Differential effects of sodium butyrate and hexamethylene bisacetamide on growth and secretion of cultured human endocrine tumor cells.
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 significant 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.
Parekh
D
D
Department of Surgery, University of Texas Medical Branch, Galveston 77550.
Ishizuka
J
J
Townsend
C M
CM
Haber
B E
BE
Beauchamp
R D
RD
Rajaraman
S
S
Karp
G
G
Hsieh
J
J
Thompson
J C
JC
D006916:5-Hydroxytryptophan / Q000378:metabolism; D000081:Acetamides / Q000494:pharmacology*; D000704:Analysis of Variance; D002087:Butyrates / Q000494:pharmacology*; D020148:Butyric Acid; D002276:Carcinoid Tumor / Q000378:metabolism* / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D015408:Gastrinoma / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D012701:Serotonin / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000081:Acetamides; D002087:Butyrates; D016212:Transforming Growth Factor beta; D020148:Butyric Acid; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D006916:5-Hydroxytryptophan; C014026:hexamethylene bisacetamide