-term culture . Am J Physiol . 1988;255:G596-G602. 25. Powers AC, Phillippe J, Hermann H, Habener JF. Sodium butyrate increases glucagon and insulin gene expression by recruiting immunocytochemically negative cells to produce hormone . Diabetes . 1988;37:1405-1410.Crossref 26. Green R, Shields D. Sodium butyrate stimulates somatostatin production by cultured cells . Endocrinology . 1984;84:1990-1994.Crossref 27. Nakagawa T, Nelkin BD, Baylin SB, de Bustros A. Transcriptional and posttranscriptional modulation of calcitonin gene expression by sodium n-butyrate in cultured human medullary thyroid carcinoma . Cancer Res . 1988;48:2096-2100. 28. Corin RE, Haspel HC, Peretz AM, Sonenberg M, Rifkind RA. Antagonistic effect of butyrate on hexamethylene bisacetamide induced differentiation of murine erythroleukemia cells . Cancer Res . 1986;46:1136-1141. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Surgery American Medical Association

Differential Effects of Sodium Butyrate and Hexamethylene Bisacetamide on Growth and Secretion of Cultured Human Endocrine Tumor Cells

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Publisher
American Medical Association
Copyright
Copyright © 1991 American Medical Association. All Rights Reserved.
ISSN
0004-0010
eISSN
1538-3644
DOI
10.1001/archsurg.1991.01410280069010
Publisher site
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Abstract

Abstract • Advanced gastrointestinal endocrine tumors respond poorly to conventional chemotherapy. In this study we examined the effects of two agents that promote cellular differentiation, sodium butyrate and hexamethylene bisacetamide, on the in vitro growth and secretory responses of a human pancreatic carcinoid (BON) and human gastrinoma (PT-2 and PT-SM) cell lines that have been established in our laboratory. We found that both sodium butyrate and hexamethylene bisacetamide strongly inhibited growth of BON, PT-2, and PT-SM cells. With continuous exposure of BON cells to sodium butyrate (2 mmol/L), the doubling time was prolonged, from 60 hours in controls to 156 hours, and saturation density was reduced to 28% that of controls. Hexamethylene bisacetamide (4 mmol/L) reduced saturation density to 37% that of controls in BON cells and prolonged the doubling time, from 60 hours to 103 hours. Antiproliferative effects of similar magnitudes were observed in the gastrinoma cell lines. In contrast, differential effects were produced on amine biosynthesis in BON cells; sodium butyrate stimulated levels of 5-hydroxytryptamine in the cells, whereas hexamethylene bisacetamide caused a profound dose-dependent inhibition of amine biosynthesis. The sigificant antiproliferative activity of sodium butyrate and hexamethylene bisacetamide and the inhibitory effects of hexamethylene bisacetamide on amine biosynthesis warrant evaluation of these agents or analogues for treatment of metastatic carcinoid and gastrinoma. (Arch Surg. 1991;126:467-472) References 1. Akerstrom G. Surgical treatment of carcinoids and endocrine pancreatic tumours . Acta Oncol . 1989;28:409-414.Crossref 2. Kvols LK. Therapeutic considerations for the malignant carcinoid syndrome . Acta Oncol . 1989;28:433-438.Crossref 3. Townsend CM Jr, Thompson JC. Gastrinoma. Semin Surg Oncol. In press. 4. Pierce BG, Speers WC. Tumors as caricatures of the process of tissue renewal: prospects for therapy by directing differentiation . Cancer Res 1988;48:1996-2004. 5. Prasad KN. Butyric acid: a small fatty acid with diverse biological functions . Life Sci . 1980;27:1351-1358.Crossref 6. Schroy PC, Carnright K, Winawer SJ, Friedman EA. Heterogeneous responses of human colon carcinomas to hexamethylene bisacetamide . Cancer Res . 1988;48:5487-5494. 7. Semmel M, Hanania N, Huet S, Pavloff N, Gay F, Biquard JM. Differentiation of Burkitt lymphoma cells by hexamethylenbisacetamide . Mol Biol Rep . 1989;13:151-157.Crossref 8. Young WC, Fanucchi MP, Walsh TD, et al. Phase I trial and clinical pharmacological evaluation of hexamethylene bisacetamide administration by 10-day continuous intravenous infusion at 28-day intervals . Cancer Res . 1988;48:7304-7309. 9. Rephaeli A, Rabizadah E, Nordenberg J, et al. Effect of the cell differentiation inducers butyrate, retinoic acid and low dose cytosine arabinoside on leukemic cells of patients with acute non lymphatic leukemia: comparison of in vitro and in vivo study . Blood . 1986;68:192a. 10. Upp JR Jr, Alexander RW, Poston GJ, et al. Inhibition of a human malignant carcinoid growing in nude mice . Gastroenterology . 1987;92:1676. 11. Upp JR Jr, Trudel JL, Townsend CM Jr, et al. Establishment of a human gastrinoma in nude mice . Surgery . 1988;104:1037-1045. 12. McCaman MW, McCaman RE, Lees GJ. Liquid cation exchange: a basis for sensitive radiometric assays for aromatic amino decarboxylases . Anal Biochem . 1972;45:242-252.Crossref 13. Beauchamp RD, Lyons RM, Coffey RJ, Townsend CM, Moses HL. Carcinoid associated desmoplasia: a role for type beta transforming growth factors . Gastroenterology . 1989;96:A35. 14. Schroy P, Rifkin J, Coffey RJ, Winawer S, Friedman EA. Role of transforming growth factor β1 in induction of colon carcinoma differentiation by hexamethylene bisacetamide . Cancer Res . 1990;50:261-265. 15. Moertel CG, Hanley JA. Combination chemotherapy trials in metastatic carcinoid tumor and the malignant carcinoid syndrome . Cancer Clin Trials . 1979;2:327-334. 16. Bukowski RM, Johnson KG, Peterson RF, et al. A phase II trial of combination chemotherapy in patients with metastatic carcinoid tumors: a Southwest Oncology Group Study . Cancer . 1987;60:2891-2895.Crossref 17. Moertel CG, May GR, Martin JK, Rubin J, Schutt AJ. Sequential hepatic artery occlusion (HAO) and chemotherapy for metastatic carcinoid tumor and islet cell carcinoma (ICC) . Proc Am Soc Clin Oncol . 1985;4:80. 18. Friend C, Zajac-Kaye M, Holland GJ, Pogo BGT. Depletion of sodium butyrate from the culture medium of friend erythroleukemia cells undergoing differentiation . Cancer Res . 1987;47:378-383. 19. Graham KA, Buick RN. Sodium butyrate induces differentiation in breast cancer cell lines expressing the estrogen receptor . J Cell Physiol . 1988;136:63-71.Crossref 20. Muller ED, Laeng H, Schindler R. Butyrate-induced cell differentiation of cell-cycle mutants and 'wild-type' mastocytoma cells: histamine, 5-hydroxytryptamine and metachromatic granules as independently regulated differentiation markers . Differentiation . 1986;32:82-88.Crossref 21. Tanaka M, Levy J, Terada M, Breslow R, Rifkind RA, Marks PA. Induction of erythroid differentiation in murine virus infected erythroleukemia cells by highly polar compounds . Proc Natl Acad Sci USA . 1975;72:1003-1006.Crossref 22. Huet C, Sahuquillo-Merino C, Coudrier E, Louvard D. Absorptive and mucus-secreting subclones isolated from a multipotent intestinal cell line (HT29) provide new models for cell polarity and terminal differentiation . J Cell Biol . 1987;105:345-357.Crossref 23. Gower WR Jr, Ellison EC, Knierim TH, Elkhammas EA, O'Dorisio TM, Fabri PJ. Gastrinoma in vitro: morphological and physiological studies of primary cell cultures . Gastroenterology . 1990;98:936-954.Crossref 24. Elouaer-Blano L, Sobhani I, Ruszniewski P, et al. Gastrin secretion by gastrinoma cells in long-term culture . Am J Physiol . 1988;255:G596-G602. 25. Powers AC, Phillippe J, Hermann H, Habener JF. Sodium butyrate increases glucagon and insulin gene expression by recruiting immunocytochemically negative cells to produce hormone . Diabetes . 1988;37:1405-1410.Crossref 26. Green R, Shields D. Sodium butyrate stimulates somatostatin production by cultured cells . Endocrinology . 1984;84:1990-1994.Crossref 27. Nakagawa T, Nelkin BD, Baylin SB, de Bustros A. Transcriptional and posttranscriptional modulation of calcitonin gene expression by sodium n-butyrate in cultured human medullary thyroid carcinoma . Cancer Res . 1988;48:2096-2100. 28. Corin RE, Haspel HC, Peretz AM, Sonenberg M, Rifkind RA. Antagonistic effect of butyrate on hexamethylene bisacetamide induced differentiation of murine erythroleukemia cells . Cancer Res . 1986;46:1136-1141.

Journal

Archives of SurgeryAmerican Medical Association

Published: Apr 1, 1991

References